US20240041877A1 - Dosage regime and method for treating pulmonary arterial hypertension - Google Patents

Dosage regime and method for treating pulmonary arterial hypertension Download PDF

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US20240041877A1
US20240041877A1 US18/159,494 US202318159494A US2024041877A1 US 20240041877 A1 US20240041877 A1 US 20240041877A1 US 202318159494 A US202318159494 A US 202318159494A US 2024041877 A1 US2024041877 A1 US 2024041877A1
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kar5585
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kar5417
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Michelle Palacios
Eric J. Gaukel
Stephen A. Wring
Magdalena Alonso-Galicia
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Altavant Sciences GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present disclosure relates to a daily dosage regimen for treating pulmonary arterial hypertension.
  • the present disclosure also relates to methods for treating pulmonary arterial hypertension.
  • the present disclosure further relates to a method for reducing the level of serotonin biosynthesis within a period of time.
  • the present disclosure still further relates to a method for achieving an enhanced level of AUC 0-tau within a period of time.
  • the present disclosure further relates to a method for achieving a reduction in urinary 5-HIAA within a period of time.
  • Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that modulates central and peripheral functions by acting on neurons, smooth muscle, and other cell types. 5-HT is involved in the control and modulation of multiple physiological and psychological processes. In the central nervous system (CNS), 5-HT regulates mood, appetite, and other behavioral functions. In the GI system, 5-HT has a general prokinetic role and is an important mediator of sensation (e.g., nausea and satiety) between the GI tract and the brain. Dysregulation of the peripheral 5-HT signaling system has been reported to be involved in the etiology of several conditions (see for example: Mawe, G. M.
  • Atherosclerosis e.g. Ban, Y. et al., Impact of Increased Plasma Serotonin Levels and Carotid Atherosclerosis on Vascular Dementia. Atherosclerosis 195, 153-9 (2007), as well as gastrointestinal (e.g. Manocha, M. & Khan, W. I. Serotonin and GI Disorders: An Update on Clinical and Experimental Studies. Clinical and Translational Gastroenterology 3, el 3 (2012); Ghia, J.-E. et al., Serotonin has a Key Role in Pathogenesis of Experimental Colitis. Gastroenterology 137, 1649-60 (2009); Sikander, A., Rana, S. V.
  • the large number of pharmaceutical agents that block or stimulate the various 5-HT receptors is also indicative of the wide range of medical disorders that have been associated with 5-HT dysregulation (see for example: Wacker, D. et al., Structural Features for Functional Selectivity at Serotonin Receptors, Science (New York N Y.) 340, 615-9 (2013).
  • the rate-limiting step in 5-HT biosynthesis is the hydroxylation of tryptophan by dioxygen, which is catalyzed by tryptophan hydroxylase (TPH; EC 1.14.16.4) in the presence of the cofactor (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4).
  • TPH tryptophan hydroxylase
  • 6R cofactor 6-R
  • 5-hydroxy tryptophan 5-HTT
  • AAAD aromatic amino acid decarboxylase
  • TPH belongs to the pterin-dependent aromatic amino acid hydroxylase family.
  • TPH1 and TPH2 Two vertebrate isoforms of TPH, namely TPH1 and TPH2, have been identified.
  • TPH1 is primarily expressed in the pineal gland and non-neuronal tissues, such as entero chromaffin (EC) cells located in the gastrointestinal (GI) tract.
  • TPH2 (the dominant form in the brain) is expressed exclusively in neuronal cells, such as dorsal raphe or myenteric plexus cells.
  • the peripheral and central systems involved in 5-HT biosynthesis are isolated, with 5-HT being unable to cross the blood-brain barrier. Therefore, the peripheral pharmacological effects of 5-HT can be modulated by agents affecting TPH in the periphery, mainly TPH1 in the gut.
  • p-chlorophenylalanine a very weak and unselective irreversible inhibitor of TPH
  • pCPA p-chlorophenylalanine
  • pCPA is distributed centrally and, as a result, its administration has been linked to the onset of depression and other alterations of CNS functions in patients and animals.
  • p-Ethynyl phenylalanine is a more selective and more potent TPH inhibitor than pCPA (Stokes, A, H., et al.
  • p-Ethynylphenylalanine A Potent Inhibitor of Tryptophan Hydroxylase. Journal of Neurochemistry 74, 2067-73 (2000), but also affects central 5-HT production and, like pCPA, is believed to irreversibly interfere with the synthetic behavior of TPH (and possibly interact with other proteins).
  • LX-1031 A Tryptophan 5-hydroxylase Inhibitor, and its Potential in Chronic Diarrhea Associated with Increased Serotonin. Neurogastroenterology and Motility: The Official Journal of the European Gastrointestinal Motility Society 23, 193-200 (2011); Cianchetta, G., et al., Mechanism of Inhibition of Novel Tryptophan Hydroxylase Inhibitors Revealed by Co-crystal Structures and Kinetic Analysis. Current Chemical Genomics 4, 19-26 (2010); Jin, H., et al., Substituted 3-(4-(l,3,5-triazin-2-yl)-phenyl)-2-aminopropanoic Acids as Novel Tryptophan Hydroxylase Inhibitors.
  • Spirocyclic compounds that act as inhibitors of THP and are useful in the treatment of various diseases and disorders associated with peripheral serotonin, including the cardiovascular diseases of pulmonary arterial hypertension (PAH) and associated pulmonary arterial hypertension (APAH) and carcinoid syndrome are known.
  • PAH pulmonary arterial hypertension
  • APAH pulmonary arterial hypertension
  • carcinoid syndrome carcinoid syndrome
  • tissue 5-HT particularly intestinal 5-HT and lung 5-HT
  • 5-HT-associated diseases and modulation and/or reduction of serotonin levels, particularly peripheral serotonin levels, as well as 5-HIAA levels in the urine There is also a need to achieve desirable AUC 0-tau levels in the bloodstream.
  • PAH pulmonary arterial hypertension
  • APAH pulmonary arterial hypertension
  • a daily dosage regimen for treating pulmonary arterial hypertension takes the form of two discrete dosage forms.
  • Each dosage form includes an amount from about 600 mg to about 800 mg of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.
  • a daily dosage regimen for treating pulmonary arterial hypertension has an amount from about 1200 mg to about 1600 mg of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]deca ne-3-carboxylate.
  • a method for treating pulmonary arterial hypertension has the step of administering to a human patient in need thereof an amount from about 1200 mg to about 1600 mg of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate per day.
  • a method for reducing the level of serotonin biosynthesis by at least 50% in a human patient in need thereof within 14 days after commencement of treatment has the step of administering to the human patient an amount from about 800 mg to about 1600 mg of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate per day.
  • the method has the step of administering daily to the human patient an effective amount of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.
  • a method of achieving a >50% reduction in urinary 5-HIAA in a human patient within 14 days after commencement of administration has the step of administering daily to a human patient an effective amount of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.
  • a method for treating pulmonary arterial hypertension has the step of administering daily to a human patient in need thereof an amount of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate sufficient to achieve an AUC 0-tau of ⁇ 2530 ng.hr/mL of (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid within 14 days after commencement of administration.
  • a method for treating pulmonary arterial hypertension has the step of administering daily to a human patient in need thereof an amount of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate sufficient to achieve a >50% reduction in urinary 5-HIAA within 14 days after commencement of administration.
  • FIG. 1 is a plot of an XRPD of a crystalline compound of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate according to the present disclosure (crystalline Form 3).
  • FIG. 2 is a plot of an XRPD of a crystalline compound of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate of a different polymorphic form than that of FIG. 1 (crystalline Form 1).
  • FIG. 3 a is a plot of mean ( ⁇ SD) plasma concentration-time profiles of KAR5585 following administration of 100-2000 mg of KAR5585 under fasting conditions—Cohorts 1-6 (linear scale).
  • FIG. 3 b is a plot of mean ( ⁇ SD) plasma concentration-time profiles of KAR5417 following administration of 100-2000 mg of KAR5585 under fasting conditions—Cohorts 1-6 (linear scale) for KAR5417.
  • FIG. 4 a is a plot of mean ( ⁇ SD) plasma concentration-time profiles of KAR5585 and KAR5417 following administration of 100-2000 mg of KAR5585 under fasting conditions—Cohorts 1-6 (log scale) for KAR5585.
  • FIG. 4 b is a plot of mean ( ⁇ SD) plasma concentration-time profiles of KAR5585 and KAR5417 following administration of 100-2000 mg of KAR5585 under fasting conditions—Cohorts 1-6 (log scale) for KAR5417.
  • FIG. 5 a is a plot of dose vs. plasma C max values for KAR5585 and KAR5417 in fasted healthy volunteers following a single oral dose of KAR5585.
  • FIG. 5 b is a plot of dose vs. plasma C max values for KAR5585 and KAR5417 in fasted healthy volunteers following a single oral dose of KAR5417.
  • FIG. 6 a is a plot of dose vs. plasma AUC inf values for KAR5585 and KAR5417 in fasted healthy volunteers following a single oral dose of KAR5585.
  • FIG. 6 b is a plot of dose vs. plasma AUC inf values for KAR5585 and KAR5417 in fasted healthy volunteers following a single oral dose of KAR5585.
  • FIG. 7 is a bar graph of mean ( ⁇ SD) total percent of dose excreted in urine as KAR5417 in fasted healthy volunteers following a single oral dose of KAR5585.
  • FIG. 8 is a plot of cumulative mean ( ⁇ SD) urine recoveries vs. sampling time of KAR5417 in fasted healthy volunteers following a single oral dose of KAR5585.
  • FIG. 9 a is a plot of mean concentration vs. time profiles of KAR5585 in fasted and fed healthy volunteers following BID oral administration of KAR5585 for 14 days (semi-log scale)
  • FIG. 9 b is a plot of mean concentration vs. time profiles of KAR5417 in fasted and fed healthy volunteers following BID oral administration of KAR5585 for 14 days (semi-log scale)
  • FIG. 10 is a plot of mean ( ⁇ SD) concentration vs. time profiles of KAR5585 and KAR5417 in fasted healthy volunteers following BID oral administration of 100 mg KAR5585 for 14 days.
  • FIG. 11 is a plot of mean ( ⁇ SD) concentration vs. time profiles of KAR5585 and KAR5417 in fed healthy volunteers following BID oral administration of 100 mg KAR5585 for 14 days.
  • FIG. 12 is a plot of mean ( ⁇ SD) concentration vs. time profiles of KAR5585 and KAR5417 in fed healthy volunteers following BID oral administration of 200 mg KAR5585 for 14 days.
  • FIG. 13 is a plot of mean ( ⁇ SD) concentration vs. time profiles of KAR5585 and KAR5417 in fed healthy volunteers following BID oral administration of 400 mg KAR5585 for 14 days.
  • FIG. 14 a is a plot of dose vs. C max for KAR5585 in fed healthy volunteers following BID oral administration of KAR5585 for 14 days.
  • FIG. 14 b is a plot of dose vs. C max for KAR5417 in fed healthy volunteers following BID oral administration of KAR5585 for 14 days.
  • FIG. 15 a is a plot of dose vs. C max for KAR5585 in fed healthy volunteers following BID oral administration of KAR5585 for 14 days.
  • FIG. 15 b is a plot of dose vs. C max for KAR5417 in fed healthy volunteers following BID oral administration of KAR5585 for 14 days.
  • FIG. 16 a is a plot of dose vs. AUC 0-12 for KAR5585 in fed healthy volunteers following BID oral administration of KAR5585 for 14 days.
  • FIG. 16 b is a plot of dose vs. AUC 0-12 for KAR5417 in fed healthy volunteers following BID oral administration of KAR5585 for 14 days.
  • FIG. 17 a is a plot of dose vs. AUC 0-12 for KAR5585 in fed healthy volunteers following BID oral administration of KAR5585 for 14 days.
  • FIG. 17 b is a plot of dose vs. AUC 0-12 for KAR5417 in fed healthy volunteers following BID oral administration of KAR5585 for 14 days.
  • FIG. 18 a is a plot of mean ( ⁇ SD) plasma concentration-time profiles of KAR5585 following administration of 400 mg of KAR5585 under fed and fasting conditions—Cohorts 3A and 3B (linear scale).
  • FIG. 18 b is a plot of mean ( ⁇ SD) plasma concentration-time profiles of KAR5417 following administration of 400 mg of KAR5585 under fed and fasting conditions—Cohorts 3A and 3B (linear scale).
  • FIG. 19 a is a plot of mean ( ⁇ SD) plasma concentration-time profiles of KAR5585 following administration of 400 mg of KAR5585 under fed and fasting conditions—Cohorts 3A and 3B (log scale).
  • FIG. 19 b is a plot of mean ( ⁇ SD) plasma concentration-time profiles of KAR5417 following administration of 400 mg of KAR5585 under fed and fasting conditions—Cohorts 3A and 3B (log scale).
  • FIG. 20 is a plot of relative change from baseline percentage of plasma 5-HIAA vs AUC 0-24 at Day 14.
  • KAR5585 is a useful TPH1 inhibitor.
  • the amorphous form of KAR5585 is disclosed at Example 63i of U.S. Pat. No. 9,199,994.
  • KAR5585 has the following structure:
  • crystalline Form 3 Two crystalline forms of KAR5585, i.e., polymorphs are known. One is denoted as “crystalline Form 3” and the other as “crystalline Form 1”. Form 3 exhibits substantially greater thermodynamic stability compared to Form 1 and is supportive of longer shelf life, particularly at temperatures of less than 95° C. and more particularly at temperatures of less than 80° C.
  • the crystalline Form 3 exhibits the XRPD (X-ray powder diffraction) pattern set forth below in Table 1.
  • Form 3 exhibits prominent XRPD peaks set forth below in Table 2.
  • Form 3 exhibits a characteristic XRPD peak at 19.05 ⁇ 0.20 (°2 ⁇ ).
  • Crystalline Form 1 crystalline compound exhibits the XRPD (X-ray powder diffraction) pattern set forth below in Table 3.
  • Form 1 exhibits prominent XRPD peaks set forth below in Table 4.
  • the amorphous form of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate can be prepared by the method set forth in Example 63i of U.S. Pat. No. 9,199,994, which is incorporated herein by reference in its entirety.
  • the amorphous form can then be converted to crystalline form by methods described in U.S. Ser. No. 16/683,509, filed Nov. 14, 2019, which is incorporated herein by reference in its entirety.
  • Forms 1 and 3 can be prepared by the methods set forth in U.S. Ser. No. 16/683,509.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the Form 3 compound can be used to inhibit the activity of the TPH1 enzyme in a cell by contacting the cell with an inhibiting amount of a compound of the disclosure.
  • the cell can be part of the tissue of a living organism, or can be in culture, or isolated from a living organism. Additionally, the Form 3 compound can be used to inhibit the activity of the TPH1 enzyme in an animal, individual, or patient, by administering an inhibiting amount of a compound of the disclosure to the cell, animal, individual, or human patient.
  • the Form 3 compound can also lower peripheral serotonin levels in an animal, individual, or patient, by administering an effective amount of a compound of the disclosure to the animal, individual, or patient.
  • the Form 3 compound can lower levels of peripheral serotonin (e.g., 5-HT in the GI tract or lung tissue) selectively over non-peripheral serotonin (e.g., 5-HT in the CNS).
  • the selectivity can be 2-fold or more, 3-fold or more, 5-fold or more, 10-fold or more, 50-fold or more, or 100-fold or more.
  • the Form 3 compound is useful in the treatment and prevention of various diseases associated with abnormal expression or activity of the TPH1 enzyme, or diseases associated with elevated or abnormal peripheral serotonin levels.
  • the treatment or prevention includes administering to a patient in need thereof a therapeutically effective amount of a TPH1 inhibitor of the Form 3 compound.
  • the Form 3 compound is also useful in the treatment and prevention of serotonin syndrome.
  • Biological assays can be used to determine the inhibitory effect of compounds against TPH (such as TPH1) in vitro and/or in vivo.
  • TPH such as TPH1
  • In vitro biochemical assays for human, mouse, and rat TPH1 and human TPH2, PheOH, and TH may be used to measure inhibition of enzyme activity and the selectivity among TPH1, TPH2, PheOH, and TH.
  • the efficacy of these compounds can be determined, for example, by measuring their effect on intestinal 5-HT levels in rodents after oral administration.
  • the metabolite of KAR5585 is (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1T-biphenyl]-2-yl)-2,2,2-trifluoroeth-oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid, which is of the formula
  • KAR5417 (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1T-biphenyl]-2-yl)-2,2,2-trifluoroeth-oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid is referred to herein as KAR5417.
  • KAR5585 enters the bloodstream, it substantially converts to KAR5417.
  • the amorphous form of KAR5417 can be prepared by the method set forth in Example 34c of U.S. Pat. No. 9,199,994.
  • KAR5585 has been found to be particularly useful in treating and preventing pulmonary arterial hypertension (PAH).
  • PAH pulmonary arterial hypertension
  • One aspect of the present disclosure is a daily dosage regimen for treatment of PAH in adults.
  • the regimen takes the form of two discrete dosage forms.
  • Each dosage form includes an amount from about 600 mg to about 800 mg of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate of Form 3.
  • a preferred daily regimen employs two oral dosage forms taken twice per day (BID) up to 14 days.
  • Another preferred aspect are dosage forms having 600 mg or 800 mg of KAR5585 (Form 3).
  • Another aspect of the dosage regimen for treating pulmonary arterial hypertension is administration of an amount from about 1200 mg to about 1600 mg of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate per day.
  • Another aspect of the present disclosure is a method for reducing the level of serotonin (5-HT) biosynthesis by at least 50% in a human patient within 14 days after commencement of treatment.
  • the method has the step of administering to the human patient about 800 mg to about 1600 mg of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate per day.
  • Serotonin levels are determined by the methods disclosed in the examples below.
  • Another aspect of the present disclosure is treatment of pulmonary arterial hypertension by achievement an AUC 0-tau of ⁇ 2530 ng.hr/mL of (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid in a human patient within 14 days after commencement of administration of a sufficient amount to the human patient.
  • AUC 0-tau is determined by methods disclosed in the examples below.
  • Another aspect of the present disclosure is treatment of pulmonary arterial hypertension by achievement of a >50% reduction in urinary 5-HIAA in a human patient within 14 days after commencement of administration of a sufficient amount to the human patient.
  • Urinary 5-HIAA is determined by methods disclosed in the examples below.
  • osteoporosis such as, for example, osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, fractures, and bone metastasis
  • osteoporosis such as primary type 1 (e.g., postmenopausal osteoporosis), primary type 2 (e.g., senile osteoporosis), and secondary (e.g., steroid- or glucocorticoid-induced osteoporosis).
  • primary type 1 e.g., postmenopausal osteoporosis
  • primary type 2 e.g., senile osteoporosis
  • secondary e.g., steroid- or glucocorticoid-induced osteoporosis
  • cardiovascular diseases such as atherosclerosis and pulmonary hypertension (PH), including idiopathic or familial PH, and including PH associated with or brought on by other diseases or conditions.
  • PH disease is pulmonary arterial hypertension (PAH).
  • PAH idiopathic
  • FPAH familial
  • APAH associated
  • PAH PAH which is associated with other medical conditions including, for example, (1) collagen vascular disease (or connective tissue disease) that include autoimmune diseases such as scleroderma or lupus; (2) congenital heart and lung disease; (3) portal hypertension (e.g., resulting from liver disease); (4) HIV infection; (5) drugs (e.g., appetite suppressants, cocaine, and amphetamines; and (6) other conditions including thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, and splenectomy.
  • collagen vascular disease or connective tissue disease
  • portal hypertension e.g., resulting from liver disease
  • drugs e.g., appetite suppressants, cocaine, and amphetamines
  • other conditions including thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic tel
  • APAH can also be PAH associated with abnormal narrowing in the pulmonary veins and/or capillaries such as in pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis.
  • PVOD pulmonary veno-occlusive disease
  • PPHN pulmonary capillary hemangiomatosis
  • Another type of PAH is associated with persistent pulmonary hypertension of the newborn (PPHN).
  • Further diseases treatable or preventable by the methods of the present disclosure include metabolic diseases such as diabetes and hyperlipidemia; pulmonary diseases such as chronic obstructive pulmonary disease (COPD), and pulmonary embolism; gastrointestinal diseases such as IBD, colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, or other gastrointestinal inflammatory conditions; liver diseases such as chronic liver disease; cancers such as liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, and bone cancer (e.g., osteosarcoma, chrondrosar
  • a further treatable disease is the treatment and prevention of carcinoid syndrome.
  • Carcinoid syndrome is a paraneoplastic syndrome exhibiting the signs and symptoms that occur secondary to carcinoid tumors.
  • Carcinoid syndrome is caused by a carcinoid tumor that secretes serotonin or other hormones into the bloodstream.
  • Carcinoid tumors usually occur in the gastrointestinal tract, including the stomach, appendix, small intestine, colon, and rectum or in the lungs.
  • Common symptoms include skin flushing, facial skin lesions, diarrhea, irritable bowel syndrome, cramping, difficulty breathing, and rapid heartbeat.
  • the present disclosure includes methods of lowering plasma cholesterol, lowering plasma triglycerides, lowering plasma glycerol, lowering plasma free fatty acids in a patient by administering to said patient a therapeutically effective amount of a compound of the disclosure.
  • KAR5585 is also useful in the treatment and prevention of inflammatory disease, such as allergic airway inflammation (e.g., asthma).
  • inflammatory disease such as allergic airway inflammation (e.g., asthma).
  • an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal.
  • an in vitro cell can be a cell in a cell culture.
  • an in vivo cell is a cell living in an organism such as a mammal.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • “contacting” the enzyme with a compound of the disclosure includes the administration of a compound of the present disclosure to an individual or patient, such as a human, having the TPH1 enzyme, as well as, for example, introducing a compound of the disclosure into a sample containing a cellular or purified preparation containing the TPH1 enzyme.
  • the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • treating refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology) or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
  • the term “preventing” or “prevention” refers to inhibiting onset or worsening of the disease; for example, in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
  • KAR5585 can be administered to human patients in need of such treatment in appropriate dosages that will provide prophylactic and/or therapeutic efficacy.
  • the dose required for use in the treatment or prevention of any particular disease or disorder will typically vary from patient to patient depending on, for example, particular compound or composition selected, the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors.
  • the appropriate dosage can be determined by the treating physician.
  • KAR5585 can be administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles.
  • Parenteral administration can involve subcutaneous injections, intravenous or intramuscular injections or infusion techniques.
  • Treatment duration can be as long as deemed necessary by a treating physician.
  • the compositions can be administered one to four or more times per day. A treatment period can terminate when a desired result, for example, a particular therapeutic effect, is achieved. Alternatively, a treatment period can be continued indefinitely.
  • the pharmaceutical compositions can be prepared as solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules and the like).
  • a tablet can be prepared by compression or molding.
  • Compressed tablets can include one or more binders, lubricants, glidants, inert diluents, preservatives, disintegrants, or dispersing agents.
  • Tablets and other solid dosage forms, such as capsules, pills and granules can include coatings, such as enteric coatings.
  • Solid and liquid dosage forms can be formulated so that they conform to a desired release profile, e.g., immediate release, delayed release, and extended or sustained release.
  • KAR5585 to be administered will vary depending on factors such as the following: method of administration, release profile, and composition formulation.
  • a typical dosage will be about 1 mg/kg/day to about 50 mg/kg/day and more typically from about 5 mg/kg/day to about 30 mg/kg/day, based on the weight of the patient.
  • a most preferred active is Form 3.
  • Individual oral dosage forms typically have from about 50 mg to about 3000 mg of KAR5585 and additional amounts of one or more pharmaceutically acceptable excipients.
  • KAR5585 in amounts of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg, 450 mg, 500 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, and about 1200 mg.
  • wt % means weight percent based on the total weight of the composition or formulation.
  • Preferred dosage forms have the crystalline compound of Form 3 present in a proportion that is 90 wt % or more, and more preferably 95 wt % or more, by weight of any (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate present.
  • Dosage forms have the crystalline compound of Form 3 therein in any amount or proportion.
  • Typical proportions include about 20 wt % or more, about 60 wt % or more, and about 90 wt % or more, based on the total weight of the dosage form (with the balance predominantly excipients, carriers, and vehicles). Particularly useful proportions are 25 wt % and 60 wt %.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders.
  • Liquid dosage forms for oral administration can include, for example, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • Suspensions can include one or more suspending agents.
  • Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions and patches.
  • the Form 3 compound and compositions containing same can be administered in the form of an aerosol, which can be administered, for example, by a sonic nebulizer.
  • compositions suitable for parenteral administration can include the Form 3 compound together with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions.
  • the composition can be in the form of a sterile powder which can be reconstituted into a sterile injectable solutions or dispersion just prior to use.
  • CRU clinical research unit ddHR placebo-adjusted mean change from Baseline in heart rate
  • ddQTcF placebo-adjusted mean change from Baseline in QTcF
  • ECG electrocardiogram eCRF electronic case report form Estimated urine 5-HIAA the 5-HIAA measured in urine during 24 hours, corrected for the estimated creatinine excretion based on subject weight, age, gender, and race FDA Food and Drug Administration GCP Good Clinical Practice GGT gamma-glutamyl transpeptidase Geo.
  • KAR5417 an active metabolite of the investigational product KAR5585 KAR5585 the investigational product; it is a prodrug of KAR5417 LDH lactate dehydrogenase Max maximum Measured urine 5-HIAA the 5-HIAA measured in urine during 24 hours, without adjustment for daily variations in creatinine excretion MedDRA Medical Dictionary for Regulatory Activities Min minimum MOA mechanism of action N, n number OAE other significant adverse event OTC over the counter PAH pulmonary arterial hypertension Param.
  • PK pharmacokinetic(s) PT preferred term QD once daily (from Latin, quaque die) QTcF QT interval corrected for heart rate by applying Fridericia's formula; the unit for QTcF is milliseconds (msec) R AUC0-12 accumulation ratio for AUC 0-12 R Cmax accumulation ratio for C max SAE serious adverse event SAP Statistical Analysis Plan SD standard deviation SOC system organ class Stat.
  • Study KAR5585-101 was a first-in-human, Phase 1, randomized, double-blind, placebo-controlled, single-center trial conducted in 2 parts to assess the safety, tolerability, PK, cardiac conduction, and biomarkers of target engagement effects of single ascending doses (SAD, Part 1) and multiple ascending doses (MAD, Part 2) of KAR5585 in healthy adult subjects.
  • Food effect was to be evaluated in Part 1, Period 2.
  • Part 2 was permitted to begin before Part 1 was completed and, in each part, the data from each dose Cohort were to be reviewed for safety before the next dose Cohort was enrolled.
  • the KAR5585 administered doses were the following:
  • Active drug capsules containing KAR5585 were provided in 50, 200, and 300 mg strengths; thus, more than 1 capsule was required to achieve some of the study doses.
  • Part 1 had 6 Cohorts of 12 subjects each (for a total of 72 subjects) and Part 2 had 4 Cohorts of 12 subjects each (for a total of 48 subjects).
  • the 12 subjects in Cohort 3 400 mg
  • Batches were Batch PID-19JUL15-111 (50 mg), PID-19JUL15-110 (200 mg), PID-19JUL15-109 (300 mg)
  • SAD Single dose under fasted conditions; subjects included in the fed Cohort were to receive a second dose of KAR5585 (same dose level) or placebo.
  • MAD Part 2
  • Biomarkers were to be evaluated in Part 2 by measuring concentrations of serotonin (5-hydroxytryptamine [5-HT]) in serum and 5-hydroxyindoleacetic acid (5-HIAA) in plasma and urine. As well, the relationship of biomarkers to PK parameters was to be evaluated.
  • the biomarker analysis was to be based on the Biomarker Population (all subjects with evaluable biomarker measurements at baseline [Day 1 predose] and at least one after dosing [Day 7 or Day 14]).
  • AUC concentration versus time curve
  • C min minimum observed concentration
  • C max maximum observed concentration
  • Biomarker data were to be collected only in Part 2. The following biomarkers were to be analyzed:
  • the a priori primary biomarker endpoint was to be the change in plasma 5-HIAA concentration on Day 14 from Day 1.
  • the null hypothesis to be tested was that there was no difference between the change from Day 1 predose to Day 14 between placebo and KAR5585.
  • Linear regression was to be performed using biomarker changes, absolute and relative (%), from Day 1, at predose on Day 7 or Day 14 versus AUC 0-24 , C max , and C min in corresponding study days.
  • the slopes and corresponding 95% confidence intervals (CIs) were to be tabulated.
  • the PK analysis was to be based on the PK Concentration Population (all subjects receiving active study medication and having any measurable plasma concentration of study medication at any time point) and the PK Evaluable Population (all subjects with sufficient KAR5585 and KAR5417 concentration-time data to support PK analysis). Pharmacokinetic data were to be summarized descriptively.
  • KAR5585 is a prodrug for the active tryptophan hydroxylate 1 (TPH1) inhibitor KAR5417. Following KAR5585 administration, KAR5585 was rapidly absorbed. The median time of maximum observed concentration (t max ) ranged between 1.5 and 3 hours postdose. Following administration of KAR5585, KAR5417 appeared rapidly in plasma, an observation consistent with rapid absorption of KAR5585 and efficient conversion to KAR5417.
  • TPH1 active tryptophan hydroxylate 1
  • At doses greater than 700 mg there were less than dose-proportional increases in AUC 0-24 and AUC 0-inf values, with a 1.7-fold and 1.81-fold increase over the 2.86-fold increase in dose between 700 mg and 2000 mg.
  • the mean apparent terminal half-life (t 1/2 ) after oral administration of KAR5417 increased with increasing dose levels studied, and ranged between 4.7 hours (100 mg dose) and 22.6 hours (2000 mg dose) after oral administration of KAR5585.
  • KAR5585 under fed conditions increased the extent and peak of exposure of both KAR5585 and KAR5417, with KAR5417 mean AUC from time 0 extrapolated to infinity (AUC 0-inf ) increasing 1.8-fold from 3650 ng ⁇ hr/mL to 6710 ng ⁇ hr/mL and C max increasing 1.8-fold from 485 ng/mL to 860 ng/mL, under fasting and fed conditions, respectively. This was considered to be a clinically relevant change in exposure.
  • KAR5585 was rapidly absorbed following oral administration.
  • Steady-state plasma levels of KAR5417 were achieved by Day 7 as assessed by comparison of Day 7 and Day 14 AUC 0-12 and concentration obtained 12 hours after an administered dose (C 12 hr ) values following BID oral administration of KAR5585 for 14 days. Accumulation ratios for KAR5417 compared accumulation ratio for C max (R Cmax ) and accumulation ratio for AUC 0-12 (RAUC0-12) for Day7/Day 1 and Day 14/Day 1, and verified that steady-state was achieved by Day 7.
  • the R AUC0-12 values for KAR5417 ranged from 2.19-2.57, 1.09-1.34 and 1.65-2.38 for the 100 mg, 200 mg, and 400 mg doses of KAR5585, respectively, suggesting that the PK of KAR5417 was independent of time, and that steady-state was achieved on Day 7 following repeated BID administration for14-days.
  • KAR5585 administered as a single ascending oral dose (100 mg, 200 mg, 400 mg, 700 mg, 1200 mg or 2000 mg), was safe and well-tolerated in 54 healthy adult subjects.
  • KAR5585 400 mg administered as a single oral dose under fed conditions, was well-tolerated in 9 healthy adult subjects.
  • KAR5585 administered as multiple ascending oral doses of 100 mg (fasting), 100 mg (fed), 200 mg (fed), and 400 mg (fed), BID for up to 14 days (27 doses), was safe and well-tolerated in 36 healthy adult subjects.
  • One or more of the MAD Cohorts could have been dosed QD, but none was.
  • KAR5585 prodrug
  • KAR5417 active TPH1 inhibitor
  • PK SAP As described in the PK SAP, the following PK parameters (as appropriate) were to be generated from KAR5585 and KAR5417 individual plasma concentrations from Part 1, Day 1; and Part 2, Days 1, 7, and 14 within the PK Evaluable Population:
  • Mean plasma concentration time profiles of KAR5585 and KAR5417 following administration of 400 mg of KAR5417 under fasting and fed conditions Cohorts 3A and 3B (linear and semi-log scales) are presented in 18 a and 18 b and FIGS. 19 a and 19 b , respectively.
  • the mean peak plasma KAR5585 concentrations were reached between 1.5 and 3 hours following single-dose fasting oral administration of 100, 200, 400, 700, 1200 and 2000 mg KAR5585.
  • doses of 100 to 1200 mg KAR5585 the time to peak plasma concentrations of KAR5585 were reached between 0.75 and 6 hours.
  • time to peak plasma concentrations of KAR5585 ranged from 0.75 to 12 hours.
  • Mean KAR5585 concentrations increased with increasing doses.
  • KAR5585 concentrations remained above the LLOQ (4.94 ng/mL) up to 4 hours in most subjects following the 100 mg dose, in one subject KAR5585 was BLQ at all time-points and in another subject KAR5585 was measurable up to 8 hours.
  • KAR5585 concentrations remained above the LLOQ (4.94 ng/mL) up to 12 hours following the 400, 700, 1200 and 200 mg doses of KAR5585.
  • the mean peak plasma KAR5417 concentrations were reached between 1.5 and 3 hours following single-dose fasting oral administration of 100, 200, 400, 700, 1200 and 2000 mg KAR5585.
  • doses of 100 to 1200 mg KAR5585 the time to peak plasma concentrations of KAR5417 were reached between 2 and 6 hours.
  • 2000 mg dose of KAR5585 the time to peak plasma concentrations of KAR5417 ranged from 3 to 12 hours.
  • Mean KAR5417 concentrations increased with increasing doses. KAR5417 concentrations remained above the LLOQ (7.65 ng/mL) up to 12, 24, 36, 48, 48 and 72 hours following the 100, 200, 400, 700, 1200 and 2000 mg doses, respectively.
  • the plasma concentrations of KAR5417 were approximately 10-fold higher than the plasma concentrations of KAR5585.
  • KAR5585 Peak mean plasma KAR5585 concentrations were observed at later times and sustained longer under fed relative to fasting conditions (t max was 3.0 and 2.07 hour postdose, for fed and fasted states, respectively).
  • KAR5417 is the active metabolite of the prodrug, KAR5585. Following administration of KAR5585, KAR5417 appeared rapidly in plasma, an observation consistent with rapid absorption of KAR5585 and efficient conversion to KAR5417; all subjects had measurable concentrations of KAR5417 by 0.25 hours postdose, and the median t max was comparable across all fasting Cohorts and ranged between 3 and 6 hours postdose.
  • mean peak plasma KAR5417 concentrations appeared to increase in a dose-proportional manner from 100-700 mg, mean C max values increased 7.27-fold over the 7-fold increase in dose between the 100 mg dose (Cohort 1) and the 700 mg dose (Cohort 4).
  • mean C max values increased 7.27-fold over the 7-fold increase in dose between the 100 mg dose (Cohort 1) and the 700 mg dose (Cohort 4).
  • doses greater than 700 mg there was a moderate increase in C max values, with a 1.38-fold increase over the 2.86-fold increase in dose between 700 mg (Cohort 4) and 2000 mg (Cohort 6).
  • the mean apparent elimination half-life of KAR5417 increased with increasing dose levels studied, and ranged between 4.67 (100 mg dose) and 22.6 hours (2000 mg dose) after oral administration of KAR5585.
  • the elimination phase of KAR5417 was characterized based on the last 3 to 6 measurable time points.
  • FIGS. 5 a and 5 b and FIGS. 6 a and 6 b Scatter plots of individual plasma KAR5585 and KAR5417 C max and AUC 0-inf , versus KAR5585 dose are presented in FIGS. 5 a and 5 b and FIGS. 6 a and 6 b , respectively.
  • the dose proportionality assessment of plasma KAR5585 and KAR5417 PK parameters are summarized in Table 18. Dose proportionality was assessed for KAR5585 and KAR5417 after single-dose administration using the power model. From plots of exposure (e.g., C max , AUC 0-12 , AUC 0-tau , and/or AUC 0-inf ) versus dose, increases in exposure were deemed dose proportional if the 90% confidence intervals (CIs) for the slope ( ⁇ in the following equation(s) included unity (e.g., 1.0).
  • CIs 90% confidence intervals
  • AUC 0-12 area under the concentration versus time curve from time 0 to 12 hours after dosing, using the trapezoidal rule
  • AUC 0-inf area under the concentration versus time curve from time 0 extrapolated to infinity
  • AUC 0-tau area under the concentration-time curve from time 0 to time of last quantifiable concentration
  • C max maximum observed concentration
  • CI confidence interval NC, not calculated.
  • Geometric LS means are calculated by exponentiating the LS means from the ANOVA.
  • Geometric Mean Ratio (test/reference) Cohort 3A (Fasting): 400 mg KAR5585 Administered as a Single Oral Dose Under Fasting Conditions (reference)
  • ANOVA analysis of variance
  • AUC 0-inf area under the concentration versus time curve from time 0 extrapolated to infinity
  • AUC 0-tau area under the concentration-time curve from time 0 to time of last quantifiable concentration
  • CI confidence interval
  • C max maximum observed concentration
  • LS means least-squares means.
  • the exposure as assessed by AUC 0-tau and AUC 0-inf , to KAR5585 following administration of 400 mg KAR5585 under fed conditions was approximately 3.1-4.8-fold relative to when the KAR5585 was administered under fasting conditions. Peak exposure (C max ) was approximately 3.9-fold higher.
  • the exposure as assessed by AUC 0-tau and AUC 0-inf , to KAR5417 following administration of the 400 mg KAR5585 under fed conditions was approximately 2-fold higher relative to when the KAR5585 was administered under fasting conditions. Peak exposure was approximately 1.87-fold higher.
  • KAR5585 could not be quantified in urine samples and the amount excreted (Ae) in urine was less than 0.004% of the administered dose at all dose levels (Table 20).
  • KAR5417 could be quantified in urine samples and the amount excreted (Ae) in urine ranged from 0.102 to 0.331% of the administered dose (Table 13), assuming complete conversion of KAR5585 to KAR5417. The highest amount of KAR5417 excreted, 0.331% of the dose.
  • FIG. 7 was in the 400 mg fed Cohort (Cohort 3B) and was consistent with the effect of food to increase oral absorption of KAR5585.
  • the amount of KAR5417 excreted in urine was independent of dose in fasted subjects. The majority of urinary excretion of KAR5417 occurred in the first 24 hours after an oral dose of KAR5585.
  • Renal clearance of KAR5417 was calculated from the area under the plasma time concentration curve (AUC 0-96 ) for KAR5417 and the amount of KAR5417 recovered in urine (Table 21). Renal clearance of KAR5417 ranged from 157 to 296 mL/hr and was largely independent of administered dose of KAR5585 (Table 21).
  • KAR5585 and KAR5417 The measurement of KAR5585 and KAR5417 in human urine indicates that renal clearance and elimination of KAR5585 and KAR5417 was a very minor route of elimination of KAR5585 following single dose administration in humans.
  • KAR5585 is a prodrug for the active TPH1 inhibitor KAR5417. Following KAR5585 administration, KAR5585 was rapidly absorbed the median t max ranged between 1.5 and 3 hours postdose. Following administration of KAR5585, KAR5417 appeared rapidly in plasma, an observation consistent with rapid absorption of KAR5585 and efficient conversion to KAR5417; the median t max was comparable across all fasting Cohorts and ranged between 3 and 6 hours postdose.
  • the mean apparent elimination half-life of KAR5585 increased with increasing dose levels studied, and ranged between 1.89 and 4.84 hours after oral administration of KAR5585.
  • the mean apparent elimination half-life of KAR5417 increased with increasing dose levels studied, and ranged between 4.67 (100 mg dose) and 22.6 hours (2000 mg dose) after oral administration of KAR5585.
  • Mean CL/F estimates of KAR5585 ranged from 1480 to 3850 L/h with the higher CL/F values noted for the 1200 mg (Cohort 5) and 2000 mg (Cohort 6) dose levels and is associated with non-linear PK related to decreased absorption of KAR5585 at the higher dose levels.
  • the V z /F increased with increasing dose levels and ranged between 5680 to 25100 L, the higher V z /F values noted for the 1200 mg (Cohort 5) and 2000 mg (Cohort 6) dose levels was attributed to decreased absorption of KAR5585 at the higher dose levels.
  • KAR5585 and KAR5417 Urinary excretion of KAR5585 and KAR5417 was a minor mechanism of elimination. KAR5585 was not quantifiable in urine in almost all subjects. KAR5417 could be quantified in urine samples and the amount excreted (Ae) in urine ranged from 0.102 to 0.331% of the administered dose of KAR5585.
  • KAR5585 is a prodrug for the active TPH1 inhibitor KAR5417. Following KAR5585 administration, KAR5585 was rapidly absorbed the median t max ranged between 1.5 and 3 hours postdose. Following administration of KAR5585, KAR5417 appeared rapidly in plasma, an observation consistent with rapid absorption of KAR5585 and efficient conversion to KAR5417.
  • At dose greater than 700 mg there was a slightly less than dose-proportional increase in AUC 0-24 and AUC 0-inf values, with a 1.7-fold and 1.81-fold increase over the 2.86-fold increase in dose between 700 mg and 2000 mg.
  • the mean apparent elimination half-life of KAR5417 increased with increasing dose levels studied, and ranged between 4.7 hours (100 mg dose) and 22.6 hours (2000 mg dose) after oral administration of KAR5585.
  • FIGS. 9 a and 9 b Mean plasma concentration-time profiles of KAR5585 and KAR5417 following administration of 100 mg KAR5585 under fasting conditions (Part 2, Cohort 1) and 100, 200 and 400 mg KAR5585 under fed conditions (Part 2, Cohorts 2-4) in healthy adult subjects twice daily for 14-days (semi-log scale) are presented in FIGS. 9 a and 9 b .
  • KAR5585 was detectable in circulation at each dose level, and concentrations generally increased with escalating dose. In addition, the length of time with measurable KAR5585 concentrations increased at higher dose levels.
  • the peak plasma KAR5585 concentrations were reached between 0.75-2.0 and 0.75 and 3.0 hours on Day 1 and Day 14 following oral twice-daily administration of 100 mg of KAR5585, Part 2, Cohort 1 (fasted state).
  • the peak mean concentrations of KAR5585 were 16.7 and 21.3 ng/mL on Day 1 and Day 14, respectively.
  • the time to median peak plasma concentrations of KAR5585 ranged from 0.75-4 hours, 1.5 to 6 hours, and 1.5 to 6 hours, respectively, on all dosing days and times.
  • the t max of KAR5585 were 4 hours, 6 hours, and 6 hours, for the 100, 200 and 400 mg doses, respectively.
  • the Day 7 PM t max values were on the upper end of the t max values determined in Day 1, Day 7 and Day 14.
  • the mean C max plasma concentrations of KAR5585 ranged from 18.4-44.1 ng/mL, 42.6-90.9 ng/mL, and 69.0-124 ng/mL, respectively, on all dosing days.
  • KAR5417 In general, circulating concentrations of KAR5417 were notably higher than those for KAR5585 on all days and at all dose levels. In addition, KAR5417 concentrations generally increased with increasing doses of KAR5585.
  • the peak plasma KAR5417 concentrations were reached between 2.0-6.0 and 2.0 and 4.0 hours on Day 1 and Day 14 following oral twice-daily administration of 100 mg of KAR5585, Part 2, Cohort 1 (fasted state).
  • the mean peak concentrations of KAR5417 were 121 and 194 ng/mL on Day 1 and Day 14, respectively. These values were approximately 7.25-fold and 9.1-fold greater than the corresponding peak mean concentrations of KAR5585.
  • the time to median peak plasma concentrations of KAR5417 ranged from 2 to 6 hours, 3 to 8 hours, and 3 to 6 hours, respectively, on all dosing days and times. There was some evidence for a delayed t max for KAR5417 on Day 7 for the evening dose, where the median time to peak plasma concentrations of KAR5417 was 6 hours, 8 hours, and 6 hours, for the 100, 200 and 400 mg doses, respectively.
  • the Day 7 PM median t max values for KAR5417 were on the upper end of the median t max values determined on Day 1, Day 7 and Day 14.
  • the mean C max plasma concentrations of KAR5417 rangedfrom 85.9-168 ng/mL, 222-359 ng/mL, and 595-1000 ng/mL, respectively, on all dosing days.
  • C max 860 ng/mL
  • C max 485 ng/mL
  • KAR5585 and KAR5417 PK parameters The summary of plasma KAR5585 and KAR5417 PK parameters following a repeat-dose oral administration of 100, 200 and 400 mg KAR5585 administered in healthy adult subjects are presented in 15 and Table 16, respectively. Accumulation ratios for KAR5417 and KAR5585 in healthy volunteers following BID oral administration of KAR5585 for 14 days are presented in Table 17.
  • mean peak plasma KAR5585 concentrations appeared to increase in a dose proportional manner from 100-400 mg (Part 2, Cohort 2-4, fed state).
  • Mean C max values increased 4.4-fold over the 4-fold increase in dose between the 100 mg dose (Cohort 2) and the 400 mg dose (Cohort 4) on Day 1.
  • Mean C max values increased ⁇ 3.0-fold over the 4-fold increase in dose between the 100 mg dose (Part 2, Cohort 2) and the 400 mg dose (Part 2, Cohort 4) on Day 14.
  • the mean apparent elimination half-life of KAR5585 increased with increasing dose levels, and the mean values were 2.73, 4.08 and 6.45 hrs on Day 14 after oral administration of repeat dose twice-daily administration of 100, 200 and 400 mg of KAR5585 (Part 2, Cohort 2-4, fed state), respectively.
  • the half-life of KAR5585 was 2.49 hrs on Day 14 after oral administration of repeat dose administration of 100 mg in the fasted state, and was comparable to the half-life in the fed state (2.73 hrs) for the 100 mg dose.
  • Mean CL/F estimates of KAR5585 were 2100, 830 and 1730 L/h for the 100, 200 and 400 mg (Part 2, Cohort 2-4, fed state) doses on Day 1, respectively.
  • Mean steady-state CL/F estimates of KAR5585, in the fed state were 880, 1200 and 1140 L/h for the 100, 200 and 400 mg (Part 2, Cohort 2-4, fed state) doses on Day 14, respectively.
  • Ranges (mean ⁇ SD) were generally overlapping on both days and across the dose range studied here.
  • V z /F was 4100, 3220 and 6800 L for the 100, 200 and 400 mg (Part 2, Cohort 2-4, fed state) doses, respectively.
  • V z /F increased with increasing dose levels on Day 14 and were 3520, 7010 and 10300 L for the 100, 200 and 400 mg doses, respectively.
  • the highest mean V z /F values were noted for the 400 mg dose (Cohort 4) and is attributed to better characterization of the elimination half-life of KAR5585 at higher doses.
  • KAR5585 plasma levels achieved steady-state exposure by Day 7 as assessed by comparison of Day 7 and Day 14 AUC 0-12 and concentration, obtained 12 hours after an administered dose (C 12 hr ) values following twice daily administration of KAR5585 for 14-days.
  • Accumulation ratios for KAR5585 comparing accumulation ratio for C max (R Cmax ) and accumulation ratio for AUC 0-12 (R AUC0-12 ) for Day 7/1 and Day 14/Day 1 are presented in Table 17.
  • the R AUC0-12 values for KAR5585 ranged from 2.75-3.32, 0.76-0.93 and 1.6-2.01 for the 100, 200 and 400 mg doses of KAR5585 suggesting that the PK of KAR5417 was independent of time and steady-state was achieved on Day 7 following repeated twice-daily administration for 14-days.
  • KAR5417 is the active metabolite of the prodrug, KAR5585. Following administration of KAR5585, KAR5417 appeared in plasma, an observation consistent with rapid absorption of KAR5585 and efficient conversion to KAR5417. In general, mean peak plasma KAR5417 concentrations, as measured by mean C max , appeared to increase in a greater that dose proportional manner from 100-400 mg (Part 2, Cohort 2-4, fed state). Mean C max values increased 6.9-fold over the 4-fold increase in dose between the 100 mg dose (Cohort 2) and the 400 mg dose (Cohort 4) on Day 1. Day 14 mean C max values increased in an approximately dose proportional manner with an ⁇ 4.5-fold increase in C max over the 4-fold increase in dose between the 100 mg dose (Part 2, Cohort 2) and the 400 mg dose (Part 2, Cohort 4).
  • AUC 0-inf 6710 ng ⁇ hr/mL
  • the mean apparent elimination half-life of KAR5417 increased with increasing dose levels studied, and mean values were 19.6, 25.0 and 30.6 hrs on Day 14 after oral administration of repeat dose twice-daily administration of 100, 200 and 400 mg of KAR5585 (Part 2, Cohort 2-4, fed state), respectively, determined from a single AM dose on Day 14.
  • the half-life of KAR5417 was 18.8 hrs on Day 14 after oral administration of repeat dose twice-daily administration of 100 mg in the fasted state, and was comparable to the half-life in the fed state (19.6 hrs) for the 100 mg dose.
  • KAR5417 plasma levels achieved steady-state exposure by Day 7 as assessed by comparison of Day 7 and Day 14 AUC 0-12 and C 12 hr values following twice daily administration of KAR5585 for 14-days.
  • Accumulation ratios for KAR5417 comparing R Cmax and R AUC0-12 for Day 7/Day 1 and Day 14/Day 1 are presented in Table 17.
  • the R AUC0-12 values for KAR5417 ranged from 2.19-2.57, 1.09-1.34 and 1.65-2.38 for the 100, 200 and 400 mg doses of KAR5585 suggesting that the PK of KAR5417 was independent of time and steady-state was achieved on Day 7 following repeated twice-daily administration for 14-days.
  • PK pharmacokinetic
  • PM after noon (post meridiem);
  • Param. parameter;
  • R AUC0-12 accumulation ratio for AUC 0-12 ;
  • R Cmax accumulation ratio for C max ;
  • SD standard deviation;
  • Stat. statistical; t1 ⁇ 2, apparent terminal half-life after oral administration;
  • t max time of maximum observed concentration.
  • CV % 52.5 52.2 54.0 59.6 Abbreviations: AM, before noon (ante meridiem); BID, twice daily; Geo., geometric; hr, hour; N, number; PM, after noon (post meridiem); R AUC0-12 , accumulation ratio for AUC 0-12 ; R Cmax , accumulation ratio for C max ; SD, standard deviation; t1 ⁇ 2, apparent terminal half-life after oral administration.
  • FIGS. 14 a and 14 b and FIGS. 15 a and 15 b Scatter plots of individual plasma KAR5585 and KAR5417 Day 1 and Day 14 C max KAR5585 dose are presented in FIGS. 14 a and 14 b and FIGS. 15 a and 15 b , respectively.
  • Scatter plots of individual plasma KAR5585 and KAR5417 Day 1 and Day 14 AUC 0-12 KAR5585 dose are presented in FIGS. 16 a and 16 b and FIGS. 17 a and 17 b .
  • the dose proportionality assessment of plasma KAR5585 and KAR5417 PK parameters are summarized in Table 16. Dose proportionality was assessed for KAR5585 and KAR5417 after repeat-dose, twice-daily administration of KAR5585 using the power model.
  • KAR5585 was rapidly absorbed.
  • the median time to peak plasma concentrations of KAR5585 ranged from 0.75-4 hours, 1.5 to 6 hours, and 1.5 to 6 hours, respectively, on all dosing days and times.
  • the median time to peak plasma concentrations of KAR5585 were 4 hours, 6 hours, and 6 hours, for the 100, 200 and 400 mg doses, respectively.
  • the Day 7 PM t max values were on the upper end of the t max values determined in
  • Peak plasma KAR5585 concentrations as measured by mean C max , increased in a dose proportional manner from 100-400 mg (Part 2, Cohort 2-4, fed state).
  • Mean C max values increased 4.4-fold over the 4-fold increase in dose between the 100 mg dose (Cohort 2) and the 400 mg dose (Cohort 4) on Day 1.
  • Mean C max values increased ⁇ 3.0-fold over the 4-fold increase in dose between the 100 mg dose (Part 2, Cohort 2) and the 400 mg dose (Part 2, Cohort 4) on Day 14.
  • the mean apparent elimination half-life of KAR5585 increased with increasing dose levels studied, and the mean values were 2.73, 4.08 and 6.45 hrs on Day 14 after oral administration of repeat dose twice-daily administration of 100, 200 and 400 mg of KAR5585 (Part 2, Cohort 2-4,fed state), respectively.
  • the half-life of KAR5585 was 2.49 hrs on Day 14 after oral administration of repeat dose twice-daily administration of 100 mg in the fasted state, and was comparable to the half-life in the fed state (2.73 hrs) for the 100 mg dose.
  • Peak plasma KAR5417 concentrations appeared to increase in a greater that dose proportional manner from 100-400 mg (Part 2, Cohort 2-4, fed state).
  • Mean C max values increased 6.9-fold over the 4-fold increase in dose between the 100 mg dose (Cohort 2) and the 400 mg dose (Cohort 4) on Day 1.
  • Day 14 mean C max values increased in an approximately dose proportional manner with an ⁇ 4.5-fold increase in C max over the 4-fold increase in dose between the 100 mg dose (Part 2, Cohort 2) and the 400 mg dose (Part 2, Cohort 4).
  • Day 14 mean AUC 0-12 and mean AUC 0-24 estimates, increased 4.6-fold and 4.45-fold respectively, for a 4-fold increase in dose between the 100 mg dose (Part 1, Cohort 2) and the 400 mg dose (Part 2, Cohort 4).
  • Steady-state plasma levels of KAR5417 were achieved by Day 7 as assessed by comparison of Day 7 and Day 14 AUC 0-12 and C 12 hr values following twice daily oral administration of KAR5585 for 14-days. Accumulation ratios for KAR5417 compared R Cmax and R AUC0-12 for Day 7/Day 1 and Day 14/Day 1, and verified that steady-state was achieved by Day 7.
  • the R AUC0-12 values for KAR5417 ranged from 2.19-2.57, 1.09-1.34 and 1.65-2.38 for the 100, 200 and 400 mg doses of KAR5585, respectively, suggesting that the PK of KAR5417 was independent of time, and steady-state was achieved on Day 7 following repeated twice-daily administration for 14-days.
  • KAR5585 is a prodrug for the active TPH1 inhibitor KAR5417. Following KAR5585 administration, KAR5585 was rapidly absorbed and converted to KAR5417.
  • Peak plasma KAR5417 concentrations appeared to increase in a greater that dose proportional manner from 100-400 mg (Part 2, Cohort 2-4, fed state).
  • Mean C max values increased 6.9-fold over the 4-fold increase in dose between the 100 mg dose (Cohort 2) and the 400 mg dose (Cohort 4) on Day 1.
  • mean C max values increased in an approximately dose proportional manner with an ⁇ 4.5-fold increase in C max over the 4-fold increase in dose between the 100 mg dose (Part 2, Cohort 2) and the 400 mg dose (Part 2, Cohort 4).
  • the median time to peak plasma concentrations of KAR5417 ranged from 2 to 6 hours, 3 to 8 hours, and 3 to 6 hrs.
  • the mean apparent elimination half-life of KAR5417 was 19.6, 25.0 and 30.6 hrs on Day 14 after oral administration of repeat dose twice-daily administration of 100, 200 and 400 mg of KAR5585 (Part 2, Cohort 2-4, fed state).
  • the elimination half —life (30.6 hrs) of KAR5417 on repeat dose administration of 400 mg doses of KAR5585 was similar to the elimination half-life of KAR5417 (20.5 hrs) following single-dose administration of 400 mg KAR5585 (Part 1 Cohort 3B).
  • KAR5417 plasma levels achieved steady-state exposure by Day 7 as assessed by comparison of Day 7 and Day 14 AUC 0-12 and C 12 hr values following twice daily administration of KAR5585 for 14-days.
  • Accumulation ratios for KAR5417 compared R Cmax and R AUC0-12 for Day 7/Day 1 and Day 14/Day 1.
  • the R AUC0-12 values for KAR5417 ranged from 2.19-2.57, 1.09-1.34 and 1.65-2.38 for the 100, 200 and 400 mg doses of KAR5585 suggesting that the PK of KAR5417 was independent of time and steady-state was achieved on Day 7 following repeated, twice-daily administration for 14-days.
  • Biomarker evaluations were carried out in subjects dosed with KAR5585 or placebo.
  • the biomarker portion of the study was conducted in Part 2 MAD using the Biomarker Population.
  • the biomarkers evaluated were serum 5-HT and plasma 5-HIAA, as well as urine 5-HIAA/24 hours (as measured, adjusted, estimated, and per gram creatinine).
  • Urinary 5-HIAA was determined by a validated (21 C.F.R. 58, GLP-compliant) method using liquid chromatographic separation and tandem mass spectrometry detection.
  • the Biomarker Population consisted of all subjects with evaluable baseline (Day 1 predose) and at least one postdose (Day 7 or Day 14) biomarker measurements.
  • Baseline characteristics are presented in Table 23. Baseline levels of the biomarkers serum 5-HT, plasma-5HIAA, the 5-HIAA measured in urine during 24 hours, without adjustment for daily variations in creatinine excretion (measured urine 5-HIAA), the 5-HIAA measured in urine during 24 hours, adjusted for the mean 24-hour creatinine excretion on Days 1, 7, and 14 (adjusted urine 5-HIAA), estimated urine 5-HIAA, and urine 5-HIAA were similar among the 5 treatment groups (placebo, KAR5585 100 mg fasting, KAR5585 100 mg fed, KAR5585 200 mg fed, and KAR5585 400 mg fed).
  • Biomarker data were analyzed for each KAR5585 dose separately, for all KAR5585 doses pooled, and for all placebo subjects pooled.
  • Dosing with KAR5585 reduced plasma 5-HIAA concentration Mean percent change in plasma 5-HIAA was ⁇ 56.67 from Day 1 to Day 7 and ⁇ 53.33 from Day 1 to Day 14 in subjects randomized to KAR5575 400 mg under fed conditions. Mean percent change at Day 7 was +19.79 and at Day 14 was +20.12 in subjects randomized to placebo. Mean difference of both absolute and percent changes from Day 1 to Day 14 in plasma 5-HIAA concentration was statistically significant in favor of KAR5585 compared to placebo in each dose group and for all doses combined at Day 14 (Table 17).
  • Urine 5 HIAA/24 hour was analyzed in 4 different manners: as measured in the 24-hour collection and (in order to correct for any collection errors) adjusted for creatinine excretion, estimated by the expected creatinine excretion for the subject (as defined in and expressed per gram creatinine. Results were similar for each of the 4 manners and are presented in this report for measured urine. Tables and figures for adjusted, estimated, and per-gram creatinine results are presented in Section 14.
  • Dosing with KAR5585 reduced measured urine 5-HIAA concentration.
  • Mean percent change in measured urine 5-HIAA was ⁇ 39.97 from Day 1 to Day 7 and ⁇ 50.85 from Day 1 to Day 14 in subjects randomized to KAR5575 400 mg under fed conditions.
  • Mean percent change at Day 7 was +9.44 and at Day 14 was +3.97 in subjects randomized to placebo.
  • KAR5585 was rapidly absorbed and the active moiety KAR5417 appeared rapidly in plasma.
  • PK parameters AUC 0-24 , C min , concentration, obtained 12 hr after an administered dose (C 12 hr), and AUC 0-12 were included in the PK-Biomarker analyses.
  • the PK parameters AUC 0-24 , C min , C 12 hr , and AUC 0-12 were adjusted from those stated in the protocol (AUC 0-24 , C min , and C max ) to account for the double daily dosing.
  • FIG. 23 shows the relationship between relative changes from baseline in plasma 5-HIAA and KAR5417 AUC 0-24 .
  • FIG. 23 discloses absolute and relative changes at day 14 of Plasma 5-HIAA from Day 1 Predose vs. AUC [0-24] in subjects who received KAR5585—Part 2 MAD Biomarker Population.
  • Serum 5-HT did not reveal the strong association between the biomarker of serotonin and KAR5585 dose or duration of dosing. The differences of changes from Day 1 between KAR5585 and placebo were statistically significant for the highest dose group (400 mg fed) and for all KAR5585 doses pooled.
  • 5-HIAA a PD marker of 5-HT synthesis
  • the KAR5585 doses administered were the following:
  • KAR5585 prodrug
  • KAR5417 active TPH1 inhibitor
  • Biomarkers Dose- and time-dependent reductions were observed in 5-HIAA (a PD marker of 5-HT synthesis) in both plasma and urine.
  • KAR5585 prodrug
  • KAR5417 active TPH1 inhibitor

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Abstract

There is provided a daily dosage regimen for treating pulmonary arterial hypertension. The regimen takes the form of two discrete dosage forms. Each dosage form includes an amount of about 600 mg to about 800 mg of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate. There is also another method for providing a daily dosage regimen. There is also provided several methods for treating pulmonary arterial hypertension. There is provided a method for reducing the level of serotonin biosynthesis by at least 50%. There is also provided a method for achieving an AUC0-tau of ≥2530 ng·hr/mL of (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid. There is provided a method of achieving a >50% reduction in urinary 5-HIAA.

Description

    CROSS-REFERENCE TO A RELATED APPLICATION
  • The present application is a continuation of U.S. patent application Ser. No. 16/777,458, filed on Jan. 30, 2020, which claims priority to U.S. Provisional Application No. 62/798827, filed Jan. 30, 2019. The entire contents of the foregoing applications are incorporated herein by reference in entirety.
    • BACKGROUND OF THE DISCLOSURE 1. Field of the Disclosure
  • The present disclosure relates to a daily dosage regimen for treating pulmonary arterial hypertension. The present disclosure also relates to methods for treating pulmonary arterial hypertension. The present disclosure further relates to a method for reducing the level of serotonin biosynthesis within a period of time. The present disclosure still further relates to a method for achieving an enhanced level of AUC0-tau within a period of time. The present disclosure further relates to a method for achieving a reduction in urinary 5-HIAA within a period of time.
    • 2. Description of the Prior Art
  • Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that modulates central and peripheral functions by acting on neurons, smooth muscle, and other cell types. 5-HT is involved in the control and modulation of multiple physiological and psychological processes. In the central nervous system (CNS), 5-HT regulates mood, appetite, and other behavioral functions. In the GI system, 5-HT has a general prokinetic role and is an important mediator of sensation (e.g., nausea and satiety) between the GI tract and the brain. Dysregulation of the peripheral 5-HT signaling system has been reported to be involved in the etiology of several conditions (see for example: Mawe, G. M. & Hoffman, J., Serotonin Signaling in the Gut-functions, Dysfunctions and Therapeutic Targets. Nature Reviews. Gastroenterology & Hepatology 10, 473-486 (2013); Gershon, M. D. 5-hydroxytryptamine (serotonin) in the Gastrointestinal Tract. Current Opinion in Endocrinology, Diabetes, and Obesity 20, 14-21 (2013); Lesurtel, M., Soil, C, Graf, R. & Ciavien, P.-A. Role of Serotonin in the Hepato-gastrointestinal Tract: An Old Molecule for New Perspectives. Cellular and Molecular Life Sciences: CMLS 65, 940-52 (2008)). These include osteoporosis (e.g. Kode, A, et al., FOXO1 Orchestrates the Bone-suppressing Function of Gut-derived Serotonin, The Journal of Clinical Investigation 122, 3490-503 (2012); Yadav, V, K. et al., Pharmacological Inhibition of Gut-derived Serotonin Synthesis is a Potential Bone Anabolic Treatment for Osteoporosis. Nature Medicine 16, 308-12 (2010); Yadav, V. K, et al., Lrp5 Controls Bone Formation by Inhibiting Serotonin Synthesis in the Duodenum, Cell 135, 825-37 (2008), cancer (e.g. Liang, C, et al., Serotonin Promotes the Proliferation of Serum-deprived Hepatocellular Carcinoma Cells Via Upregulation of FOX03a. Molecular Cancer 12, 14 (2013); Soli, C. et al., Serotonin Promotes Tumor Growth in Human Hepatocellular Cancer. Hepatology 51, 1244-1254 (2010); Pai, V. P et al., Altered Serotonin Physiology in Human Breast Cancers Favors Paradoxical Growth and Cell Survival. Breast Cancer Research: BCR 11, R81 (2009); Engelman, K., Lovenberg, W. & Sjoerdsma, A. Inhibition of Serotonin Synthesis by Para-chlorophenylalanine in Patients with The Carcinoid Syndrome. The New England Journal of Medicine 277, 1103-8 (1967)), cardiovascular (e.g. Robiolio, P. A, et al., Carcinoid Heart Disease: Correlation of High Serotonin Levels with Valvular Abnormalities Detected by Cardiac Catheterization and Echocardiography. Circulation 92, 790-795 (1995), diabetes (e.g. Sumara, G., Sumara, O., Kim, J. K. & Karsenty, G. Gut-derived Serotonin is a Multifunctional Determinant to Fasting Adaptation. Cell Metabolism 16, 588-600 (2012), atherosclerosis (e.g. Ban, Y. et al., Impact of Increased Plasma Serotonin Levels and Carotid Atherosclerosis on Vascular Dementia. Atherosclerosis 195, 153-9 (2007), as well as gastrointestinal (e.g. Manocha, M. & Khan, W. I. Serotonin and GI Disorders: An Update on Clinical and Experimental Studies. Clinical and Translational Gastroenterology 3, el 3 (2012); Ghia, J.-E. et al., Serotonin has a Key Role in Pathogenesis of Experimental Colitis. Gastroenterology 137, 1649-60 (2009); Sikander, A., Rana, S. V. & Prasad, K. K., Role of Serotonin in Gastrointestinal Motility and Irritable Bowel Syndrome. Clinica Chimica Acta; International Journal of Clinical Chemistry 403, 47-55 (2009); Spiller, R, Recent Advances in Understanding the Role of Serotonin in Gastrointestinal Motility in Functional Bowel Disorders: Alterations In 5-HT Signaling and Metabolism in Human Disease. Neurogastroenterology and Motility: The Official Journal of The European Gastrointestinal Motility Society 19 Suppl 2, 25-31 (2007); Costedio, M. M., Hyman, N. & Mawe, G, M, Serotonin and its Role in Colonic Function and In Gastrointestinal Disorders. Diseases of the Colon and Rectum 50, 376-88 (2007); Gershon, M. D. & Tack, J., The Serotonin Signaling System: From Basic Understanding to Drug Development for Functional GI Disorders. Gastroenterology 132, 397-14 (2007); Mawe, G. M., Coates, M. D. & Moses, P. L. Review Article: Intestinal Serotonin Signaling In Irritable Bowel Syndrome. Alimentary Pharmacology & Therapeutics 23, 1067-76 (2006); Crowell, M. D. Role of Serotonin in the Pathophysiology of The Irritable Bowel Syndrome. British Journal of Pharmacology 141, 1285-93 (2004)), pulmonary (e.g. Lau, W. K. W. et al., The Role of Circulating Serotonin in the Development of Chronic Obstructive Pulmonary Disease. PloS One 7, e31617 (2012); Egermayer, P., Town, G. I. & Peacock, A. J. Role of Serotonin in the Pathogenesis of Acute and Chronic Pulmonary Hypertension. Thorax 54, 161-168 (1999), inflammatory (e.g. Margolis, K. G. et al., Pharmacological Reduction of Mucosal but Not Neuronal Serotonin Opposes Inflammation in Mouse Intestine. Gut doi: 10.1 136/gutjnl-2013-304901 (2013); Duerschmied, D. et al., Platelet Serotonin Promotes the Recruitment of Neutrophils to Sites of Acute Inflammation in Mice. Blood 121, 1008-15 (2013); Li, N. et al., Serotonin Activates Dendritic Cell Function in the Context of Gut Inflammation. The American Journal of Pathology 178, 662-71 (2011), or liver diseases or disorders (e.g. Ebrahimkhani, M. R. et al., Stimulating Healthy Tissue Regeneration by Targeting The 5-HT2B Receptor in Chronic Liver Disease. Nature Medicine 17, 1668-73 (2011). The large number of pharmaceutical agents that block or stimulate the various 5-HT receptors is also indicative of the wide range of medical disorders that have been associated with 5-HT dysregulation (see for example: Wacker, D. et al., Structural Features for Functional Selectivity at Serotonin Receptors, Science (New York N Y.) 340, 615-9 (2013).
  • The rate-limiting step in 5-HT biosynthesis is the hydroxylation of tryptophan by dioxygen, which is catalyzed by tryptophan hydroxylase (TPH; EC 1.14.16.4) in the presence of the cofactor (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4). The resulting oxidized product, 5-hydroxy tryptophan (5-HTT) is subsequently decarboxylated by an aromatic amino acid decarboxylase (AAAD; EC 4.1.1.28) to produce 5-HT. Together with phenylalanine hydroxylase (PheOH) and tyrosine hydroxylase (TH), TPH belongs to the pterin-dependent aromatic amino acid hydroxylase family.
  • Two vertebrate isoforms of TPH, namely TPH1 and TPH2, have been identified. TPH1 is primarily expressed in the pineal gland and non-neuronal tissues, such as entero chromaffin (EC) cells located in the gastrointestinal (GI) tract. TPH2 (the dominant form in the brain) is expressed exclusively in neuronal cells, such as dorsal raphe or myenteric plexus cells. The peripheral and central systems involved in 5-HT biosynthesis are isolated, with 5-HT being unable to cross the blood-brain barrier. Therefore, the peripheral pharmacological effects of 5-HT can be modulated by agents affecting TPH in the periphery, mainly TPH1 in the gut.
  • A small number of phenylalanine-derived TPH1 inhibitors are known. One example, p-chlorophenylalanine (pCPA), a very weak and unselective irreversible inhibitor of TPH, has proven effective in treating chemotherapy-induced emesis, as well as diarrhea, in carcinoid tumor patients. However, pCPA is distributed centrally and, as a result, its administration has been linked to the onset of depression and other alterations of CNS functions in patients and animals. p-Ethynyl phenylalanine is a more selective and more potent TPH inhibitor than pCPA (Stokes, A, H., et al. p-Ethynylphenylalanine: A Potent Inhibitor of Tryptophan Hydroxylase. Journal of Neurochemistry 74, 2067-73 (2000), but also affects central 5-HT production and, like pCPA, is believed to irreversibly interfere with the synthetic behavior of TPH (and possibly interact with other proteins).
  • More recently, bulkier phenylalanine-derived TPH inhibitors have been reported to reduce intestinal 5-HT concentration without affecting brain 5-HT levels (Zhong, H. et al., Molecular dynamics simulation of tryptophan hydroxylase-1: binding modes and free energy analysis to phenylalanine derivative inhibitors. International Journal of Molecular Sciences 14, 9947-62 (2013); Ouyang, L., et al., Combined Structure-Based Pharmacophore and 3D-QSA Studies on Phenylalanine Series Compounds as TPH1 Inhibitors. International Journal of Molecular Sciences 13, 5348-63 (2012); Camilleri, M. LX-1031, A Tryptophan 5-hydroxylase Inhibitor, and its Potential in Chronic Diarrhea Associated with Increased Serotonin. Neurogastroenterology and Motility: The Official Journal of the European Gastrointestinal Motility Society 23, 193-200 (2011); Cianchetta, G., et al., Mechanism of Inhibition of Novel Tryptophan Hydroxylase Inhibitors Revealed by Co-crystal Structures and Kinetic Analysis. Current Chemical Genomics 4, 19-26 (2010); Jin, H., et al., Substituted 3-(4-(l,3,5-triazin-2-yl)-phenyl)-2-aminopropanoic Acids as Novel Tryptophan Hydroxylase Inhibitors. Bioorganic & Medicinal Chemistry Letters 19, 5229-32 (2009); Shi, Z.C., et al., Modulation of Peripheral Serotonin Levels by Novel Tryptophan Hydroxylase Inhibitors for the Potential Treatment of Functional Gastrointestinal Disorders. Journal of Medicinal Chemistry 51, 3684-7 (2008); Liu, Q., et al., Discovery and Characterization of Novel Tryptophan Hydroxylase Inhibitors That Selectively Inhibit Serotonin Synthesis in the Gastrointestinal Tract. The Journal of Pharmacology and Experimental Therapeutics 325, 47-55 (2008).
  • Spirocyclic compounds that act as inhibitors of THP and are useful in the treatment of various diseases and disorders associated with peripheral serotonin, including the cardiovascular diseases of pulmonary arterial hypertension (PAH) and associated pulmonary arterial hypertension (APAH) and carcinoid syndrome are known. (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate and (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1T-biphenyl]-2-yl)-2,2,2-trifluoroeth-oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid are known compounds.
  • There is a need to selectively reduce tissue 5-HT (particularly intestinal 5-HT and lung 5-HT) levels as a means for treating and preventing 5-HT-associated diseases and modulation and/or reduction of serotonin levels, particularly peripheral serotonin levels, as well as 5-HIAA levels in the urine. There is also a need to achieve desirable AUC0-tau levels in the bloodstream. There is a more particular need to treat or prevent the cardiovascular diseases of pulmonary arterial hypertension (PAH) and associated pulmonary arterial hypertension (APAH).
    • SUMMARY OF THE DISCLOSURE
  • According to the present disclosure, there is provided a daily dosage regimen for treating pulmonary arterial hypertension. The regimen takes the form of two discrete dosage forms. Each dosage form includes an amount from about 600 mg to about 800 mg of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.
  • Further according to the present disclosure, there is provided a daily dosage regimen for treating pulmonary arterial hypertension. The regimen has an amount from about 1200 mg to about 1600 mg of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]deca ne-3-carboxylate.
  • Also according to the present disclosure, there is provided a method for treating pulmonary arterial hypertension. The method has the step of administering to a human patient in need thereof an amount from about 1200 mg to about 1600 mg of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate per day.
  • Further according to the present disclosure, there is provided a method for reducing the level of serotonin biosynthesis by at least 50% in a human patient in need thereof within 14 days after commencement of treatment. The method has the step of administering to the human patient an amount from about 800 mg to about 1600 mg of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate per day.
  • Still further according to the present disclosure, there is provided a method for achieving an AUC0-tau of ≥2530 ng.hr/mL of (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid in a human patient within 14 days after commencement of administration. The method has the step of administering daily to the human patient an effective amount of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.
  • According to the present disclosure, there is provided a method of achieving a >50% reduction in urinary 5-HIAA in a human patient within 14 days after commencement of administration. The method has the step of administering daily to a human patient an effective amount of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.
  • Further according to the present disclosure, there is provided a method for treating pulmonary arterial hypertension. The method has the step of administering daily to a human patient in need thereof an amount of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate sufficient to achieve an AUC0-tau of ≥2530 ng.hr/mL of (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid within 14 days after commencement of administration.
  • According to the present disclosure, there is provided a method for treating pulmonary arterial hypertension. The method has the step of administering daily to a human patient in need thereof an amount of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate sufficient to achieve a >50% reduction in urinary 5-HIAA within 14 days after commencement of administration.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • Embodiments of the present disclosure are described herein with reference to the following figures.
  • FIG. 1 is a plot of an XRPD of a crystalline compound of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate according to the present disclosure (crystalline Form 3).
  • FIG. 2 is a plot of an XRPD of a crystalline compound of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate of a different polymorphic form than that of FIG. 1 (crystalline Form 1).
  • FIG. 3 a is a plot of mean (±SD) plasma concentration-time profiles of KAR5585 following administration of 100-2000 mg of KAR5585 under fasting conditions—Cohorts 1-6 (linear scale).
  • FIG. 3 b is a plot of mean (±SD) plasma concentration-time profiles of KAR5417 following administration of 100-2000 mg of KAR5585 under fasting conditions—Cohorts 1-6 (linear scale) for KAR5417.
  • FIG. 4 a is a plot of mean (±SD) plasma concentration-time profiles of KAR5585 and KAR5417 following administration of 100-2000 mg of KAR5585 under fasting conditions—Cohorts 1-6 (log scale) for KAR5585.
  • FIG. 4 b is a plot of mean (±SD) plasma concentration-time profiles of KAR5585 and KAR5417 following administration of 100-2000 mg of KAR5585 under fasting conditions—Cohorts 1-6 (log scale) for KAR5417.
  • FIG. 5 a is a plot of dose vs. plasma Cmax values for KAR5585 and KAR5417 in fasted healthy volunteers following a single oral dose of KAR5585.
  • FIG. 5 b is a plot of dose vs. plasma Cmax values for KAR5585 and KAR5417 in fasted healthy volunteers following a single oral dose of KAR5417.
  • FIG. 6 a is a plot of dose vs. plasma AUCinf values for KAR5585 and KAR5417 in fasted healthy volunteers following a single oral dose of KAR5585.
  • FIG. 6 b is a plot of dose vs. plasma AUCinf values for KAR5585 and KAR5417 in fasted healthy volunteers following a single oral dose of KAR5585.
  • FIG. 7 is a bar graph of mean (±SD) total percent of dose excreted in urine as KAR5417 in fasted healthy volunteers following a single oral dose of KAR5585.
  • FIG. 8 is a plot of cumulative mean (±SD) urine recoveries vs. sampling time of KAR5417 in fasted healthy volunteers following a single oral dose of KAR5585.
  • FIG. 9 a is a plot of mean concentration vs. time profiles of KAR5585 in fasted and fed healthy volunteers following BID oral administration of KAR5585 for 14 days (semi-log scale)
  • FIG. 9 b is a plot of mean concentration vs. time profiles of KAR5417 in fasted and fed healthy volunteers following BID oral administration of KAR5585 for 14 days (semi-log scale)
  • FIG. 10 is a plot of mean (±SD) concentration vs. time profiles of KAR5585 and KAR5417 in fasted healthy volunteers following BID oral administration of 100 mg KAR5585 for 14 days.
  • FIG. 11 is a plot of mean (±SD) concentration vs. time profiles of KAR5585 and KAR5417 in fed healthy volunteers following BID oral administration of 100 mg KAR5585 for 14 days.
  • FIG. 12 is a plot of mean (±SD) concentration vs. time profiles of KAR5585 and KAR5417 in fed healthy volunteers following BID oral administration of 200 mg KAR5585 for 14 days.
  • FIG. 13 is a plot of mean (±SD) concentration vs. time profiles of KAR5585 and KAR5417 in fed healthy volunteers following BID oral administration of 400 mg KAR5585 for 14 days.
  • FIG. 14 a is a plot of dose vs. Cmax for KAR5585 in fed healthy volunteers following BID oral administration of KAR5585 for 14 days.
  • FIG. 14 b is a plot of dose vs. Cmax for KAR5417 in fed healthy volunteers following BID oral administration of KAR5585 for 14 days.
  • FIG. 15 a is a plot of dose vs. Cmax for KAR5585 in fed healthy volunteers following BID oral administration of KAR5585 for 14 days.
  • FIG. 15 b is a plot of dose vs. Cmax for KAR5417 in fed healthy volunteers following BID oral administration of KAR5585 for 14 days.
  • FIG. 16 a is a plot of dose vs. AUC0-12 for KAR5585 in fed healthy volunteers following BID oral administration of KAR5585 for 14 days.
  • FIG. 16 b is a plot of dose vs. AUC0-12 for KAR5417 in fed healthy volunteers following BID oral administration of KAR5585 for 14 days.
  • FIG. 17 a is a plot of dose vs. AUC0-12 for KAR5585 in fed healthy volunteers following BID oral administration of KAR5585 for 14 days.
  • FIG. 17 b is a plot of dose vs. AUC0-12 for KAR5417 in fed healthy volunteers following BID oral administration of KAR5585 for 14 days.
  • FIG. 18 a is a plot of mean (±SD) plasma concentration-time profiles of KAR5585 following administration of 400 mg of KAR5585 under fed and fasting conditions—Cohorts 3A and 3B (linear scale).
  • FIG. 18 b is a plot of mean (±SD) plasma concentration-time profiles of KAR5417 following administration of 400 mg of KAR5585 under fed and fasting conditions—Cohorts 3A and 3B (linear scale).
  • FIG. 19 a is a plot of mean (±SD) plasma concentration-time profiles of KAR5585 following administration of 400 mg of KAR5585 under fed and fasting conditions—Cohorts 3A and 3B (log scale).
  • FIG. 19 b is a plot of mean (±SD) plasma concentration-time profiles of KAR5417 following administration of 400 mg of KAR5585 under fed and fasting conditions—Cohorts 3A and 3B (log scale).
  • FIG. 20 is a plot of relative change from baseline percentage of plasma 5-HIAA vs AUC0-24 at Day 14.
    •  DETAILED DESCRIPTION OF THE DISCLOSURE
  • (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (“KAR5585”) is a useful TPH1 inhibitor. The amorphous form of KAR5585 is disclosed at Example 63i of U.S. Pat. No. 9,199,994. KAR5585 has the following structure:
  • Figure US20240041877A1-20240208-C00001
  • Two crystalline forms of KAR5585, i.e., polymorphs are known. One is denoted as “crystalline Form 3” and the other as “crystalline Form 1”. Form 3 exhibits substantially greater thermodynamic stability compared to Form 1 and is supportive of longer shelf life, particularly at temperatures of less than 95° C. and more particularly at temperatures of less than 80° C.
  • The crystalline Form 3 exhibits the XRPD (X-ray powder diffraction) pattern set forth below in Table 1.
  • TABLE 1
    Observed Peaks for X-ray Powder Diffraction
    Pattern for KAR5585, Form 3
    Peak position (°2θ) d space (Å) Intensity (%)
     8.78 ± 0.20 10.077 ± 0.235  90
    12.00 ± 0.20 7.375 ± 0.125 25
    13.47 ± 0.20 6.573 ± 0.099 39
    14.02 ± 0.20 6.316 ± 0.091 12
    14.87 ± 0.20 5.956 ± 0.081 71
    15.39 ± 0.20 5.757 ± 0.075 72
    15.61 ± 0.20 5.677 ± 0.073 78
    15.89 ± 0.20 5.576 ± 0.071 50
    16.31 ± 0.20 5.434 ± 0.067 7
    17.70 ± 0.20 5.011 ± 0.057 34
    18.45 ± 0.20 4.809 ± 0.052 70
    19.05 ± 0.20 4.658 ± 0.049 100
    20.12 ± 0.20 4.413 ± 0.044 42
    20.57 ± 0.20 4.317 ± 0.042 68
    20.84 ± 0.20 4.262 ± 0.041 39
    21.46 ± 0.20 4.141 ± 0.039 49
    21.94 ± 0.20 4.051 ± 0.037 18
    22.56 ± 0.20 3.941 ± 0.035 31
    22.90 ± 0.20 3.884 ± 0.034 17
    23.90 ± 0.20 3.723 ± 0.031 35
    24.32 ± 0.20 3.660 ± 0.030 13
    25.07 ± 0.20 3.552 ± 0.028 12
    26.54 ± 0.20 3.359 ± 0.025 17
    26.76 ± 0.20 3.332 ± 0.025 18
    27.79 ± 0.20 3.210 ± 0.023 8
    28.21 ± 0.20 3.163 ± 0.022 19
    29.48 ± 0.20 3.030 ± 0.020 9
  • In another aspect, Form 3 exhibits prominent XRPD peaks set forth below in Table 2.
  • TABLE 2
    Prominent Observed Peaks for X-ray Powder
    Diffraction Pattern for KAR5585, Form 3
    Peak position (°2θ) d space (Å) Intensity (%)
     8.78 ± 0.20 10.077 ± 0.235  90
    14.87 ± 0.20 5.956 ± 0.081 71
    15.39 ± 0.20 5.757 ± 0.075 72
    15.61 ± 0.20 5.677 ± 0.073 78
    18.45 ± 0.20 4.809 ± 0.052 70
    19.05 ± 0.20 4.658 ± 0.049 100
  • In yet another aspect, Form 3 exhibits a characteristic XRPD peak at 19.05±0.20 (°2θ).
  • Crystalline Form 1 crystalline compound exhibits the XRPD (X-ray powder diffraction) pattern set forth below in Table 3.
  • TABLE 3
    Observed Peaks for X-Ray Powder Diffraction Pattern for Form 1
    Peak position (°2θ) d space (Å) Intensity (%)
     5.92 ± 0.20 14.936 ± 0.522  27
     9.01 ± 0.20 9.816 ± 0.222 11
     9.68 ± 0.20 9.140 ± 0.192 9
    10.38 ± 0.20 8.523 ± 0.167 9
    10.95 ± 0.20 8.082 ± 0.150 30
    11.85 ± 0.20 7.468 ± 0.128 6
    12.90 ± 0.20 6.861 ± 0.108 43
    13.89 ± 0.20 6.376 ± 0.093 65
    14.62 ± 0.20 6.057 ± 0.084 31
    15.04 ± 0.20 5.890 ± 0.079 44
    15.41 ± 0.20 5.750 ± 0.075 38
    17.13 ± 0.20 5.176 ± 0.061 30
    17.83 ± 0.20 4.974 ± 0.056 37
    18.72 ± 0.20 4.741 ± 0.051 14
    19.44 ± 0.20 4.567 ± 0.047 100
    19.79 ± 0.20 4.487 ± 0.045 30
    20.11 ± 0.20 4.417 ± 0.044 97
    20.34 ± 0.20 4.366 ± 0.043 44
    20.84 ± 0.20 4.262 ± 0.041 14
    21.41 ± 0.20 4.151 ± 0.039 10
    21.88 ± 0.20 4.063 ± 0.037 11
    22.28 ± 0.20 3.991 ± 0.036 25
    22.83 ± 0.20 3.895 ± 0.034 60
    23.85 ± 0.20 3.731 ± 0.031 13
    24.40 ± 0.20 3.648 ± 0.030 9
    25.45 ± 0.20 3.500 ± 0.027 9
    25.97 ± 0.20 3.431 ± 0.026 12
    27.22 ± 0.20 3.276 ± 0.024 15
    27.58 ± 0.20 3.235 ± 0.023 23
    28.06 ± 0.20 3.180 ± 0.022 12
    28.66 ± 0.20 3.115 ± 0.021 7
  • In still another aspect, Form 1 exhibits prominent XRPD peaks set forth below in Table 4.
  • TABLE 4
    Prominent Observed Peaks for X-Ray Powder
    Diffraction Pattern for Compound 1, Form 1
    Peak position (°2θ) d space (Å) Intensity (%)
    12.90 ± 0.20 6.861 ± 0.108 43
    13.89 ± 0.20 6.376 ± 0.093 65
    15.04 ± 0.20 5.890 ± 0.079 44
    19.44 ± 0.20 4.567 ± 0.047 100
    20.11 ± 0.20 4.417 ± 0.044 97
    20.34 ± 0.20 4.366 ± 0.043 44
    22.83 ± 0.20 3.895 ± 0.034 60
  • The amorphous form of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate can be prepared by the method set forth in Example 63i of U.S. Pat. No. 9,199,994, which is incorporated herein by reference in its entirety. The amorphous form can then be converted to crystalline form by methods described in U.S. Ser. No. 16/683,509, filed Nov. 14, 2019, which is incorporated herein by reference in its entirety. Forms 1 and 3 can be prepared by the methods set forth in U.S. Ser. No. 16/683,509.
  • The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • The Form 3 compound can be used to inhibit the activity of the TPH1 enzyme in a cell by contacting the cell with an inhibiting amount of a compound of the disclosure. The cell can be part of the tissue of a living organism, or can be in culture, or isolated from a living organism. Additionally, the Form 3 compound can be used to inhibit the activity of the TPH1 enzyme in an animal, individual, or patient, by administering an inhibiting amount of a compound of the disclosure to the cell, animal, individual, or human patient.
  • The Form 3 compound can also lower peripheral serotonin levels in an animal, individual, or patient, by administering an effective amount of a compound of the disclosure to the animal, individual, or patient. In some embodiments, the Form 3 compound can lower levels of peripheral serotonin (e.g., 5-HT in the GI tract or lung tissue) selectively over non-peripheral serotonin (e.g., 5-HT in the CNS). In some embodiments, the selectivity can be 2-fold or more, 3-fold or more, 5-fold or more, 10-fold or more, 50-fold or more, or 100-fold or more.
  • As TPH1 inhibitors that can lower peripheral serotonin levels, the Form 3 compound is useful in the treatment and prevention of various diseases associated with abnormal expression or activity of the TPH1 enzyme, or diseases associated with elevated or abnormal peripheral serotonin levels. In some embodiments, the treatment or prevention includes administering to a patient in need thereof a therapeutically effective amount of a TPH1 inhibitor of the Form 3 compound. The Form 3 compound is also useful in the treatment and prevention of serotonin syndrome.
  • The efficacy of amorphous (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate in inhibiting TPH1 in mice was demonstrated in U.S. Pat. No. 9,199,994 in biological assays at Example 63i and Table 27.
  • Biological assays, some of which are described herein, can be used to determine the inhibitory effect of compounds against TPH (such as TPH1) in vitro and/or in vivo. In vitro biochemical assays for human, mouse, and rat TPH1 and human TPH2, PheOH, and TH may be used to measure inhibition of enzyme activity and the selectivity among TPH1, TPH2, PheOH, and TH. In addition, the efficacy of these compounds can be determined, for example, by measuring their effect on intestinal 5-HT levels in rodents after oral administration.
  • The metabolite of KAR5585 is (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1T-biphenyl]-2-yl)-2,2,2-trifluoroeth-oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid, which is of the formula
  • Figure US20240041877A1-20240208-C00002
  • (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1T-biphenyl]-2-yl)-2,2,2-trifluoroeth-oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid is referred to herein as KAR5417. When KAR5585 enters the bloodstream, it substantially converts to KAR5417. The amorphous form of KAR5417 can be prepared by the method set forth in Example 34c of U.S. Pat. No. 9,199,994.
  • KAR5585 has been found to be particularly useful in treating and preventing pulmonary arterial hypertension (PAH). Prior studies have characterized treatment of PAH in rats, but there remains a need for efficacy and dosage to be characterized such that effective treatment of human adults can be carried out.
  • One aspect of the present disclosure is a daily dosage regimen for treatment of PAH in adults. The regimen takes the form of two discrete dosage forms. Each dosage form includes an amount from about 600 mg to about 800 mg of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate of Form 3. A preferred daily regimen employs two oral dosage forms taken twice per day (BID) up to 14 days. Another preferred aspect are dosage forms having 600 mg or 800 mg of KAR5585 (Form 3).
  • Another aspect of the dosage regimen for treating pulmonary arterial hypertension is administration of an amount from about 1200 mg to about 1600 mg of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate per day.
  • Another aspect of the present disclosure is a method for reducing the level of serotonin (5-HT) biosynthesis by at least 50% in a human patient within 14 days after commencement of treatment. The method has the step of administering to the human patient about 800 mg to about 1600 mg of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate per day. Serotonin levels are determined by the methods disclosed in the examples below.
  • Another aspect of the present disclosure is treatment of pulmonary arterial hypertension by achievement an AUC0-tau of ≥2530 ng.hr/mL of (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid in a human patient within 14 days after commencement of administration of a sufficient amount to the human patient. A preferred level of AUC0-tau of ≥2530 ng.hr/mL. AUC0-tau is determined by methods disclosed in the examples below.
  • Another aspect of the present disclosure is treatment of pulmonary arterial hypertension by achievement of a >50% reduction in urinary 5-HIAA in a human patient within 14 days after commencement of administration of a sufficient amount to the human patient. Urinary 5-HIAA is determined by methods disclosed in the examples below.
  • Other diseases treatable or preventable by administering a TPH1 inhibitor of the disclosure include bone disease such as, for example, osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, fractures, and bone metastasis, In some embodiments, the disease is osteoporosis, such as primary type 1 (e.g., postmenopausal osteoporosis), primary type 2 (e.g., senile osteoporosis), and secondary (e.g., steroid- or glucocorticoid-induced osteoporosis).
  • Further diseases treatable or preventable by the methods of the disclosure include cardiovascular diseases such as atherosclerosis and pulmonary hypertension (PH), including idiopathic or familial PH, and including PH associated with or brought on by other diseases or conditions. In some embodiments, the PH disease is pulmonary arterial hypertension (PAH).
  • The types of PAH treatable according to the methods of the disclosure include (1) idiopathic (IPAH), (2) familial (FPAH), and (3) associated (APAH) which is the most common type of PAH. The latter is PAH which is associated with other medical conditions including, for example, (1) collagen vascular disease (or connective tissue disease) that include autoimmune diseases such as scleroderma or lupus; (2) congenital heart and lung disease; (3) portal hypertension (e.g., resulting from liver disease); (4) HIV infection; (5) drugs (e.g., appetite suppressants, cocaine, and amphetamines; and (6) other conditions including thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, and splenectomy. APAH can also be PAH associated with abnormal narrowing in the pulmonary veins and/or capillaries such as in pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis. Another type of PAH is associated with persistent pulmonary hypertension of the newborn (PPHN).
  • Further diseases treatable or preventable by the methods of the present disclosure include metabolic diseases such as diabetes and hyperlipidemia; pulmonary diseases such as chronic obstructive pulmonary disease (COPD), and pulmonary embolism; gastrointestinal diseases such as IBD, colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, or other gastrointestinal inflammatory conditions; liver diseases such as chronic liver disease; cancers such as liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, and bone cancer (e.g., osteosarcoma, chrondrosarcoma, Ewings sarcoma, osteoblastoma, osteoid osteoma, osteochondroma, enchondroma, chondromyxoid fibroma, aneurysmal bone cyst, unicameral bone cyst, giant cell tumor, and bone tumors); blood diseases (e.g., myeloproliferative syndrome, myelodysplasia syndrome, Hodgkin's lymphoma, non-Hodgkin's lymphoma, myeloma, and anemia such as aplastic anemia and anemia associated with kidney disease; and blood cancers (e.g., leukemias such as acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML)).
  • A further treatable disease is the treatment and prevention of carcinoid syndrome. Carcinoid syndrome is a paraneoplastic syndrome exhibiting the signs and symptoms that occur secondary to carcinoid tumors. Carcinoid syndrome is caused by a carcinoid tumor that secretes serotonin or other hormones into the bloodstream. Carcinoid tumors usually occur in the gastrointestinal tract, including the stomach, appendix, small intestine, colon, and rectum or in the lungs. Common symptoms include skin flushing, facial skin lesions, diarrhea, irritable bowel syndrome, cramping, difficulty breathing, and rapid heartbeat.
  • In some embodiments, the present disclosure includes methods of lowering plasma cholesterol, lowering plasma triglycerides, lowering plasma glycerol, lowering plasma free fatty acids in a patient by administering to said patient a therapeutically effective amount of a compound of the disclosure.
  • KAR5585 is also useful in the treatment and prevention of inflammatory disease, such as allergic airway inflammation (e.g., asthma).
  • As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.
  • As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” the enzyme with a compound of the disclosure includes the administration of a compound of the present disclosure to an individual or patient, such as a human, having the TPH1 enzyme, as well as, for example, introducing a compound of the disclosure into a sample containing a cellular or purified preparation containing the TPH1 enzyme.
  • As used herein, the term “individual” or “patient” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and, most preferably, humans.
  • As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • As used herein, the term “treating” or “treatment” refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology) or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
  • As used herein, the term “preventing” or “prevention” refers to inhibiting onset or worsening of the disease; for example, in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
  • KAR5585 can be administered to human patients in need of such treatment in appropriate dosages that will provide prophylactic and/or therapeutic efficacy. The dose required for use in the treatment or prevention of any particular disease or disorder will typically vary from patient to patient depending on, for example, particular compound or composition selected, the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors. The appropriate dosage can be determined by the treating physician.
  • KAR5585 can be administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles. Parenteral administration can involve subcutaneous injections, intravenous or intramuscular injections or infusion techniques. Treatment duration can be as long as deemed necessary by a treating physician. The compositions can be administered one to four or more times per day. A treatment period can terminate when a desired result, for example, a particular therapeutic effect, is achieved. Alternatively, a treatment period can be continued indefinitely.
  • In some embodiments, the pharmaceutical compositions can be prepared as solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules and the like). A tablet can be prepared by compression or molding. Compressed tablets can include one or more binders, lubricants, glidants, inert diluents, preservatives, disintegrants, or dispersing agents. Tablets and other solid dosage forms, such as capsules, pills and granules, can include coatings, such as enteric coatings.
  • Solid and liquid dosage forms can be formulated so that they conform to a desired release profile, e.g., immediate release, delayed release, and extended or sustained release.
  • The amount of KAR5585 to be administered will vary depending on factors such as the following: method of administration, release profile, and composition formulation. Typically, for KAR5585 in an oral dosage form to treat or prevent a disease, particularly PH/PAH/APAH/IPAH/FPAH, a typical dosage will be about 1 mg/kg/day to about 50 mg/kg/day and more typically from about 5 mg/kg/day to about 30 mg/kg/day, based on the weight of the patient. A most preferred active is Form 3. Individual oral dosage forms typically have from about 50 mg to about 3000 mg of KAR5585 and additional amounts of one or more pharmaceutically acceptable excipients. Other useful individual oral dosage forms can, by way of example, have KAR5585 in amounts of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg, 450 mg, 500 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, and about 1200 mg. Other amounts between 50 mg to 3000 mg are possible, for example, from about 325 mg to about 475 mg, from about 350 mg to about 500 mg, from about 375 to about 525 mg, from about 400 mg to about 550 mg, from about 425 mg to about 575 mg, from about 450 mg to about 600 mg, from about 475 mg to about 625 mg, from about 500 mg to about 650 mg, from about 525 mg to about 675 mg, from about 550 mg to about 700 mg, from about 575 mg to about 725 mg, from about 600 mg to about 750 mg, from about 625 mg to about 775 mg, from about 650 mg to about 800 mg, from about 675 mg to about 825 mg, from about 700 mg to about 850 mg, from about 725 mg to about 875 mg, from about 750 mg to about 900 mg, from about 775 mg to about 925 mg, from about 800 mg to about 950 mg, from about 825 to about 975, from about 850 mg to about 1000 mg, from about 900 mg to about 1150 mg, from about 1000 mg to about 1150 mg, from about 1100 mg to about 1250 mg, from about 1200 mg to about 1350 mg, and from about 1200 mg to about 1350 mg. Particularly preferred dosage regimens are 600 mg to 800 mg twice per day (BID). Especially preferred regimen embodiments are 600 mg BID and 800 mg BID.
  • “wt %” means weight percent based on the total weight of the composition or formulation.
  • Preferred dosage forms have the crystalline compound of Form 3 present in a proportion that is 90 wt % or more, and more preferably 95 wt % or more, by weight of any (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate present.
  • Dosage forms have the crystalline compound of Form 3 therein in any amount or proportion. Typical proportions include about 20 wt % or more, about 60 wt % or more, and about 90 wt % or more, based on the total weight of the dosage form (with the balance predominantly excipients, carriers, and vehicles). Particularly useful proportions are 25 wt % and 60 wt %.
  • Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration can include, for example, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Suspensions can include one or more suspending agents.
  • Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions and patches.
  • The Form 3 compound and compositions containing same can be administered in the form of an aerosol, which can be administered, for example, by a sonic nebulizer.
  • Pharmaceutical compositions suitable for parenteral administration can include the Form 3 compound together with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions.
  • Alternatively, the composition can be in the form of a sterile powder which can be reconstituted into a sterile injectable solutions or dispersion just prior to use.
  • The disclosure is further illustrated herein by the following non-limiting examples.
    • EXAMPLES
  • TABLE 5
    Abbreviations used in the examples include the following:
    Abbreviation Explanation
    % CV percent coefficient of variation
    β-hCG beta human chorionic gonadotropin
    5-HIAA 5-hydroxyindoleacetic acid
    5-HT 5-hydroxytryptamine (serotonin)
    Adjusted urine 5-HIAA the 5-HIAA measured in urine during 24 hours, adjusted for the mean 24-
    hour creatinine excretion on Days 1, 7, and 14
    AE adverse event
    AESI adverse event of special interest
    ALP alkaline phosphatase
    ALT alanine aminotransferase
    AST aspartate aminotransferase
    AUC area under the concentration versus time curve
    AUC0-12 area under the concentration versus time curve from time 0 to 12 hours
    after dosing, computed using the trapezoidal rule
    AUC0-24 area under the concentration versus time curve from time 0 to 24 hours
    after dosing, computed using the trapezoidal rule
    AUC0-inf area under the concentration versus time curve from time 0
    extrapolated to infinity
    AUC0-tau area under the concentration-time curve from time 0 to time of last
    quantifiable concentration
    BID twice daily (from Latin, bis in die)
    BILI bilirubin
    BLQ below the lower limit of quantitation
    BMI body mass index
    BP blood pressure
    C12 hr concentration, obtained 12 hr after an administered dose
    Cmax maximum (or peak) serum concentration
    Cmin minimum serum concentration
    CI confidence interval
    CL/F apparent oral clearance
    CRO contract research organization; Ce3, Inc.
    CRU clinical research unit
    ddHR placebo-adjusted mean change from Baseline in heart rate
    ddQTcF placebo-adjusted mean change from Baseline in QTcF
    ECG electrocardiogram
    eCRF electronic case report form
    Estimated urine 5-HIAA the 5-HIAA measured in urine during 24 hours, corrected for
    the estimated creatinine excretion based on subject weight,
    age, gender, and race
    FDA Food and Drug Administration
    GCP Good Clinical Practice
    GGT gamma-glutamyl transpeptidase
    Geo. geometric
    Hg millimeters of mercury
    HR heart rate
    ICF informed consent form
    ICH International Council for Harmonisation of Technical
    Requirements for Pharmaceuticals for Human Use
    IRB Institutional Review Board
    IUD intrauterine device
    KAR5417 an active metabolite of the investigational product KAR5585
    KAR5585 the investigational product; it is a prodrug of KAR5417
    LDH lactate dehydrogenase
    Max maximum
    Measured urine 5-HIAA the 5-HIAA measured in urine during 24 hours, without
    adjustment for daily variations in creatinine excretion
    MedDRA Medical Dictionary for Regulatory Activities
    Min minimum
    MOA mechanism of action
    N, n number
    OAE other significant adverse event
    OTC over the counter
    PAH pulmonary arterial hypertension
    Param. parameter
    PCS potentially clinically significant
    PD pharmacodynamics(s)
    PI Principal Investigator; the investigator who leads the study
    conduct at an individual study center. Every study center has
    a PI.
    PK pharmacokinetic(s)
    PT preferred term
    QD once daily (from Latin, quaque die)
    QTcF QT interval corrected for heart rate by applying Fridericia's
    formula; the unit for QTcF is milliseconds (msec)
    RAUC0-12 accumulation ratio for AUC0-12
    RCmax accumulation ratio for Cmax
    SAE serious adverse event
    SAP Statistical Analysis Plan
    SD standard deviation
    SOC system organ class
    Stat. statistical
    SRC Safety Review Committee
    Study drug investigational product, reference product (placebo), or both
    t1/2 apparent terminal half-life after oral administration
    TEAE treatment-emergent adverse event
    tmax time of maximum observed concentration
    TPH1 tryptophan hydroxylase 1
    Urine 5-HIAA/24 urine 5-HIAA/24 hours divided by corresponding total creatinine
    hours/g creatinine (gram) measured/24 hours
    WHODD World Health Organization Drug Dictionary
    • Methodology
  • Study KAR5585-101 was a first-in-human, Phase 1, randomized, double-blind, placebo-controlled, single-center trial conducted in 2 parts to assess the safety, tolerability, PK, cardiac conduction, and biomarkers of target engagement effects of single ascending doses (SAD, Part 1) and multiple ascending doses (MAD, Part 2) of KAR5585 in healthy adult subjects. Food effect was to be evaluated in Part 1, Period 2. Part 2 was permitted to begin before Part 1 was completed and, in each part, the data from each dose Cohort were to be reviewed for safety before the next dose Cohort was enrolled.
  • The KAR5585 administered doses were the following:
      • In Part 1 (SAD) Period 1 (fasting): 100 mg, 200 mg, 400 mg, 700 mg, 1200 mg, or 2000 mg or matching placebo in Cohorts 1 through 6, respectively
      • In Part 1 (SAD) Period 2 (fed, high-fat food effect): 400 mg in Cohort 3 only
      • In Part 2 (MAD): 100 mg (fasting), 100 mg (fed), 200 mg (fed), and 400 mg (fed) or matching placebo administered twice daily (BID) approximately every 12 hours for 27 doses in Cohorts 1 through 4, respectively.
      • Doses of KAR5585 and placebo were to be administered orally in a capsule dosage form.
  • Active drug capsules containing KAR5585 were provided in 50, 200, and 300 mg strengths; thus, more than 1 capsule was required to achieve some of the study doses.
    • Number of Patients (Planned and Analyzed):
  • Enrollment of 60 adult subjects (5 Cohorts of 12 subjects each) was originally planned in each part. In addition, up to 2 Cohorts of 12 subjects each may have been added to either or both parts, if necessary, based upon safety and PK data from the previous Cohorts, for a total of up to 168 subjects participating in the trial. Subjects were allowed to participate in Part 1 or Part 2, but not in both parts.
  • Part 1 had 6 Cohorts of 12 subjects each (for a total of 72 subjects) and Part 2 had 4 Cohorts of 12 subjects each (for a total of 48 subjects). In Part 1, the 12 subjects in Cohort 3 (400 mg)were studied twice, once under fasting conditions (Period 1) and once under fed conditions (Period 2) for food-effect assessment.
    • Test Product, Dose and Mode of Administration, Batch Number:
  • KAR5585, 50, 200 and 300 mg oral capsules administered as single doses of 100 mg, 200 mg, 400 mg, 700 mg, 1200 mg or 2000 mg (Part 1) or multiple doses of 100 mg, 200 mg or 400 mg every 12 hours for 14 days (27 doses) (Part 2). Batches were Batch PID-19JUL15-111 (50 mg), PID-19JUL15-110 (200 mg), PID-19JUL15-109 (300 mg)
    • Duration of Treatment:
  • Part 1 (SAD): Single dose under fasted conditions; subjects included in the fed Cohort were to receive a second dose of KAR5585 (same dose level) or placebo.
  • Part 2 (MAD): BID doses (separated by approximately 12 hours on Days 1 to 13) and a single AM dose on Day 14. One or more of the MAD Cohort could have been dosed once daily (QD).
    • Reference Therapy, Dose and Mode of Administration, Batch Number:
  • Placebo, oral capsules. Batch PID-19JUL15-108 (matching 50 mg); PID-19JUL15-107 (matching 200 mg and 300 mg)
    • Pharmacokinetics:
  • Pharmacokinetic characteristics of KAR5585 and KAR5417 were to be evaluated in Parts 1 and 2 by measuring drug concentrations in plasma and urine and calculating PK parameters. Biomarkers:
  • Biomarkers were to be evaluated in Part 2 by measuring concentrations of serotonin (5-hydroxytryptamine [5-HT]) in serum and 5-hydroxyindoleacetic acid (5-HIAA) in plasma and urine. As well, the relationship of biomarkers to PK parameters was to be evaluated.
    • Biomarker Analysis:
  • The biomarker analysis was to be based on the Biomarker Population (all subjects with evaluable biomarker measurements at baseline [Day 1 predose] and at least one after dosing [Day 7 or Day 14]). For analyses focused on the relationship between the PK parameters area under the concentration versus time curve (AUC) computed using the trapezoidal rule from time 0 to 24 hours after dosing (AUC0-24), minimum observed concentration (Cmin), and maximum observed concentration (Cmax), and biomarkers, only subjects who had all biomarkers and these PK parameters assessed were to be included.
  • Biomarker data were to be collected only in Part 2. The following biomarkers were to be analyzed:
      • Serum 5-HT
      • Plasma 5-HIAA
      • Urine 5-HIAA/24 hours (as measured, adjusted, estimated, and per gram creatinine)
  • The a priori primary biomarker endpoint was to be the change in plasma 5-HIAA concentration on Day 14 from Day 1. The null hypothesis to be tested was that there was no difference between the change from Day 1 predose to Day 14 between placebo and KAR5585.
  • Linear regression was to be performed using biomarker changes, absolute and relative (%), from Day 1, at predose on Day 7 or Day 14 versus AUC0-24, Cmax, and Cmin in corresponding study days. The slopes and corresponding 95% confidence intervals (CIs) were to be tabulated.
  • Summary statistics (mean, standard deviation [SD], median, minimum [Min], and maximum [Max]) were to be tabulated for each biomarker, by Cohort, with absolute and relative (%) changes from Day 1 predose. Corresponding time course plots of the mean measurement for each biomarker were to be displayed graphically. The time course for each individual subject, by Cohort, was also to be displayed graphically.
  • For each biomarker, least mean squared differences and the corresponding 95% CIs were to be estimated for change from baseline between KAR5585 treatment groups and placebo at Day 7 or Day 14. The values were to be tabulated with P values testing whether the difference of changes was equal to 0.
  • Absolute and relative changes in each biomarker at Day 7 and Day 14 from Day 1 predose versus AUC0-24, Cmax, and Cmin were to be displayed graphically.
  • Blood and urine sample collection details for biomarker analysis and the biomarker concentrations were to be listed.
    • Pharmacokinetic Analysis:
  • The PK analysis was to be based on the PK Concentration Population (all subjects receiving active study medication and having any measurable plasma concentration of study medication at any time point) and the PK Evaluable Population (all subjects with sufficient KAR5585 and KAR5417 concentration-time data to support PK analysis). Pharmacokinetic data were to be summarized descriptively.
    • Summary—Conclusions Pharmacokinetics Results: Part 1 SAD PK:
  • KAR5585 is a prodrug for the active tryptophan hydroxylate 1 (TPH1) inhibitor KAR5417. Following KAR5585 administration, KAR5585 was rapidly absorbed. The median time of maximum observed concentration (tmax) ranged between 1.5 and 3 hours postdose. Following administration of KAR5585, KAR5417 appeared rapidly in plasma, an observation consistent with rapid absorption of KAR5585 and efficient conversion to KAR5417.
  • The mean extent of systemic exposure to the active TPH1 inhibitor, KAR5417, as measured by mean AUC0-24 and AUC from time 0 extrapolated to infinity (AUC0-inf), appeared to increase in a dose-proportional manner between the 100 and 700 mg dose levels, with a 6.3-fold and 6.8-fold increase in mean AUC0-24 and mean AUC0-inf estimates, respectively, for a 7-fold increase in dose between the 100 mg dose and the 700 mg dose. At doses greater than 700 mg, there were less than dose-proportional increases in AUC0-24 and AUC0-inf values, with a 1.7-fold and 1.81-fold increase over the 2.86-fold increase in dose between 700 mg and 2000 mg. The mean apparent terminal half-life (t1/2) after oral administration of KAR5417 increased with increasing dose levels studied, and ranged between 4.7 hours (100 mg dose) and 22.6 hours (2000 mg dose) after oral administration of KAR5585.
  • Administration of KAR5585 under fed conditions increased the extent and peak of exposure of both KAR5585 and KAR5417, with KAR5417 mean AUC from time 0 extrapolated to infinity (AUC0-inf) increasing 1.8-fold from 3650 ng·hr/mL to 6710 ng·hr/mL and Cmax increasing 1.8-fold from 485 ng/mL to 860 ng/mL, under fasting and fed conditions, respectively. This was considered to be a clinically relevant change in exposure.
    • Part 2 MAD PK
  • KAR5585 was rapidly absorbed following oral administration.
  • Overall, the mean extent of systemic exposure to KAR5417, as measured by mean AUC from time 0 to 12 hours after dosing (AUC0-12) and mean AUC0-24, appeared to be comparable under fasted conditions (Part 2, Cohort 1; Day 1 AUC0-12=741 hr*ng/mL; Day 14 AUC0-24=1650 hr*ng/mL) relative to fed conditions (Part 2, Cohort 2; Day 1 AUC0-12=470 hr*ng/mL; Day 14 AUC0-24=1220 hr*ng/mL). This observation is in contrast to the food-effect comparison in Part 1, Cohort 3A and 3B KAR5585 400 mg).
  • In Part 1, a high-fat, high-calorie meal resulted in AUC0-inf of KAR5417 that was approximately 1.8-fold higher following drug administration of KAR5585 400 mg under fed conditions (AUC0-inf=6710 ng·hr/mL) relative to fasting conditions (AUC0-inf=3650 ng·hr/mL).
  • Steady-state plasma levels of KAR5417 were achieved by Day 7 as assessed by comparison of Day 7 and Day 14 AUC0-12 and concentration obtained 12 hours after an administered dose (C12 hr) values following BID oral administration of KAR5585 for 14 days. Accumulation ratios for KAR5417 compared accumulation ratio for Cmax (RCmax) and accumulation ratio for AUC0-12 (RAUC0-12) for Day7/Day 1 and Day 14/Day 1, and verified that steady-state was achieved by Day 7. The RAUC0-12 values for KAR5417 ranged from 2.19-2.57, 1.09-1.34 and 1.65-2.38 for the 100 mg, 200 mg, and 400 mg doses of KAR5585, respectively, suggesting that the PK of KAR5417 was independent of time, and that steady-state was achieved on Day 7 following repeated BID administration for14-days.
    • Biomarker Results
  • Dose- and time-dependent reductions were observed in 5-HIAA (a PD marker of 5-HT synthesis) in both plasma and urine. At the highest KAR5585 dose, 400 mg, mean percent change in plasma 5-HIAA concentration was 53.33 from Day 1 to Day 14, whereas mean percent change in subjects randomized to placebo was +20.12. Mean differences of both absolute and percent changes from Day 1 to Day 14 in plasma 5-HIAA concentration were statistically significant in favor of KAR5585 compared to placebo in each dose group and for all doses combined at Day 14.
  • There was a strong association between urine 5-HIAA/24 hours and KAR5585 dose. At the highest KAR5585 dose, 400 mg, mean percent change in measured urine 5-HIAA was
    Figure US20240041877A1-20240208-P00001
    50.85 from Day 1 to Day 14, whereas mean percent change in subjects randomized to placebo was +3.97. Mean differences of absolute and relative changes from Day 1 to day 14 were statistically significant in favor of KAR5585 in all dose groups except one (the relative change on Day 14 for the KAR5585 100 mg fasting dose group). Results were comparable in urine 5-HIAA/24 hours as adjusted, estimated, and per gram creatinine.
  • A strong relationship was seen between KAR5417 exposure and 5-HIAA reductions. A strong relationship between both plasma and urine 5-HIAA is supported by the observation that higher exposure to KAR5417, as measured by the PK parameters AUC0-24, Cmax, C12, and AUC0-12, was associated with greater reduction in 5-HIAA.
    • Safety Results Part 1, SAD, Period 1—Fasting Administration
  • KAR5585, administered as a single ascending oral dose (100 mg, 200 mg, 400 mg, 700 mg, 1200 mg or 2000 mg), was safe and well-tolerated in 54 healthy adult subjects.
    • Part 1, SAD, Period 2—Fed Administration (Food Effect):
  • KAR5585 400 mg, administered as a single oral dose under fed conditions, was well-tolerated in 9 healthy adult subjects.
    • Part 2, MAD—Fasting and Fed Administration:
  • KAR5585, administered as multiple ascending oral doses of 100 mg (fasting), 100 mg (fed), 200 mg (fed), and 400 mg (fed), BID for up to 14 days (27 doses), was safe and well-tolerated in 36 healthy adult subjects. One or more of the MAD Cohorts could have been dosed QD, but none was.
    • Conclusion
  • No safety, tolerability, PK, or cardiac-conduction concerns were identified during the course of the study. The administration of KAR5585 was well tolerated throughout the trial: in Part 1 (SAD) Period 1, at doses of 100 mg, 200 mg, 400 mg, 700 mg, 1200 mg or 2000 mg under fasting conditions; in Part 1 (SAD) Period 2, at a dose of 400 mg under fed conditions; and in Part 2 (MAD) at doses of 100 mg (fasting), 100 mg (fed), 200 mg (fed), and 400 mg (fed).
  • Following administration of KAR5585 (prodrug), KAR5417 (active TPH1 inhibitor) appeared rapidly in plasma, an observation consistent with rapid absorption of KAR5585 and efficient conversion to KAR5417. A strong relationship was seen between KAR5417 exposure and 5-HIAA reductions.
  • Neither the prodrug (KAR5585) nor the active drug (KAR5417) showed any tendency to increase QTcF in a dose-dependent manner.
  • As described in the PK SAP, the following PK parameters (as appropriate) were to be generated from KAR5585 and KAR5417 individual plasma concentrations from Part 1, Day 1; and Part 2, Days 1, 7, and 14 within the PK Evaluable Population:
      • Cmax1 Maximum concentration, obtained after first daily dose
      • Cmax2 Maximum concentration, obtained after second daily dose
      • C12 hr Concentration, obtained 12 hours after an administered dose
      • Cmax1/C12 hr Ratio of maximum concentration, obtained after first daily dose to the concentration, obtained 12 hours after first administered daily dose
      • Cmax1/D Dose-normalized Cmax, obtained after first daily dose
      • tmax1 Time to maximum concentration, obtained after first daily dose
      • tmax2 Time to maximum concentration, obtained after second daily dose
      • AUC0-tau Area under the concentration versus time curve from time 0 to the last quantifiable point within the dosing interval, using the trapezoidal rule
      • AUC0-12 Area under the concentration versus time curve from time 0 to 12 hours after dosing, using the trapezoidal rule
      • AUC0-24 Area under the concentration versus time curve from time 0 to 24 hours after dosing, using the trapezoidal rule
      • AUC0-24/D Dose-normalized AUC0-24 (Day for SAD, Day 1 and Day 7 for MAD)
      • λz Apparent terminal rate constant after oral administration
      • t1/2 Apparent terminal half-life after oral administration
      • AUC0-inf Area under the concentration versus time curve from time 0 to infinity (SAD only)
      • AUC Extrap Percent of AUC0-∞ extrapolated after the last quantifiable concentration
      • CL/F Apparent oral clearance
      • CLss/F Apparent oral clearance at steady-state
      • Vz/F Apparent oral volume of distribution dependent during the terminal phase
        The doses administered were the following:
      • In Part 1 (SAD) Period 1: single KAR5585 doses of 100 mg, 200 mg, 400 mg, 700 mg, 1200 mg, or 2000 mg or matching placebo in Cohorts 1 through 6, respectively.
      • In Part 1 (SAD) Period 2: 400 mg in Cohort 3 only.
      • In Part 2 (MAD): KAR5585 100 mg (fasting), 100 mg (fed), 200 mg (fed), and 400 mg (fed) or matching placebo administered BID (approximately every 12 hours) for 27 doses in Cohorts 1 through 4, respectively.
  • Doses were administered using the capsule strengths or sizes shown in Table 9.
  • TABLE 6
    Doses and Capsule Strengths Administered
    Part 1 (SAD) Part 2 (MAD)
    Dose Capsules Administered Dose Capsules Administered
    Cohort (mg) (KAR5585 or Placebo) (mg) (KAR5585 or Placebo)
    1 100 Two 50 mg or matching placebo 100 Two 50 mg or matching placebo
    2 200 One 200 mg or matching placebo 100 Two 50 mg or matching placebo
    3 400 Two 200 mg or matching placebo 200 One 200 mg or matching placebo
    4 700 Two 200 mg + one 300 mg or 400 Two 200 mg or matching placebo
    matching placebo
    5 1200 Four 300 mg or matching placebo
    6 2000 Six 300 mg or matching placebo +
    one 200 mg or matching placebo
    Abbreviations: MAD, multiple ascending dose; SAD, single ascending dose
    • Pharmacokinetics Results and Tabulations of Individual Subject Data: Plasma Concentrations:
  • The locations of individual and mean estimates of plasma KAR5585 and KAR5417 concentrations are tabulated below:
  • Mean plasma concentration-time profiles of KAR5585 and KAR5417 following administration of 100-2000mg KAR5585 under fasting conditions in healthy adult subjects—Cohorts 1-6 (linear and semi-log scales) are presented in FIGS. 3 a and 3 b 5 and FIGS. 4 a and 4 b , respectively. Mean plasma concentration time profiles of KAR5585 and KAR5417 following administration of 400 mg of KAR5417 under fasting and fed conditions—Cohorts 3A and 3B (linear and semi-log scales) are presented in 18 a and 18 b and FIGS. 19 a and 19 b , respectively.
  • The mean peak plasma KAR5585 concentrations were reached between 1.5 and 3 hours following single-dose fasting oral administration of 100, 200, 400, 700, 1200 and 2000 mg KAR5585. For doses of 100 to 1200 mg KAR5585 the time to peak plasma concentrations of KAR5585 were reached between 0.75 and 6 hours. For the 2000 mg dose the time to peak plasma concentrations of KAR5585 ranged from 0.75 to 12 hours. Mean KAR5585 concentrations increased with increasing doses. KAR5585 concentrations remained above the LLOQ (4.94 ng/mL) up to 4 hours in most subjects following the 100 mg dose, in one subject KAR5585 was BLQ at all time-points and in another subject KAR5585 was measurable up to 8 hours. KAR5585 concentrations remained above the LLOQ (4.94 ng/mL) up to 12 hours following the 400, 700, 1200 and 200 mg doses of KAR5585.
  • The mean peak plasma KAR5417 concentrations were reached between 1.5 and 3 hours following single-dose fasting oral administration of 100, 200, 400, 700, 1200 and 2000 mg KAR5585. For doses of 100 to 1200 mg KAR5585 the time to peak plasma concentrations of KAR5417 were reached between 2 and 6 hours. For the 2000 mg dose of KAR5585 the time to peak plasma concentrations of KAR5417 ranged from 3 to 12 hours. Mean KAR5417 concentrations increased with increasing doses. KAR5417 concentrations remained above the LLOQ (7.65 ng/mL) up to 12, 24, 36, 48, 48 and 72 hours following the 100, 200, 400, 700, 1200 and 2000 mg doses, respectively. The plasma concentrations of KAR5417 were approximately 10-fold higher than the plasma concentrations of KAR5585.
  • Following administration of 400 mg KAR5585, peak mean plasma KAR5585 concentrations were observed at later times and sustained longer under fed relative to fasting conditions (tmax was 3.0 and 2.07 hour postdose, for fed and fasted states, respectively). The peak mean concentrations were approximately 320% higher following drug administration under fedconditions (Cmax=169 ng/mL) relative to fasting conditions (Cmax=52.8 ng/mL). KAR5585 mean concentrations following drug administration under fed conditions were higher relative to fasting conditions and KAR5585 levels were measurable to 24 hours in the fed state, relative to 12 hours in the fasted state.
  • Following administration of 400 mg KAR5585, peak mean plasma KAR5417 concentrations were observed at similar times under fasting and fed conditions (4 hour postdose). The peak mean concentrations were approximately 177% higher following drug administration underfed conditions (Cmax=860 ng/mL) relative to fasting conditions (Cmax=485 ng/mL). KAR5417 mean concentrations following drug administration under fed conditions were higher relative to fasting conditions and KAR5585 levels were measurable to 72 hours in the fed state, relative to 36 hours in the fasted state.
  • TABLE 7
    (Summary of the Mean Pharmacokinetic Parameters of KAR5585 Following a Single Oral Dose of KAR5585 (Cohorts 1-6) (Pharmacokinetic Evaluable Population))
    Dose Stat. tma x a Cmax Cmax/D C12 Cmax/ AUC0-tau AUC0-12 AUC0-24 AUC0-24/D AUC0-∞ Vz/F CL/F
    (mg) Param. t1 (hr) (hr) (ng/ml) [(ng/mL)/mg] (ng/ml) C12 (hr*ng/ml) (hr*ng/ml) (hr*ng/ml) [(hr*ng/ml)/mg] (hr*ng/ml) (L) (L/hr)
    100 N 3 8 8 8 0 0 8 3 3 3 3 3 3
    (fasted) Mean 1.89 1.50 13.9 0.139 BLQ ND 35.0 48.1 49.6 0.496 49.5 5680 2210
    Cohort 1 SD 1.11 0.750, 6.00 5.35 0.0535 NR ND 24.9 16.2 16.6 0.166 16.5 2830 849
    CV % 58.5 NA 38.4 38.4 NR ND 71.1 33.7 33.4 33.4 33.4 49.9 38.5
    Geo. Mean 1.71 NA 13.2 0.132 BLQ ND 27.4 46.2 47.5 0.475 47.5 5190 2110
    Geo. CV % 58.2 NA 33.6 33.6 NR ND 91.3 36.8 37.9 37.9 37.9 56.8 37.9
    200 N 7 8 8 8 0 0 8 7 7 7 7 7 7
    (fasted) Mean 3.63 1.78 19.2 0.0961 BLQ ND 61.4 85.8 97.1 0.485 99.5 10300 2220
    Cohort 2 SD 2.02 0.750, 3.00 7.84 0.0392 NR ND 27.3 20.5 25.9 0.130 28.0 4060 925
    CV % 55.7 NA 40.8 40.8 NR ND 44.5 23.8 26.7 26.7 28.1 39.5 41.6
    Geo. Mean 3.17 NA 17.5 0.0875 BLQ ND 52.0 83.3 93.4 0.467 95.3 9610 2100
    Geo. CV % 61.6 NA 53.0 53.0 NR ND 85.5 28.0 33.1 33.1 35.4 40.5 35.4
    400 N 7 9 9 9 7 7 9 8 7 7 7 7 7
    (fasted) Mean 4.08 2.07 52.8 0.132 7.45 8.44 219 246 297 0.742 302 8330 1480
    Cohort 3A SD 0.635 1.00, 6.00 34.0 0.0851 0.879 4.64 112 86.6 90.4 0.226 93.2 2240 606
    CV % 15.5 NA 64.4 64.4 11.8 55.0 51.0 35.3 30.5 30.5 30.8 26.9 41.1
    Geo. Mean 4.04 NA 42.0 0.105 7.40 7.20 176 231 283 0.707 288 8100 1390
    Geo. CV % 16.0 NA 88.1 88.1 12.0 72.0 103.0 40.4 36.4 36.4 37.0 25.3 37.0
    400 N 9 9 9 9 9 9 9 9 9 9 9 9 9
    (fed) Mean 4.45 3.00 169 0.422 21.0 9.35 868 761 885 2.21 915 2780 449
    Cohort 3B SD 1.27 1.50, 6.00 36.2 0.0904 7.97 4.39 152 86.7 128 0.321 148 549 85.2
    CV % 28.6 NA 21.4 21.4 38.0 47.0 17.5 11.4 14.5 14.5 16.1 19.8 18.9
    Geo. Mean 4.26 NA 165 0.413 19.7 8.36 854 756 876 2.19 903 2730 443
    Geo. CV % 32.5 NA 22.6 22.6 38.4 55.7 19.6 12.3 15.8 15.8 17.7 21.2 17.7
    700 N 8 8 8 8 6 6 8 8 8 8 8 8 8
    (fasted) Mean 3.46 1.75 99.4 0.142 10.7 12.2 386 392 432 0.617 436 9120 1810
    Cohort 4 SD 0.561 1.00, 3.00 29.3 0.0418 4.73 6.65 135 127 148 0.211 150 4190 701
    CV % 16.2 NA 29.4 29.4 44.3 54.4 35.1 32.3 34.2 34.2 34.4 45.9 38.8
    Geo. Mean 3.42 NA 95.2 0.136 9.84 10.5 362 372 409 0.584 412 8390 1700
    Geo. CV % 16.8 NA 33.7 33.7 47.2 69.7 41.7 36.5 38.0 38.0 38.1 45.0 38.1
    1200 N 8 9 9 9 7 7 9 8 8 8 8 8 8
    (fasted) Mean 3.58 2.00 83.0 0.0692 11.8 9.78 364 402 453 0.378 462 16900 3850
    Cohort 5 SD 1.35 1.00, 4.00 49.0 0.0408 4.33 5.27 189 164 182 0.152 186 12300 4080
    CV % 37.8 NA 59.0 59.0 36.8 53.9 51.9 40.7 40.2 40.2 40.2 72.7 106
    Geo. Mean 3.40 NA 68.1 0.0568 11.0 8.63 296 356 400 0.333 406 14500 2960
    Geo. CV % 33.9 NA 85.0 85.0 44.4 59.3 93.9 67.4 70.9 70.9 73.0 58.7 73.0
    2000 N 8 9 9 9 8 8 9 9 9 9 8 8 8
    (fasted) Mean 4.84 2.00 104 0.0522 37.4 5.70 773 624 806 0.403 778 25100 3820
    Cohort 6 SD 1.05 0.750, 12.0 43.6 0.0218 36.7 3.98 418 239 377 0.188 383 21900 3560
    CV % 21.6 NA 41.8 41.8 98.1 69.9 54.0 38.3 46.7 46.7 49.2 87.5 93.1
    Geo. Mean 4.76 NA 95.1 0.0475 26.2 4.11 638 558 696 0.348 667 20600 3000
    Geo. CV % 20.2 NA 51.6 51.6 105 125 86.9 63.1 73.3 73.3 75.2 63.8 75.2
    aMedian and range (Min, Max) presented;
    Abbreviations: AUC0-12, area under the concentration versus time curve from time 0 to 12 hours after dosing, using the trapezoidal rule; AUC0-24, area under the concentration versus time curve from time 0 to 24 hours after dosing, using the trapezoidal rule; AUC0-tau, area under the concentration-time curve from time 0 to time of last quantifiable concentration; BLQ, below the limit of quantitation; CL/F, apparent oral clearance; CV, coefficient of variation; Geo., geometric; hr, hour; N, number; NA, not applicable; NR, not reported; ND, not determined; Param., parameter; SD, standard deviation; Stat., statistical; t½, apparent terminal half-life after oral administration; tmax, time of maximum observed concentration; Vz/F, volume of distribution during the terminal phase
  • TABLE 8
    (Summary of the Mean Pharmacokinetic Parameters of KAR5417 Following a Single Oral Dose of KAR5585 (Cohorts 1-6) (Pharmacokinetic Evaluable Population))
    Dose Stat. t1/2 tmax a Cmax Cmax/D C12 Cmax/ AUC0-tau AUC0-12 AUC0-24 AUC0-24/D AUC0-∞
    (mg) Param. (hr) (hr) (ng/ml) (ng/ml)/mg (ng/ml) C12 (hr*ng/mL) (hr*ng/ml) (hr*ng/ml) (hr*ng/mL)/mg (hr*ng/ml)
    100 N 8 9 9 9 8 8 9 8 8 8 8
    (fasted) Mean 4.67 4.00 107 1.07 23.8 5.23 718 704 847 8.47 886
    Cohort 1 SD 1.35 2.00, 6.00 44.2 0.442 8.61 1.64 358 172 251 2.51 293
    CV % 28.9 NA 41.5 41.5 36.1 31.3 49.8 24.5 29.6 29.6 33.1
    Geo. Mean 4.51 NA 93.1 0.931 22.5 5.04 605 686 816 8.16 847
    Geo. CV % 28.7 NA 72.6 72.6 36.6 28.7 83.2 24.2 29.1 29.1 32.6
    200 N 9 9 9 9 9 9 9 9 9 9 9
    (fasted) Mean 5.40 3.00 160 0.801 32.9 4.92 1120 947 1160 5.81 1230
    Cohort 2 SD 1.08 2.00, 4.00 98.2 0.491 21.5 1.07 816 629 781 3.90 838
    CV % 20.0 NA 61.3 61.3 65.5 21.7 72.5 66.4 67.2 67.2 68.0
    Geo. Mean 5.29 NA 132 0.658 27.3 4.82 866 771 940 4.70 988
    Geo. CV % 21.6 NA 78.8 78.8 72.1 22.4 94.2 79.2 80.8 80.8 83.6
    400 N 9 9 9 9 9 9 9 9 9 9 9
    (fasted) Mean 11.3 4.00 485 1.21 82.5 6.04 3500 2690 3250 8.12 3650
    Cohort 3A SD 9.24 3.00, 6.00 183 0.456 30.5 1.44 1440 1020 1210 3.02 1490
    CV % 81.6 NA 37.7 37.7 37.0 23.9 41.0 38.0 37.2 37.2 40.9
    Geo. Mean 9.29 NA 444 1.11 75.2 5.90 3120 2460 2970 7.43 3280
    Geo. CV % 67.8 NA 52.5 52.5 55.6 22.9 63.4 52.9 53.9 53.9 59.1
    400 N 9 9 9 9 9 9 9 9 9 9 9
    (fed) Mean 20.5 4.00 860 2.15 169 5.39 6440 4240 5430 13.6 6710
    Cohort 3B SD 5.21 3.00, 6.00 224 0.561 34.7 2.06 1000 790 816 2.04 1070
    CV % 25.4 NA 26.1 26.1 20.6 38.2 15.6 18.6 15.0 15.0 15.9
    Geo. Mean 19.8 NA 831 2.08 165 5.03 6360 4170 5370 13.4 6630
    Geo. CV % 33.3 NA 28.8 28.8 20.8 42.2 17.3 20.2 16.2 16.2 17.9
    700 N 9 9 9 9 9 9 9 9 9 9 9
    (fasted) Mean 13.5 4.00 778 1.11 144 5.97 5840 4350 5310 7.58 6020
    Cohort 4 SD 6.04 2.00, 6.00 537 0.767 126 1.53 4350 3010 3800 5.43 4410
    CV % 44.9 NA 69.0 69.0 87.4 25.5 74.4 69.3 71.5 71.5 73.2
    Geo. Mean 12.1 NA 544 0.777 93.8 5.80 3870 3050 3720 5.31 4170
    Geo. CV % 53.6 NA 157 157 153 26.6 180 153 149 149 150
    1200 N 9 9 9 9 9 9 9 9 9 9 9
    (fasted) Mean 14.9 6.00 896 0.747 213 4.53 7700 5350 6790 5.66 7970
    Cohort 5 SD 5.60 3.00, 6.00 453 0.377 130 1.40 4000 2710 3480 2.90 4040
    CV % 37.5 NA 50.5 50.5 60.9 30.9 52.0 50.6 51.2 51.2 50.7
    Geo. Mean 14.0 NA 764 0.636 175 4.36 6580 4580 5810 4.84 6880
    Geo. CV % 41.5 NA 75.0 75.0 81.0 29.0 73.0 73.3 72.8 72.8 69.5
    2000 N 9 9 9 9 9 9 9 9 9 9 9
    (fasted) Mean 22.6 5.00 1080 0.542 354 4.23 10600 6910 9080 4.54 10900
    Cohort 6 SD 5.07 3.00, 12.0 345 0.173 271 1.94 3510 2110 3000 1.50 3570
    CV % 22.4 NA 31.9 31.9 76.6 45.8 33.3 30.6 33.0 33.0 32.9
    Geo. Mean 22.1 NA 1030 0.515 280 3.67 9880 6550 8520 4.26 10200
    Geo. CV % 22.4 NA 37.2 37.2 83.8 70.2 43.9 38.3 42.6 42.6 43.0
    aMedian and range (Min, Max) presented; Vz/F and CL/F were not calculated for KAR5417 as this is a metabolite of KAR5585
    Abbreviations: AUC0-12, area under the concentration versus time curve from time 0 to 12 hours after dosing, using the trapezoidal rule; AUC0-24, area under the concentration versus time curve from time 0 to 24 hours after dosing, using the trapezoidal rule; AUC0-tau, area under the concentration-time curve from time 0 to time of last quantifiable concentration; BLQ, below the limit of quantitation; CL/F, apparent oral clearance; CV, coefficient of variation; Geo., geometric; hr, hour; Max, maximum; Min, minimum; N, number; NA, not applicable; NR, not reported; ND, not determined; Param., parameter; SD, standard deviation; Stat., statistical; t½, apparent terminal half-life after oral administration; tmax, time of maximum observed concentration; Vz/F, volume of distribution during the terminal phase.
    • Pharmacokinetics of KAR5417:
  • KAR5417 is the active metabolite of the prodrug, KAR5585. Following administration of KAR5585, KAR5417 appeared rapidly in plasma, an observation consistent with rapid absorption of KAR5585 and efficient conversion to KAR5417; all subjects had measurable concentrations of KAR5417 by 0.25 hours postdose, and the median tmax was comparable across all fasting Cohorts and ranged between 3 and 6 hours postdose.
  • In general, mean peak plasma KAR5417 concentrations, as measured by mean Cmax, appeared to increase in a dose-proportional manner from 100-700 mg, mean Cmax values increased 7.27-fold over the 7-fold increase in dose between the 100 mg dose (Cohort 1) and the 700 mg dose (Cohort 4). At doses greater than 700 mg, there was a moderate increase in Cmax values, with a 1.38-fold increase over the 2.86-fold increase in dose between 700 mg (Cohort 4) and 2000 mg (Cohort 6).
  • Overall, the mean extent of systemic exposure to KAR5417, as measured by mean AUC0-24 and AUC0-inf, appeared to increase in a dose-proportional manner between the 100 and 700 mg dose levels, with a 6.3-fold and 6.8-fold increase in mean AUC0-24 and mean AUC0-inf estimates, respectively, for a 7-fold increase in dose between the 100 mg dose (Cohort 1) and the 700 mg dose (Cohort 4). At dose levels greater than 700 mg, there was a less than dose-proportional increase in AUC0-24 and AUC0-inf values, with a 1.7-fold and 1.81-fold increase over the 2.86-fold increase in dose between 700 mg (Cohort 4) and 2000 mg (Cohort 6).
  • Administration of the KAR5585 under fed conditions increased the extent and peak of exposure of KAR5417 with mean AUCs (AUC0-inf) increasing 1.8-fold from 3650 ng·hr/mL to 6710 ng·hr/mL and Cmax increasing 1.8-fold from 485 ng/mL to 860 ng/mL, under fasting and fed conditions, respectively. This was considered to be a clinically relevant change in exposure.
  • The mean apparent elimination half-life of KAR5417 increased with increasing dose levels studied, and ranged between 4.67 (100 mg dose) and 22.6 hours (2000 mg dose) after oral administration of KAR5585. The elimination phase of KAR5417 was characterized based on the last 3 to 6 measurable time points.
    • Dose Proportionality Assessment of KAR5585 and KAR5417
  • Scatter plots of individual plasma KAR5585 and KAR5417 Cmax and AUC0-inf, versus KAR5585 dose are presented in FIGS. 5 a and 5 b and FIGS. 6 a and 6 b , respectively.
  • The dose proportionality assessment of plasma KAR5585 and KAR5417 PK parameters are summarized in Table 18. Dose proportionality was assessed for KAR5585 and KAR5417 after single-dose administration using the power model. From plots of exposure (e.g., Cmax, AUC0-12, AUC0-tau, and/or AUC0-inf) versus dose, increases in exposure were deemed dose proportional if the 90% confidence intervals (CIs) for the slope (β in the following equation(s) included unity (e.g., 1.0).
  • TABLE 9
    (Summary of Dose Proportionality Analysis of Plasma KAR5417 and KAR5585
    Pharmacokinetic Parameters AUC0-12, AUC0-inf, AUC0-tau, and Cmax Following
    100 to 2000 mg of KAR5585 Administered as a Single Oral Dose under
    Fasting Conditions (Pharmacokinetic Evaluable Population))
    Degrees 95%
    Pharmacokinetic of Standard Confidence
    Parameter Analyte Effect Estimate Freedom Error Interval
    AUC0-12 KAR5417 Intercept 14.5 51 NC NC
    Slope (β) 0.812 51 0.0898  0.632-0.992
    KAR5585 Intercept 1.51 41 NC NC
    Slope (β) 0.794 41 0.0822  0.629-0.960
    AUC0-inf KAR5417 Intercept 12.3 51 NC NC
    Slope (β) 0.891 51 0.0915 0.707-1.07
    KAR5585 Intercept 1.46 39 NC NC
    Slope (β) 0.822 39 0.0908 0.638-1.01
    AUC0-tau KAR5417 Intercept 6.54 52 NC NC
    Slope (β) 0.975 52 0.101 0.772-1.18
    KAR5585 Intercept 0.258 49 NC NC
    Slope (β) 1.04 49 0.105 0.829-1.25
    Cmax KAR5417 Intercept 1.95 52 NC NC
    Slope (β) 0.845 52 0.0938 0.657-1.03
    KAR5585 Intercept 0.534 49 NC NC
    Slope (β) 0.707 49 0.0827  0.541-0.873
    Dose proportionality was not rejected if the 95% CI for the slope included the value of 1.
    Abbreviations: AUC0-12, area under the concentration versus time curve from time 0 to 12 hours after dosing, using the trapezoidal rule; AUC0-inf, area under the concentration versus time curve from time 0 extrapolated to infinity; AUC0-tau, area under the concentration-time curve from time 0 to time of last quantifiable concentration; Cmax, maximum observed concentration; CI, confidence interval NC, not calculated.
  • The 95% CI for the slope of from the power model for AUC0-inf and Cmax for KAR5417 included the value of 1. Therefore, dose proportionality was concluded for AUC0-inf and Cmax for KAR5417 in the studied dose range of 100 to 2000 mg KAR5585. Therefore, for KAR5417 AUC0-inf and Cmax PK parameters, conditions of statistical linearity were met.
  • The 95% CI for the slope of from the power model for AUC0-inf and Cmax for KAR5585 did not include the value of 1. Therefore, dose proportionality was not concluded for AUC0-inf and Cmax for KAR5585 in the studied dose range of 100 to 2000 mg KAR5585. Therefore, for KAR5585 AUC0-inf and Cmax PK parameters, conditions of statistical linearity were not met and exposure as assessed by AUC0-inf and Cmax appeared to increase in a less than dose proportional manner.
    • Food Effect Assessment of KAR5585 and KAR5417:
  • The statistical results for the food effect assessment following administration of 400 mg KAR5585 under fasting and fed conditions—Cohorts 3A and 3B is presented in Table 10.
  • TABLE 10
    (Summary of Statistical Comparison of Plasma KAR5585 and
    KAR5417 Pharmacokinetic Parameters AUC0-tau, AUC0-inf, Cmax:
    Food Effect Assessment [Cohort 3B (Fed) Versus Cohort
    3A (Fasting)] (Pharmacokinetic Evaluable Population))
    Geometric Mean
    Cohort 3B Cohort 3A Geometric LS
    Parameter (Fed) (Fasting) Mean Ratio 90% CI
    KAR5585
    Cmax 165 42.0 3.92 2.51-6.13
    AUC0-tau 854 176 4.84 3.10-7.56
    AUC0-inf 903 288 3.14 2.42-4.07
    KAR5417
    Cmax 831 444 1.87 1.47-2.38
    AUC0-tau 6360 3120 2.04 1.54-2.69
    AUC0-inf 6630 3280 2.02 1.56-2.61
    Parameters were In-transformed prior to analysis.
    Geometric LS means are calculated by exponentiating the LS means from the ANOVA. Geometric Mean Ratio = (test/reference)
    Cohort 3A (Fasting): 400 mg KAR5585 Administered as a Single Oral Dose Under Fasting Conditions (reference)
    Cohort 4B (Fed): 400 mg KAR5585 Administered as a Single Oral Dose Under Fed Conditions (test)
    Abbreviations: ANOVA, analysis of variance; AUC0-inf, area under the concentration versus time curve from time 0 extrapolated to infinity; AUC0-tau, area under the concentration-time curve from time 0 to time of last quantifiable concentration; CI, confidence interval; Cmax, maximum observed concentration; LS means, least-squares means.
  • The exposure as assessed by AUC0-tau and AUC0-inf, to KAR5585 following administration of 400 mg KAR5585 under fed conditions was approximately 3.1-4.8-fold relative to when the KAR5585 was administered under fasting conditions. Peak exposure (Cmax) was approximately 3.9-fold higher. The exposure as assessed by AUC0-tau and AUC0-inf, to KAR5417 following administration of the 400 mg KAR5585 under fed conditions was approximately 2-fold higher relative to when the KAR5585 was administered under fasting conditions. Peak exposure was approximately 1.87-fold higher. The 90% CI for Cmax, AUC0-tau, and AUC0-inf were outside the commonly accepted range of 80-125% suggesting that there was a food effect for AUC0-tau and AUC0-inf, and Cmax for KAR585 and KAR5417. The increase in systemic exposure was considered to be a clinically relevant effect on the oral absorption pharmacokinetics of KAR5585 and KAR5417.
    • Urine Concentrations:
  • The locations of individual and mean estimates of urine KAR5585 and KAR5417 concentrations and cumulative excretion tabulated below:
  • Mean total percent of dose excreted in urine as KAR5417 and mean cumulative urine recoveries in fasted healthy volunteers following administration of 100-2000 mg KAR5585 under fasting conditions in healthy adult subjects—Cohorts 1-6 are presented in FIGS. 7 and 8 .
  • Mean urine PK parameters for KAR5585 and KAR5417 in healthy volunteers following a single oral dose of KAR5585—Cohorts 1-6 are presented in Table 12 and Table 13, respectively.
  • In almost all subjects, KAR5585 could not be quantified in urine samples and the amount excreted (Ae) in urine was less than 0.004% of the administered dose at all dose levels (Table 20).
  • KAR5417 could be quantified in urine samples and the amount excreted (Ae) in urine ranged from 0.102 to 0.331% of the administered dose (Table 13), assuming complete conversion of KAR5585 to KAR5417. The highest amount of KAR5417 excreted, 0.331% of the dose.
  • FIG. 7 was in the 400 mg fed Cohort (Cohort 3B) and was consistent with the effect of food to increase oral absorption of KAR5585. In general, the amount of KAR5417 excreted in urine was independent of dose in fasted subjects. The majority of urinary excretion of KAR5417 occurred in the first 24 hours after an oral dose of KAR5585.
  • Renal clearance of KAR5417 was calculated from the area under the plasma time concentration curve (AUC0-96) for KAR5417 and the amount of KAR5417 recovered in urine (Table 21). Renal clearance of KAR5417 ranged from 157 to 296 mL/hr and was largely independent of administered dose of KAR5585 (Table 21).
  • The measurement of KAR5585 and KAR5417 in human urine indicates that renal clearance and elimination of KAR5585 and KAR5417 was a very minor route of elimination of KAR5585 following single dose administration in humans.
  • TABLE 11
    (Mean (±SD) Urine PK Parameters for KAR5585 in Healthy Volunteers Following
    a Single Oral Dose of KAR5585 (Pharmacokinetic Evaluable Population))
    Stat. Amount Total Plasma AUC0-96
    Dose (mg) Param. Excreted(Ae) (μg) Excreted (%) (ng · hr/mL) CLR (mL/hr)
    100 N 9 9 3 3
    Mean 0 0 49.7 0
    SD 0 0 16.6 0
    CV % 0 0 33.4 0
    200 N 9 9 7 7
    Mean 0 0 100 0
    SD 0 0 27.7 0
    CV % 0 0 27.7 0
    400 N 9 9 7 7
    (Fasted) Mean 13.8 0.00346 303 51.5
    SD 24.6 0.00616 93.2 88.9
    CV % 178 178 30.8 173
    400 N 9 9 9 9
    (Fed) Mean 0 0 917 0
    SD 0 0 147 0
    CV % 0 0 16.0 0
    700 N 9 9 8 9
    Mean 0 0 436 0
    SD 0 0 150 0
    CV % 0 0 34.4 0
    1200 N 9 9 8 9
    Mean 0 0 463 0
    SD 0 0 186 0
    CV % 0 0 40.1 0
    2000 N 9 9 8 8
    Mean 1.50 0.0000751 779 2.30
    SD 4.51 0.000225 384 6.50
    CV % 300 300 49.3 283
    Abbreviations: CV, coefficient of variation; N, number; Param., parameter; SD, standard deviation; Stat., statistical D, standard deviation.
  • TABLE 12
    Mean (±SD) Urine PK Parameters for KAR5417 in Healthy Volunteers Following
    a Single Oral Dose of KAR5585 (Pharmacokinetic Evaluable Population)
    Stat. Amount Total Excreted Plasma AUC0-96 CLR
    Dose (mg) Param. Excreted(Ae) (μg) (%) (ng · hr/mL) (mL/hr)
    100 N 9 9 8 8
    Mean 233 0.245 889 296
    SD 123 0.129 293 86.1
    CV % 52.7 52.7 33.0 29.1
    200 N 9 9 9 9
    Mean 211 0.111 1240 160
    SD 169 0.0885 838 66.8
    CV % 80.0 80.0 67.8 41.8
    400 N 9 9 9 9
    (fasted) Mean 769 0.202 3630 217
    SD 376 0.0986 1450 57.2
    CV % 48.8 48.8 39.9 26.4
    400 N 9 9 9 9
    (fed) Mean 1260 0.331 6590 191
    SD 259 0.0679 1020 28.9
    CV % 20.5 20.5 15.4 15.1
    700 N 9 9 9 9
    Mean 998 0.150 5990 191
    SD 515 0.0773 4360 50.8
    CV % 51.6 51.6 72.8 26.5
    1200 N 9 9 9 9
    Mean 1170 0.102 7910 157
    SD 463 0.0405 4010 32.8
    CV % 39.6 39.6 50.6 20.9
    2000 N 9 9 9 9
    Mean 2130 0.112 10700 206
    SD 967 0.0508 3480 67.9
    CV % 45.5 45.5 32.6 32.9
    Abbreviations: CV, coefficient of variation; N, number; PK, pharmacokinetic; Param., parameter; SD, standard deviation; Stat., statistical.
    • Discussion of Pharmacokinetics Results
  • KAR5585 is a prodrug for the active TPH1 inhibitor KAR5417. Following KAR5585 administration, KAR5585 was rapidly absorbed the median tmax ranged between 1.5 and 3 hours postdose. Following administration of KAR5585, KAR5417 appeared rapidly in plasma, an observation consistent with rapid absorption of KAR5585 and efficient conversion to KAR5417; the median tmax was comparable across all fasting Cohorts and ranged between 3 and 6 hours postdose. Following single oral doses of 100 mg to 2000 mg KAR5588 in healthy subjects, the total extent of exposures (AUC0-tau, and AUC0-inf) and peak of exposure to KAR5855 and KAR5417 appeared to increase in a proportional manner from 100-700 mg, and in a less than dose proportional manner from 700 mg to 2000 mg.
  • The mean extent of systemic exposure to the prodrug, KAR5585, as measured by mean AUC0-tau and AUC0-inf, appeared to increase in a dose proportional manner between the 100 and 700 mg dose levels, with a 8.7-fold and 8.8-fold increase in mean AUC0-24 and mean AUC0-inf estimates, respectively, for a 7-fold increase in dose between the 100 mg dose (Cohort 1) and the 700 mg dose (Cohort 4). At dose greater than 700 mg, there was a less than dose-proportional increase in AUC0-24 and AUC0-inf values, with a 1.86-fold and 1.78-fold increase over the 2.86-fold increase in dose between 700 mg (Cohort 4) and 2000 mg (Cohort 6).
  • The mean extent of systemic exposure to the active TPH1 inhibitor, KAR5417, as measured by mean AUC0-24 and AUC0-inf, appeared to increase in a dose proportional manner between the 100 and 700 mg dose levels, with a 6.3-fold and 6.8-fold increase in mean AUC0-24 and mean AUC0-inf estimates, respectively, for a 7-fold increase in dose between the 100 mg dose (Cohort 1) and the 700 mg dose (Cohort 4). At dose greater than 700 mg, there was a less than dose-proportional increase in AUC0-24 and AUC0-inf values, with a 1.7-fold and 1.81-fold increase over the 2.86-fold increase in dose between 700 mg (Cohort 4) and 2000 mg (Cohort 6).
  • The mean apparent elimination half-life of KAR5585 increased with increasing dose levels studied, and ranged between 1.89 and 4.84 hours after oral administration of KAR5585. The mean apparent elimination half-life of KAR5417 increased with increasing dose levels studied, and ranged between 4.67 (100 mg dose) and 22.6 hours (2000 mg dose) after oral administration of KAR5585.
  • Mean CL/F estimates of KAR5585 ranged from 1480 to 3850 L/h with the higher CL/F values noted for the 1200 mg (Cohort 5) and 2000 mg (Cohort 6) dose levels and is associated with non-linear PK related to decreased absorption of KAR5585 at the higher dose levels. The Vz/F increased with increasing dose levels and ranged between 5680 to 25100 L, the higher Vz/F values noted for the 1200 mg (Cohort 5) and 2000 mg (Cohort 6) dose levels was attributed to decreased absorption of KAR5585 at the higher dose levels.
  • Administration of the KAR5585 under fed conditions increased the extent and peak exposure of KAR5585 with mean AUCs (AUC0-inf) increasing 3-fold from 302 ng·hr/mL to 915 ng·hr/mL and Cmax increasing 3.2-fold from 52.8 ng/mL to 169 ng/mL, under fasting and fed conditions, respectively. In a similar manner, fed conditions increased the extent and peak of exposure of KAR5417 with mean AUCs (AUC0-inf) increasing 1.8-fold from 3650 ng·hr/mL to 6710 ng·hr/mL and Cmax increasing 1.8-fold from 485 ng/mL to 860 ng/mL, under fasting and fed conditions, respectively. This was considered to be a clinically relevant change in exposure.
  • Urinary excretion of KAR5585 and KAR5417 was a minor mechanism of elimination. KAR5585 was not quantifiable in urine in almost all subjects. KAR5417 could be quantified in urine samples and the amount excreted (Ae) in urine ranged from 0.102 to 0.331% of the administered dose of KAR5585.
    • Pharmacokinetics Conclusions:
  • KAR5585 is a prodrug for the active TPH1 inhibitor KAR5417. Following KAR5585 administration, KAR5585 was rapidly absorbed the median tmax ranged between 1.5 and 3 hours postdose. Following administration of KAR5585, KAR5417 appeared rapidly in plasma, an observation consistent with rapid absorption of KAR5585 and efficient conversion to KAR5417.
  • The mean extent of systemic exposure to the active TPH1 inhibitor, KAR5417, as measured by mean AUC0-24 and AUC0-inf, appeared to increase in a dose proportional manner between the 100 and 700 mg dose levels, with a 6.3-fold and 6.8-fold increase in mean AUC0-24 and mean AUC0-inf estimates, respectively, for a 7-fold increase in dose between the 100 mg dose and the 700 mg dose. At dose greater than 700 mg, there was a slightly less than dose-proportional increase in AUC0-24 and AUC0-inf values, with a 1.7-fold and 1.81-fold increase over the 2.86-fold increase in dose between 700 mg and 2000 mg. The mean apparent elimination half-life of KAR5417 increased with increasing dose levels studied, and ranged between 4.7 hours (100 mg dose) and 22.6 hours (2000 mg dose) after oral administration of KAR5585.
  • Administration of the KAR5585 under fed conditions, increased the extent and peak of exposure of both KAR5585 and KAR5417, with KAR5417 mean AUCs (AUC0-inf) increasing 1.8-fold from 3650 ng·hr/mL to 6710 ng·hr/mL and Cmax increasing 1.8-fold from 485 ng/mL to 860 ng/mL, under fasting and fed conditions, respectively. This was considered to be a clinically relevant change in exposure.
    • PART 2: MULTIPLE ASCENDING DOSE Plasma Concentrations:
  • Mean plasma concentration-time profiles of KAR5585 and KAR5417 following administration of 100 mg KAR5585 under fasting conditions (Part 2, Cohort 1) and 100, 200 and 400 mg KAR5585 under fed conditions (Part 2, Cohorts 2-4) in healthy adult subjects twice daily for 14-days (semi-log scale) are presented in FIGS. 9 a and 9 b .
  • Mean (±SD) plasma concentration-time profiles of KAR5585 and KAR5417 following administration of 100 mg KAR5585 under fasting conditions (Part 2, Cohort 1) and 100, 200 and 400 mg KAR5585 under fed conditions (Part 2, Cohorts 2-4) twice-daily for 14-days in healthy adult subjects (semi-log scale) are presented in FIGS. 10 to 13 , respectively.
  • For Part 2, Cohort 1 (fasted state), samples for KAR5585 and KAR5417 PK analysis were collected on Day 1 and Day 14 following the morning dose of KAR5585. For Part 2, Cohorts 2-4 (fed state), samples for PK analysis were collected on Day 1 and Day 7 following the morning and evening doses and following the single morning dose of KAR5585 that was administered on Day 14.
    • KAR5585 Plasma Concentrations:
  • In general, KAR5585 was detectable in circulation at each dose level, and concentrations generally increased with escalating dose. In addition, the length of time with measurable KAR5585 concentrations increased at higher dose levels.
  • The peak plasma KAR5585 concentrations were reached between 0.75-2.0 and 0.75 and 3.0 hours on Day 1 and Day 14 following oral twice-daily administration of 100 mg of KAR5585, Part 2, Cohort 1 (fasted state). The peak mean concentrations of KAR5585 were 16.7 and 21.3 ng/mL on Day 1 and Day 14, respectively.
  • For doses of 100, 200 and 400 mg of KAR5585, Part 2, Cohorts 2-4 (fed state), the time to median peak plasma concentrations of KAR5585 ranged from 0.75-4 hours, 1.5 to 6 hours, and 1.5 to 6 hours, respectively, on all dosing days and times. There was some evidence for delayed absorption of KAR5585 on Day 7 for the evening dose, where the tmax of KAR5585 were 4 hours, 6 hours, and 6 hours, for the 100, 200 and 400 mg doses, respectively. The Day 7 PM tmax values were on the upper end of the tmax values determined in Day 1, Day 7 and Day 14.
  • The peak mean concentrations of KAR5585 for doses of 100, 200 and 400 mg KAR5585, Part 2, Cohorts 2-4 (fed state), increased with dose. For doses of 100, 200 and 400 mg KAR5585, Part 2, Cohorts 2-4 (fed state), the mean Cmax plasma concentrations of KAR5585 ranged from 18.4-44.1 ng/mL, 42.6-90.9 ng/mL, and 69.0-124 ng/mL, respectively, on all dosing days.
  • There was some evidence for delayed absorption of KAR5585 on Day 7 for the evening dose, where the mean Cmax concentrations of KAR5585 for the 100, 200 and 400 mg doses were 28.4 ng/mL, 42.6 ng/mL, and 69 ng/mL, respectively. The Day 7 PM Cmax values were lower than Day 7 AM Cmax, and at the lower end of the Cmax values determined for all doses on Day 1, Day 7 and Day 14.
  • Following administration of 100 mg KAR5585, peak mean plasma KAR5585 concentrations were observed at similar times under fed relative to fasting conditions. Median tmax values were 0.75 and 1.5 hour postdose, for fed and fasted states on Day 1, and were 1.8 and 1.0 hour postdose, for fed and fasted states on Day 14, respectively.
  • The peak mean concentrations of KAR5585 were comparable under fed conditions (Day 1 Cmax=18.4 ng/mL; Day 14 Cmax=30 ng/mL,) relative to fasting conditions (Day 1 Cmax=16.7 ng/mL; Day 14 Cmax=21.3 ng/mL). This observation is in contrast to the food effect comparison in Part 1, Cohort 3A and 3B (400 mg KAR5585). In Part 1, a high-fat, high calorie meal resulted in peak mean peak concentrations of KAR5585 that were approximately 320% higher following drug administration under fed conditions (Cmax=169 ng/mL) relative to fasting conditions (Cmax=52.8 ng/mL). It should be noted that in Part 1, the food effect was evaluated in a cross-over fashion within the same subjects while the food effect was assessed in parallel (different subjects fed versus fasted) in Part 2.
    • KAR5417 Plasma Concentrations:
  • In general, circulating concentrations of KAR5417 were notably higher than those for KAR5585 on all days and at all dose levels. In addition, KAR5417 concentrations generally increased with increasing doses of KAR5585.
  • The peak plasma KAR5417 concentrations were reached between 2.0-6.0 and 2.0 and 4.0 hours on Day 1 and Day 14 following oral twice-daily administration of 100 mg of KAR5585, Part 2, Cohort 1 (fasted state). The mean peak concentrations of KAR5417 were 121 and 194 ng/mL on Day 1 and Day 14, respectively. These values were approximately 7.25-fold and 9.1-fold greater than the corresponding peak mean concentrations of KAR5585.
  • For doses of 100, 200 and 400 mg of KAR5585, Part 2, Cohorts 2-4 (fed state), the time to median peak plasma concentrations of KAR5417 ranged from 2 to 6 hours, 3 to 8 hours, and 3 to 6 hours, respectively, on all dosing days and times. There was some evidence for a delayed tmax for KAR5417 on Day 7 for the evening dose, where the median time to peak plasma concentrations of KAR5417 was 6 hours, 8 hours, and 6 hours, for the 100, 200 and 400 mg doses, respectively. The Day 7 PM median tmax values for KAR5417 were on the upper end of the median tmax values determined on Day 1, Day 7 and Day 14.
  • The peak mean concentrations of KAR5417 for doses of 100, 200 and 400 mg KAR5585, Part 2, Cohorts 2-4 (fed state), increased with dose. For doses of 100, 200 and 400 mg KAR5585,Part 2, Cohorts 2-4 (fed state), the mean Cmax plasma concentrations of KAR5417 rangedfrom 85.9-168 ng/mL, 222-359 ng/mL, and 595-1000 ng/mL, respectively, on all dosing days. There was some evidence for delayed absorption of KAR5585 and a corresponding lowered KAR5417 Cmax on Day 7 for the evening dose, where the mean Cmax concentrations of KAR5417 for the 100, 200 and 400 mg doses were 112 ng/mL, 222 ng/mL, and 608 ng/mL, respectively. The Day 7 PM Cmax values were lower than Day 7 AM Cmax, and on the lower end of the mean Cmax values determined for all doses on Day 1, Day 7 and Day 14.
  • Following administration of 100 mg KAR5585, peak mean plasma KAR5417 concentrations were observed at similar times under fed relative to fasting conditions. Median tmax values were 2.0 and 3.0 hour postdose, for fed and fasted states on Day 1, and were 3.0 and 3.0 hour postdose, for fed and fasted states on Day 14 respectively). The peak mean concentrations of KAR5417 were comparable under fed conditions (Day 1 Cmax=85.9 ng/mL; Day 14 Cmax=168 ng/mL,) relative to fasting conditions (Day 1 Cmax=121 ng/mL; Day 14 Cmax=194 ng/mL). This observation is in contrast to the food effect comparison in Part 1, Cohort 3A and 3B (400 mg KAR5585. In Part 1, a high fat, high calorie meal resulted in peak mean concentrations of KAR5417 that were approximately 177% higher following KAR5585 administration under fed conditions (Cmax 860 ng/mL) relative to fasting conditions (Cmax=485 ng/mL). Again, it should be noted that the food effect was evaluated in a cross-over fashion in Part 1 while the food effect was assessed in parallel (different subjects fed versus fasted) in Part 2.
    • Pharmacokinetics Parameters:
  • The summary of plasma KAR5585 and KAR5417 PK parameters following a repeat-dose oral administration of 100, 200 and 400 mg KAR5585 administered in healthy adult subjects are presented in 15 and Table 16, respectively. Accumulation ratios for KAR5417 and KAR5585 in healthy volunteers following BID oral administration of KAR5585 for 14 days are presented in Table 17.
    • Pharmacokinetics of KAR5585:
  • In general, mean peak plasma KAR5585 concentrations, as measured by mean Cmax, appeared to increase in a dose proportional manner from 100-400 mg (Part 2, Cohort 2-4, fed state). Mean Cmax values increased 4.4-fold over the 4-fold increase in dose between the 100 mg dose (Cohort 2) and the 400 mg dose (Cohort 4) on Day 1. Mean Cmax values increased ˜3.0-fold over the 4-fold increase in dose between the 100 mg dose (Part 2, Cohort 2) and the 400 mg dose (Part 2, Cohort 4) on Day 14.
  • Overall, the mean extent of systemic exposure to KAR5585, as measured by mean AUC012 and AUC0-24, appeared to increase in a dose proportional manner between the 100 and 400 mg dose levels, with a 5.1-fold and 3.6-fold increase in mean AUC0-12 and mean AUC0-24 estimates, respectively, for a 4-fold increase in dose between the 100 mg dose (Part 2, Cohort 2) and the 400 mg dose (Part 2, Cohort 4) on Day 1. Mean AUC0-12 and mean AUC0-24 estimates, increased 3.1-fold and 3.6-fold respectively, for a 4-fold increase in dose between the 100 mg dose (Part 2, Cohort 2) and the 400 mg dose (Part 2, Cohort 4) on Day 14.
  • Overall, the mean extent of systemic exposure to KAR5585, as measured by mean AUC0-12 and AUC0-24, appeared to be comparable under fasted conditions (Part 2, Cohort 1; Day 1 AUC0-12=62.8 hr*ng/mL; Day 14 AUC0-24=99.8 hr*ng/mL,) relative to fed conditions (Part 2, Cohort 2; Day 1 AM AUC0-12=55.5 hr*ng/mL; Day 14 AUC0-24=122 hr*ng/mL,). This observation was in contrast to the food effect comparison in Part 1, Cohort 3A and 3B (400 mg KAR5585). In Part 1, a high fat, high calorie meal resulted in AUC0-inf of KAR5585 that were approximately 3.0-fold higher following drug administration of KAR5585 400 mg under fed conditions (AUC0-inf=915 ng·hr/mL) relative to fasting conditions (AUC0-inf=302 ng·hr/mL). Again, the food effect was evaluated in a cross-over fashion in Part 1 while the food effect was assessed in parallel (different subjects fed versus fasted) in Part 2.
  • The mean apparent elimination half-life of KAR5585 increased with increasing dose levels, and the mean values were 2.73, 4.08 and 6.45 hrs on Day 14 after oral administration of repeat dose twice-daily administration of 100, 200 and 400 mg of KAR5585 (Part 2, Cohort 2-4, fed state), respectively. The half-life of KAR5585 was 2.49 hrs on Day 14 after oral administration of repeat dose administration of 100 mg in the fasted state, and was comparable to the half-life in the fed state (2.73 hrs) for the 100 mg dose.
  • Mean CL/F estimates of KAR5585 were 2100, 830 and 1730 L/h for the 100, 200 and 400 mg (Part 2, Cohort 2-4, fed state) doses on Day 1, respectively. Mean steady-state CL/F estimates of KAR5585, in the fed state, were 880, 1200 and 1140 L/h for the 100, 200 and 400 mg (Part 2, Cohort 2-4, fed state) doses on Day 14, respectively. Ranges (mean±SD) were generally overlapping on both days and across the dose range studied here.
  • There was a slight trend for increasing Vz/F increased with increasing dose levels on Day 1, noting that the ranges (mean±SD) were generally overlapping. Mean Vz/F was 4100, 3220 and 6800 L for the 100, 200 and 400 mg (Part 2, Cohort 2-4, fed state) doses, respectively. On Day 14, the Vz/F increased with increasing dose levels on Day 14 and were 3520, 7010 and 10300 L for the 100, 200 and 400 mg doses, respectively. The highest mean Vz/F values were noted for the 400 mg dose (Cohort 4) and is attributed to better characterization of the elimination half-life of KAR5585 at higher doses.
  • KAR5585 plasma levels achieved steady-state exposure by Day 7 as assessed by comparison of Day 7 and Day 14 AUC0-12 and concentration, obtained 12 hours after an administered dose (C12 hr) values following twice daily administration of KAR5585 for 14-days. Accumulation ratios for KAR5585 comparing accumulation ratio for Cmax (RCmax) and accumulation ratio for AUC0-12 (RAUC0-12) for Day 7/1 and Day 14/Day 1 are presented in Table 17. The RAUC0-12 values for KAR5585 ranged from 2.75-3.32, 0.76-0.93 and 1.6-2.01 for the 100, 200 and 400 mg doses of KAR5585 suggesting that the PK of KAR5417 was independent of time and steady-state was achieved on Day 7 following repeated twice-daily administration for 14-days.
    • Pharmacokinetics of KAR5417
  • KAR5417 is the active metabolite of the prodrug, KAR5585. Following administration of KAR5585, KAR5417 appeared in plasma, an observation consistent with rapid absorption of KAR5585 and efficient conversion to KAR5417. In general, mean peak plasma KAR5417 concentrations, as measured by mean Cmax, appeared to increase in a greater that dose proportional manner from 100-400 mg (Part 2, Cohort 2-4, fed state). Mean Cmax values increased 6.9-fold over the 4-fold increase in dose between the 100 mg dose (Cohort 2) and the 400 mg dose (Cohort 4) on Day 1. Day 14 mean Cmax values increased in an approximately dose proportional manner with an ˜4.5-fold increase in Cmax over the 4-fold increase in dose between the 100 mg dose (Part 2, Cohort 2) and the 400 mg dose (Part 2, Cohort 4).
  • Overall, the mean extent of systemic exposure to KAR5417, as measured by mean AUC0-12 and AUC0-24, appeared to increase in a greater than dose-proportional manner between the 100 and 400 mg dose levels, with a 7.0-fold and 6.45-fold increase in mean AUC0-12 and mean AUC0-24 estimates, respectively, for 4-fold increase in dose between the 100 mg dose (Part 2, Cohort 2) and the 400 mg dose (Part 2, Cohort 4) on Day 1. Mean AUC0-12 and mean AUC0-24 estimates, increased 4.6-fold and 4.45-fold respectively, for a 4-fold increase in dose between the 100 mg dose (Part 1, Cohort 2) and the 400 mg dose (Part 2, Cohort 4) on Day 14.
  • Overall, the mean extent of systemic exposure to KAR5417, as measured by mean AUC0-12 and AUC0-24, appeared to comparable under fasted conditions (Part 2, Cohort 1; Day 1 AUC0-12=741 hr*ng/mL; Day 14 AUC0-24=1650 hr*ng/mL,) relative to fed conditions (Part 2, Cohort 2; Day 1 AUC0-12=470 hr*ng/mL; Day 14 AUC0-24=1220 hr*ng/mL,). This observation is in contrast to the food effect comparison in Part 1, Cohort 3A and 3B (400 mg KAR5585). In Part 1, a high fat, high calorie meal resulted in AUC0-inf of KAR5417 that was approximately 1.8-fold higher following drug administration of KAR5585 400 mg under fed conditions (AUC0-inf=6710 ng·hr/mL) relative to fasting conditions (AUC0-inf=3650 ng·hr/mL). As noted above, the food effect was evaluated in a cross-over fashion in Part 1 while the food effect was assessed in parallel (different subjects fed versus fasted) in Part 2.
  • The mean apparent elimination half-life of KAR5417 increased with increasing dose levels studied, and mean values were 19.6, 25.0 and 30.6 hrs on Day 14 after oral administration of repeat dose twice-daily administration of 100, 200 and 400 mg of KAR5585 (Part 2, Cohort 2-4, fed state), respectively, determined from a single AM dose on Day 14. The half-life of KAR5417 was 18.8 hrs on Day 14 after oral administration of repeat dose twice-daily administration of 100 mg in the fasted state, and was comparable to the half-life in the fed state (19.6 hrs) for the 100 mg dose. The elimination half —life (30.6 hrs) of KAR5417 on repeat dose administration of 400 mg KAR5585, was similar to the elimination half-life of KAR5417 (20.5 hrs) following single dose administration of 400 mg KAR5585 (Part 1 Cohort 3B).
  • KAR5417 plasma levels achieved steady-state exposure by Day 7 as assessed by comparison of Day 7 and Day 14 AUC0-12 and C12 hr values following twice daily administration of KAR5585 for 14-days. Accumulation ratios for KAR5417 comparing RCmax and RAUC0-12 for Day 7/Day 1 and Day 14/Day 1 are presented in Table 17. The RAUC0-12 values for KAR5417 ranged from 2.19-2.57, 1.09-1.34 and 1.65-2.38 for the 100, 200 and 400 mg doses of KAR5585 suggesting that the PK of KAR5417 was independent of time and steady-state was achieved on Day 7 following repeated twice-daily administration for 14-days.
  • TABLE 13
    Mean PK Parameters for KAR5585 in Healthy Volunteers Following BID Oral Administration of KAR5585 for 14 Days (Pharmacokinetic Evaluable Population)
    Dose Cmax/D AUC0-24/D
    (mg/ Day/ Stat. t1/2 tmax a Cmax [(ng/ C12 C24 Cmax/ AUCb 0-12 AUC0-24 [(hr*ng/ AUC0-∞ CL/F
    dose) Period Param. (hr) (hr) (ng/ml) mL)/mg] (ng/ml) (ng/ml) C12 (hr*ng/ml) (hr*ng/mL) mL)/mg] (hr*ng/ml) Vz/F (L) (L/hr)
    100/ 1/ N 4 7 7 7 0 0 4 4 4 4
    Fasted AMc Mean 2.23 1.5 16.7 0.167 BLQ ND 62.8 71.1 4900 2380
    Cohort 1 SD 2.07 0.75, 2.0 5.87 0.0587 NR ND 45.6 60.8 1980 1820
    CV % 92.8 NA 35.0 35.0 NR ND 72.7 85.5 40.4 76.3
    Geo. Mean 1.73 NA 15.8 0.158 BLQ ND 50.8 54.1 4620 1850
    Geo. CV % 88.0 NA 40.2 40.2 NR ND 89.7 105 40.7 105
    14 N 7 9 9 9 1 0 1 8 8 8 7 7 8
    Mean 2.49 1.0 21.3 0.213 NR BLQ 4.61 92.4 99.8 0.998 105 4420 1450
    SD 0.900 0.75, 3.0 7.98 0.0798 NR NR NR 64.5 76.3 0.763 82.7 1370 713
    CV % 36.2 NA 37.5 37.5 NR NR NR 69.9 76.4 76.4 78.6 30.9 49.0
    Geo. Mean 2.36 NA 20.1 0.201 NR BLQ 4.61 78.2 82.3 0.823 85 4230 1280
    Geo. CV % 35.8 NA 34.8 34.8 NR NR NR 63.6 68.9 68.9 75.8 34.5 63.6
    100/ 1/ N 4 9 9 9 0 0 4 4 4 4
    Fed AM Mean 1.42 0.75 18.4 0.184 BLQ ND 55.5 55.9 4100 2100
    Cohort 2 SD 0.455 0.75, 3.0 6.72 0.0672 NR ND 24.9 24.9 1510 945
    CV % 32.1 NA 36.4 36.4 NR ND 44.9 44.6 36.7 45.1
    Geo. Mean 1.37 NA 17.7 0.177 BLQ ND 51.2 51.7 3830 1940
    Geo. CV % 29.3 NA 29.7 29.7 NR ND 49.2 49.2 49.2 49.2
    1/ N 7 9 9 9 1 1 8 3 3 7 7 7
    PMc Mean 1.87 2.0 44.1 0.441 NR 1.80 143 226 1.13 156 1820 675
    SD 0.422 1.5, 8.0 20.4 0.204 NR NR 48.8 90.2 0.451 42.9 588 154
    CV % 22.6 NA 46.2 46.2 NR NR 34.0 40.0 40.0 27.4 32.3 22.9
    Geo. Mean 1.82 NA 39.8 0.398 NR 1.80 136 214 1.07 152 1730 658
    Geo. CV % 25.4 NA 53.9 53.9 NR NR 35.9 41.3 41.3 25.4 35.7 25.4
    Dose Cmax/D AUC0-24/D
    (mg/ Day/ Stat. t1/2 tmax a Cmax [(ng/ C12 C24 Cmax/ AUCb 0-12 AUC0-24 [(hr*ng/ AUC0-∞ CL/F
    dose) Period Param. (hr) (hr) (ng/ml) mL)/mg] (ng/ml) (ng/ml) C12 (hr*ng/ml) (hr*ng/mL) mL)/mg] (hr*ng/ml) Vz/F (L) (L/hr)
    7/ N 8 9 9 9 0 0 8 8 8 8
    AM Mean 2.86 2.0 31.3 0.313 BLQ ND 129 139 3360 800
    SD 0.544 1.5, 4.0 11.3 0.113 NR ND 25.2 23.4 1110 142
    CV % 19.0 NA 35.9 35.9 NR ND 19.5 16.9 32.9 17.7
    Geo Mean 2.82 NA 29.8 0.298 BLQ ND 127 137 3210 788
    Geo. CV % 17.8 NA 34.4 34.4 NR ND 18.7 16.4 34.1 18.7
    7/ N 5 9 9 9 5 5 7 6 6 5 5 5
    PM Mean 3.80 4.0 28.4 0.284 6.29 5.37 145 282 1.41 173 3910 717
    SD 1.62 1.5, 6.0 15.1 0.151 0.633 3.59 37.6 55.0 0.275 48.5 1850 165
    CV % 42.6 NA 53.0 53.0 10.0 66.9 25.9 19.5 19.5 28.0 47.2 23.0
    Geo Mean 3.52 NA 25.8 0.258 6.27 4.66 142 278 1.39 168 3550 699
    Geo. CV % 46.2 NA 47.2 47.2 10.0 61.2 22.8 18.5 18.5 28.6 53.7 27.1
    14 N 7 8 8 8 0 0 0 7 7 7 7 7 7
    Mean 2.73 1.8 30.0 0.300 BLQ BLQ ND 115 122 1.22 122 3520 880
    SD 0.759 0.75, 3.0 10.0 0.100 NR NR ND 16.0 15.5 0.155 14.5 1290 115
    CV % 27.8 NA 33.5 33.5 NR NR ND 13.9 12.7 12.7 11.9 36.7 13.0
    Geo Mean 2.64 NA 28.5 0.285 BLQ BLQ ND 114 121 1.21 121 3330 874
    Geo. CV % 28.1 NA 35.3 35.3 NR NR ND 13.5 12.3 12.3 11.7 37.7 13.5
    200/ 1/ N 9 9 9 9 6 6 9 9 9 9
    Fed AMc Mean 2.91 1.5 87.8 0.439 5.61 18.7 257 275 3220 830
    Cohort 3 SD 0.806 0.75, 4.0 39.8 0.199 0.268 6.66 89.8 98.3 750 350
    CV % 27.7 NA 45.3 45.3 4.8 35.6 34.9 35.7 23.3 42.1
    Geo Mean 2.81 NA 80.7 0.403 5.60 17.7 243 258 3130 774
    Geo. CV % 30.9 NA 45.0 45.0 4.8 37.4 37.8 40.1 26.0 40.1
    Dose Cmax/D AUC0-24/D
    (mg/ Day Stat. t1/2 tmax a Cmax [(ng/ C12 C24 Cmax/ AUC0-b/12 AUC0-24 [(hr*ng/ AUC0-∞ CL/F
    dose) Period Param. (hr) (hr) (ng/ml) mL)/mg] (ng/ml) (ng/ml) C12 (hr*ng/ml) (hr*ng/mL) mL)/mg] (hr*ng/ml) Vz/F (L) (L/hr)
    400/ 1/ N 9 9 9 9 6 6 9 9 9 9
    Fasted AMc Mean 3.14 2. 81.8 0.205 7.49 12.8 281 305 6800 1730
    Cohort 4 SD 0.913 1.0, 2.0 34.9 0.0872 0.927 4.03 113 127 2760 1200
    CV % 29.1 NA 42.6 42.6 12.4 31.5 40.2 41.5 40.5 69.2
    Geo. Mean 3.00 NA 74.0 0.185 7.44 12.2 253 272 2360 1470
    Geo. CV % 33.7 NA 54.0 54.0 13.0 36.9 57.3 61.2 39.6 61.2
    1/ N 7 9 9 9 9 9 9 9 9 7 7 7
    PMc Mean 4.33 3.0 124 0.310 17.1 7.56 528 808 1.01 657 4030 662
    SD 1.23 2.0, 4.1 56.1 0.140 3.77 3.25 169 364 0.330 182 1400 241
    CV % 28.4 NA 45.2 45.2 22.1 43.0 32.0 32.7 32.7 27.7 34.6 36.4
    Geo. Mean 4.18 NA 110 0.276 16.6 6.64 501 760 0.950 633 3820 632
    Geo. CV % 29.6 NA 61.0 61.0 25.4 67.9 36.1 41.3 41.3 41.3 32.1 32.1
    7/ N 9 9 9 9 9 9 9 9 9 9
    AMc Mean 4.90 2.0 95.9 0.240 15.5 6.27 483 588 6220 865
    SD 1.85 1.5, 4.0 30.7 0.0769 3.86 1.76 102 124 3230 198
    CV % 37.7 NA 32.1 32.1 24.8 28.0 21.1 21.1 51.9 22.9
    Geo. Mean 4.65 NA 93.3 0.228 15.1 6.04 473 577 5680 846
    Geo. CV % 33.6 NA 34.7 34.7 24.6 30.5 22.4 21.9 45.0 22.4
    7/ N 4 9 9 9 9 9 9 9 9 4 4 4
    PMc Mean 4.93 6.0 69.0 0.172 20.8 3.90 404 887 1.11 538 6950 969
    SD 0.354 2.0, 8.0 30.8 0.0769 5.76 2.92 96.3 185 0.231 77.1 1800 196
    CV % 7.17 NA 44.6 44.6 27.6 74.7 23.8 20.9 20.9 14.3 25.9 20.3
    Geo. Mean 4.92 NA 63.4 0.158 20.1 — 3.15 394 870 1.09 534 6770 954
    Geo. CV % 7.22 NA 45.8 45.8 29.9 75.7 23.9 21.6 21.6 14.3 27.5 21.0
    Dose Cmax/D AUC0-24/D
    (mg/ Day/ Stat. t1/2 tmax a Cmax [(ng/ C12 C24 Cmax/ AUC0-12 b AUC0-24 [(hr*ng/ AUC0-∞ CL/F
    dose) Period Param. (hr) (hr) (ng/ml) mL)/mg] (ng/ml) (ng/ml) C12 (hr*ng/ml) (hr*ng/mL) mL)/mg] (hr*ng/ml) Vz/F (L) (L/hr)
    1/ N 8 9 9 9 9 9 9 9 9 8 8 8
    PMc Mean 4.34 3.0 90.9 0.455 9.92 9.98 344 601 1.5 417 3120 507
    SD 1.03 1.5, 6.0 29.6 0.148 2.81 4.65 90.8 156 0.389 102 785 129
    CV % 23.7 NA 32.6 32.6 28.4 46.5 26.4 25.9 25.9 24.4 25.2 25.6
    Geo. Mean 4.24 NA 85.4 0.427 9.57 8.93 333 583 1.46 406 3010 493
    Geo. CV % 24.2 NA 41.8 41.8 29.4 56.2 27.5 26.5 26.5 25.5 30.2 25.5
    7/ N 9 9 9 9 8 8 9 9 9 9
    AMc Mean 4.30 3.0 48.8 0.244 7.71 6.69 230 273 5960 978
    SD 0.938 2.0, 4.0 18.9 0.0943 2.78 2.02 83.9 101 2150 342
    CV % 21.8 NA 38.7 38.7 36.1 30.2 36.5 36.9 36.0 35.0
    Geo. Mean 4.21 NA 45.6 0.228 7.36 6.43 217 256 5610 924
    Geo. CV % 22.1 NA 40.7 40.7 31.7 31.3 37.4 39.1 38.4 37.4
    7/ N 2 8 8 8 8 8 8 8 8 2 2 2
    PMc Mean 6.20 6.0 42.6 0.213 12.2 4.20 207 431 1.08 290 8710 890
    SD NR 2.0, 8.0 19.5 0.0976 5.46 3.14 53.9 133 0.332 NR NR NR
    CV % NR NA 45.8 45.8 44.6 74.7 26.1 30.8 30.8 NR NR NR
    Geo. Mean 5.58 NA 39.1 0.195 11.3 3.46 201 414 1.03 289 7000 869
    Geo. CV % NR NA 46.4 43.6 24.6 68.5 25.7 30.8 30.8 NR NR NR
    14 N 7 8 8 8 3 0 3 7 7 7 7 7 7
    Mean 4.08 2.0 48.8 0.244 NR BLQ 11.2 188 212 1.06 216 7010 1200
    SD 1.06 1.0, 6.0 24.8 0.124 NR NR 4.75 69.9 81.7 0.409 83.9 3070 447
    CV % 25.9 NA 50.8 50.8 NR NR 42.3 37.2 38.6 38.6 38.9 43.8 37.2
    Geo. Mean 3.94 NA 43.5 0.217 NR BLQ 10.5 177 199 0.993 202 6430 1130
    Geo. CV % 31.0 NA 56.0 56.0 NR NR 48.9 39.6 40.9 40.9 41.3 48.2 39.6
    Dose Cmax/D AUC0-24/D
    (mg/ Day/ Stat. t1/2 tmax a Cmax [(ng/ C12 C24 Cmax/ AUC0-b/12 AUC0-24 [(hr*ng/ AUC0-∞ CL/F
    dose) Period Param. (hr) (hr) (ng/ml) mL)/mg] (ng/ml) (ng/ml) C12 (hr*ng/ml) (hr*ng/mL) mL)/mg] (hr*ng/ml) Vz/F (L) (L/hr)
    14 N 9 9 9 9 9 3 9 9 9 9 9 9 9
    Mean 6.45 1.5 89.0 0.222 11.4 NR 8.17 366 444 1.11 482 10300 1140
    SD 2.48 1.0, 2.0 26.6 0.0664 3.37 NR 3.00 72.6 103 0.257 138 3420 270
    CV % 38.4 NA 29.8 29.8 29.6 NR 36.7 19.8 23.2 23.2 28.6 33.4 23.7
    Geo. Mean 6.08 NA 85.3 0.213 11.0 NR 7.76 359 433 1.08 465 9780 1110
    Geo. CV % 36.1 NA 32.0 32.0 28.4 NR 33.7 21.7 24.4 24.4 29.2 33.6 21.7
    aMedian and range (Min, Max) Presented;
    bAUC0-4 substituted for AUC0-12 when WinNonlin did not calculate the latter and tlast was >11.90 hr;
    cAM refers to a morning dose (8AM) and PM refers to an evening dose (8PM)
    Shaded cells without data are where PK sampling regimens relative to time of dose administration did not support calculations of PK parameters (eg, no C24 hr values for BID dosing in Day 1 and Day 7)
    Abbreviations: AM, before noon (ante meridiem) AUC0-12, area under concentration versus time curve from time 0 to 12 hours after dosing, using the trapezoidal rule; AUC0-24, area under the concentration versus time curve from time 0 to 24 hours after dosing, using the trapezoidal rule; AUC0-t, area under the concentration-time curve from time 0 to time of last quantifiable concentration; BLQ, below the limit of quantitation; CL/F, apparent oral clearance; NA, not applicable; ND, not determined; NR, not reported; Pararn., parameter; PK, pharmacokinetic; PM, after noon (post meridiem). SD, standard deviation; Stat., statistical; t½, apparent terminal half-life after oral administration; tmax, time of maximum observed concentration; Vz/F, volume of distribution during the terminal phase
  • TABLE 14
    (Mean PK Parameters for KAR5417 in Healthy Volunteers Following BID Oral Administration of KAR5585 for 14 Days (Pharmacokinetic Evaluable Population))
    Cmax/D
    Cmax (ng/ C12 C24 AUC0-24 AUC0-24/D AUC0-∞
    Stat. t1/2 tma x a (ng/ ml)/ (ng/ (ng/ Cmax/ AUC0-12 b (hr*ng/ (hr*ng/ml)/ (hr*ng
    Cohort Day Period Param. (hr) (hr) ml) mg ml) ml) C12 (hr*ng/ml) mL) mg /mL) RCma d x RAUC0 d -12
    100 1 AMc N 7 9 9 9 8 8 8 7
    (fasted) Mean 3.43 3.0 121 1.21 21.3 6.08 741 876
    Cohort 1 SD 0.751 2.0, 6.0 83.3 0.833 10.6 1.32 491 545
    CV % 21.9 NA 68.9 68.9 49.5 21.7 66.3 62.2
    Geo. Mean 3.37 NA 101 1.01 19.5 5.93 643 769
    Geo. CV % 21.3 NA 70.4 70.4 45.4 24.8 56.8 55.9
    14 — N 9 9 9 9 9 9 9 9 9 9 9 9 8
    Mean 18.8 3.0 194 1.94 46.3 19.7 4.25 1280 1650 16.5 2220 2.56 1.83
    SD 6.67 2.0, 4.0 87.7 0.877 21.0 8.40 0.539 620 782 7.82 1130 2.96 0.940
    CV % 35.5 NA 45.2 45.2 45.3 42.5 12.7 48.4 47.3 47.3 50.9 116 51.4
    Geo. Mean 17.6 NA 177 1.77 42.0 18.1 4.21 1150 1490 14.9 1960 1.75 1.64
    Geo. CV % 42.0 NA 49.0 49.0 51.5 47.5 14.2 53.0 52.1 52.1 59.2 101 52.5
    100 1 AMc N 9 9 9 9 9 9 9 9
    (fed) Mean 4.18 2.0 85.9 0.859 17.2 5.26 470 564
    Cohort 2 SD 0.516 1.5, 4.0 40.4 0.404 9.54 1.24 247 288
    CV % 12.3 NA 47.0 47.0 55.4 23.6 52.5 51.0
    Geo. Mean 4.16 NA 79.2 0.792 15.4 5.14 428 516
    Geo. CV % 12.2 NA 42.6 42.6 49.9 23.3 45.1 44.0
    PMc N 7 9 9 9 9 9 9 9 9 7
    Mean 7.00 3.0 130 1.3 43.1 3.31 748 1220 6.09 1140
    SD 0.837 2.0, 12 59.8 0.598 21.6 1.36 251 454 2.27 394
    CV % 12.0 NA 46.0 46.0 50.0 41.0 33.5 37.3 37.3 34.5
    Geo. Mean 6.95 NA 119 1.19 39.5 3.01 714 1160 5.78 1090
    Geo. CV % 13.1 NA 45.9 45.9 44.0 53.2 32.6 33.8 33.8 35.7
    7 AMc N 9 9 9 9 9 9 9 9 9 9
    Mean 5.31 3.0 168 1.68 45.1 3.69 1080 1410 2.07 2.57
    SD 0.975 2.0, 4.0 60.9 0.609 9.46 0.837 296 300 0.502 0.8
    CV % 18.4 NA 36.2 36.2 21.0 22.7 27.4 21.3 24.2 31.2
    Geo. Mean 5.24 NA 160 1.60 44.3 3.61 1050 1380 2.02 2.45
    Geo. CV % 18.2 NA 33.8 33.8 20.5 21.4 26.9 20.5 24.6 34.0
    PMc N 4 9 9 9 9 9 9 9 9 4 9 9
    Mean 8.10 6.0 112 1.12 62.3 1.8 902 1990 9.93 1730 1.43 2.19
    SD 2.11 2.0, 8.0 46.4 0.464 11.5 0.629 254 533 2.67 337 0.552 0.806
    CV % 26.0 NA 41.3 41.3 18.4 34.9 28.2 26.8 26.8 19.5 38.6 36.8
    Geo. Mean 7.91 NA 106 1.06 61.4 1.73 875 1930 9.64 1700 1.34 2.04
    Geo. CV % 25.6 NA 36.0 36.0 19.0 30.8 25.9 25.8 25.8 19.2 41.8 43.0
    14 AMc N 8 8 8 8 8 8 8 8 8 8 8 8
    Mean 19.6 2.0 168 1.68 36.4 19.6 4.56 943 1270 1830 1.98 2.23
    SD 5.30 1.5, 4.0 67.2 0.672 9.46 4.11 1.43 296 366 455 0.650 0.818
    CV % 27.0 NA 40.0 40.0 26.0 20.9 31.5 31.4 28.8 24.9 32.8 36.7
    Geo. Mean 19.0 NA 155 1.55 35.4 19.3 4.37 900 1220 1780 1.90 2.09
    Geo. CV % 29.0 NA 47.7 47.7 25.7 21.0 31.6 34.4 30.9 25.7 31.1 40.2
    200 1 AMc N 9 9 9 9 9 9 9 9
    (fed) Mean 4.49 3.0 357 1.79 60.7 6.07 1700 2090
    Cohort 3 SD 0.977 2.0, 4.0 142 0.709 25.1 1.36 605 785
    CV % 21.8 NA 39.7 39.7 41.4 22.5 35.5 37.5
    Geo. Mean 4.41 NA 336 1.68 56.6 5.94 1620 1980
    Geo. CV % 20.1 NA 37.4 37.4 41.0 21.9 35.0 36.3
    PMc N 6 9 9 9 9 9 9 9 9 6
    Mean 6.03 4.0 322 1.61 112 3.24 2000 3700 9.26 2720
    SD 1.09 2.0, 6.0 103 0.513 56.0 1.28 680 1260 3.16 775
    CV % 18.1 NA 31.9 31.9 50.2 39.4 34.0 34.1 34.1 28.5
    Geo. Mean 5.95 NA 307 1.54 102 3.00 1910 3540 8.85 2640
    Geo. CV % 18.5 NA 33.8 33.8 43.6 44.6 31.5 31.9 31.9 27.9
    7 AMc N 8 9 9 9 9 9 9 8 9 9
    Mean 4.61 4.0 359 1.80 93.1 3.83 2300 2800 1.00 1.34
    SD 0.643 2.0, 6.0 176 0.879 38.8 0.393 1010 1280 0.176 0.198
    CV % 13.9 NA 49.0 49.0 41.7 10.3 44.0 45.8 17.5 14.8
    Geo. Mean 4.57 NA 332 1.66 87.2 3.81 2150 2610 0.989 1.33
    Geo. CV % 14.3 NA 40.6 40.6 38.6 10.6 38.5 39.4 18.5 14.6
    PMc N 2 8 8 8 8 8 8 8 8 2 8 8
    Mean 6.64 8.0 222 1.11 145 1.90 1540 3810 9.52 2280 0.711 0.984
    SD NR 3.0, 12 71.3 0.356 74.3 1.31 413 1440 3.60 NR 0.376 0.276
    CV % NR NA 32.1 32.1 51.1 68.9 26.9 37.8 37.8 NR 52.9 28.0
    Geo. Mean 6.48 NA 212 1.06 131 1.62 1490 3620 9.05 2270 0.645 0.955
    Geo. CV % NR NA 33.6 33.6 51.3 61.1 25.8 33.5 33.5 NR 46.5 26.1
    14 AMc N 8 8 8 8 8 8 8 8 8 8 8 8
    Mean 25.0 3.0 319 1.59 63.5 32.6 4.81 1820 2380 3480 0.901 1.09
    SD 7.06 2.0, 6.0 175 0.877 24.9 10.7 0.991 887 1090 1430 0.304 0.235
    CV % 28.3 NA 55.1 55.1 39.3 33.0 20.6 48.7 45.7 41.1 33.7 21.5
    Geo. Mean 24.1 NA 281 1.40 59.6 31.2 4.72 1670 2200 3250 0.854 1.07
    Geo. CV % 30.2 NA 57.2 57.2 38.9 32.0 22.5 45.7 43.1 41.1 36.8 24.0
    400 1 AMc N 9 9 9 9 9 9 9 9
    (fed) Mean 3.80 3.0 595 1.49 99.3 5.97 3280 3780
    Cohort 4 SD 0.883 2.0, 4.0 273 0.682 43.6 0.981 1550 1690
    CV % 23.2 NA 45.8 45.8 44.0 16.4 47.4 44.8
    Geo. Mean 3.71 NA 532 1.33 90.2 5.90 2920 3400
    Geo. CV % 24.8 NA 57.8 57.8 51.3 16.9 58.5 54.6
    PMc N 5 9 9 9 9 9 9 9 9 5
    Mean 5.31 4.0 739 1.85 252 3.05 4590 7870 9.83 7090
    SD 0.456 3.0, 8.0 343 0.859 76.7 1.29 1550 2830 3.53 1970
    CV % 8.6 NA 46.4 46.4 30.4 42.2 33.7 35.9 35.9 27.8
    Geo. Mean 5.3 NA 670 1.68 242 2.77 4340 7430 9.28 6860
    Geo. CV % 8.6 NA 50.6 50.6 31.8 52.9 37.1 37.3 37.3 30.0
    7 AMc N 6 9 9 9 9 9 9 6 9 9
    Mean 3.94 4.0 1000 2.51 240 4.36 6600 7840 2.00 2.38
    SD 0.798 3.0, 6.0 315 0.788 103 0.654 2340 2650 0.991 1.17
    CV % 20.2 NA 31.4 31.4 43.0 15.0 35.4 33.9 49.5 49.1
    Geo. Mean 3.89 NA 960 2.40 222 4.32 6250 7480 1.81 2.15
    Geo. CV % 18.1 NA 31.9 31.9 41.6 15.6 35.7 34.6 49.5 51.3
    PMc N 2 9 9 9 9 9 9 9 9 2 9 9
    Mean 5.10 6.0 608 1.52 396 1.80 4610 11200 14.0 6520 1.18 1.63
    SD NR 3.0, 12 201 0.503 198 0.961 1590 3890 4.86 NR 0.498 0.737
    CV % NR NA 33.1 33.1 50.0 53.4 34.5 34.7 34.7 NR 42.4 45.2
    Geo. Mean 5.08 NA 574 1.44 356 1.61 4360 10600 13.3 6450 1.08 1.50
    Geo. CV % NR NA 38.5 38.5 51.3 50.1 36.9 35.8 35.8 NR 46.9 45.4
    14 AMc N 9 9 9 9 9 9 9 9 9 9 9 9 9
    Mean 30.6 3.0 749 1.87 149 76.6 5.20 4350 5660 14.1 8500 1.54 1.65
    SD 3.84 2.0, 3.0 230 0.574 56.8 25.5 1.08 1420 1870 4.68 2820 0.967 1.06
    CV % 12.5 NA 30.6 30.6 38.1 33.3 20.8 32.6 33.1 33.1 33.1 63.0 63.9
    Geo. Mean 30.4 NA 717 1.79 140 73.3 5.11 4160 5410 13.5 8120 1.35 1.43
    Geo. CV % 12.5 NA 32.8 32.8 37.4 31.6 20.5 32.2 32.3 32.3 31.9 54.0 59.6
    aMedian and range (Min, Max) presented;
    bAUC0-tau substituted for AUC0-12 when WinNonlin did not calculate the latter and tlast was >11.90 hr;
    cAM refers to a morning dose (8AM) and PM refers to an evening dose (8PM)
    dRCmax and RAUC0-12 refer to accumulation ratios for Day 7/Day 1 or Day 14/Day 1 PK parameters
    Abbreviations: AM, before noon (ante meridiem); AUC0-12, area under the concentration versus time curve from time 0 to 12 hours after dosing, using the trapezoidal rule; AUC0-24, area under the concentration versus time curve from time 0 to 24 hours after dosing, using the trapezoidal rule; AUC0-tau, area under the concentration-time curve from time 0 to time of last quantifiable concentration; BID, twice daily; BLQ, below the limit of quantitation; hr, hour; Max, maximum; Min, minimum; NA, not applicable; ND, not determined; NR, not reported. PK, pharmacokinetic; PM, after noon (post meridiem); Param., parameter; RAUC0-12, accumulation ratio for AUC0-12; RCmax, accumulation ratio for Cmax; SD, standard deviation; Stat., statistical; t½, apparent terminal half-life after oral administration; tmax, time of maximum observed concentration.
  • TABLE 15
    (Accumulation Ratios for KAR5417 and KAR5585 in Healthy
    Volunteers Following BID Oral Administration of KAR5585
    for 14 Days (Pharmacokinetic Evaluable Population))
    Dose Post AM
    (mg/feeding or PM Stat. KAR5585 KAR5417
    status) Day Dose Param. RCmax RAUC0-12 RCmax RAUC0-12
    100/ 14 AM N 7 4 9 8
    Fasted Mean 1.30 1.85 2.56 1.83
    Cohort 1 SD 0.592 0.870 2.96 0.940
    CV % 45.5 47.0 116 51.4
    Geo. Mean 1.20 1.70 1.75 1.64
    Geo. CV % 43.0 52.1 101 52.5
    100/ 7 AM N 9 3 9 9
    Fed Mean 1.74 3.32 2.07 2.57
    Cohort 2 SD 0.469 1.10 0.502 0.8
    CV % 26.9 33.2 24.2 31.2
    Geo. Mean 1.69 3.18 2.02 2.45
    Geo. CV % 28.7 38.0 24.6 34.0
    7 PM N 9 3 9 9
    Mean 1.66 3.11 1.43 2.19
    SD 1.03 2.18 0.552 0.806
    CV % 62.1 70.1 38.6 36.8
    Geo. Mean 1.46 2.68 1.34 2.04
    Geo. CV % 54.5 71.6 41.8 43.0
    14 AM N 8 3 8 8
    Mean 1.68 2.75 1.98 2.23
    SD 0.465 0.938 0.650 0.818
    CV % 27.7 34.1 32.8 36.7
    Geo. Mean 1.62 2.62 1.90 2.09
    Geo. CV % 30.2 40.8 31.1 40.2
    200/ 7 AM N 9 9 9 9
    Fed Mean 0.589 0.933 1.00 1.34
    Cohort 3 SD 0.175 0.328 0.176 0.198
    CV % 29.8 35.2 17.5 14.8
    Geo. Mean 0.565 0.892 0.989 1.33
    Geo. CV % 31.1 30.6 18.5 14.6
    7 PM N 8 8 8 8
    Mean 0.597 0.895 0.711 0.984
    SD 0.379 0.304 0.376 0.276
    CV % 63.4 34.0 52.9 28.0
    Geo. Mean 0.515 0.854 0.645 0.955
    Geo. CV % 59.7 33.3 46.5 26.1
    14 AM N 8 7 8 8
    Mean 0.643 0.761 0.901 1.09
    SD 0.323 0.230 0.304 0.235
    CV % 50.2 30.2 33.7 21.5
    Geo. Mean 0.573 0.730 0.854 1.07
    Geo. CV % 56.1 32.6 36.8 24.0
    400/ 7 AM N 9 9 9 9
    Fed Mean 1.32 2.01 2.00 2.38
    Cohort 4 SD 0.627 0.872 0.991 1.17
    CV % 47.4 43.3 49.5 49.1
    Geo. Mean 1.23 1.87 1.81 2.15
    Geo. CV % 37.1 40.8 49.5 51.3
    7 PM N 9 9 9 9
    Mean 0.971 1.71 1.18 1.63
    SD 0.444 0.810 0.498 0.737
    CV % 45.7 47.3 42.4 45.2
    Geo. Mean 0.857 1.56 1.08 1.50
    Geo. CV % 63.6 48.1 46.9 45.4
    14 AM N 9 9 9 9
    Mean 1.28 1.60 1.54 1.65
    SD 0.647 0.938 0.967 1.06
    CV % 50.4 58.7 63.0 63.9
    Geo. Mean 1.15 1.42 1.35 1.43
    Geo. CV % 52.5 52.2 54.0 59.6
    Abbreviations: AM, before noon (ante meridiem); BID, twice daily; Geo., geometric; hr, hour; N, number; PM, after noon (post meridiem); RAUC0-12, accumulation ratio for AUC0-12; RCmax, accumulation ratio for Cmax; SD, standard deviation; t½, apparent terminal half-life after oral administration.
    • Dose Proportionality Assessment of KAR5585 and KAR5417:
  • Scatter plots of individual plasma KAR5585 and KAR5417 Day 1 and Day 14 Cmax KAR5585 dose are presented in FIGS. 14 a and 14 b and FIGS. 15 a and 15 b , respectively. Scatter plots of individual plasma KAR5585 and KAR5417 Day 1 and Day 14 AUC0-12 KAR5585 dose are presented in FIGS. 16 a and 16 b and FIGS. 17 a and 17 b . The dose proportionality assessment of plasma KAR5585 and KAR5417 PK parameters are summarized in Table 16. Dose proportionality was assessed for KAR5585 and KAR5417 after repeat-dose, twice-daily administration of KAR5585 using the power model. From plots of exposure (i.e., Cmax, AUC0-12 and/or AUC0-inf) versus dose, increases in exposure were deemed dose proportional if the 95% confidence intervals (CIs) for the slope (β included unity (e.g., 1.0). The CIs presented in Table 16 indicate that Cmax, AUC0-12 and/or AUC0-inf for both KAR5585 and KAR5417 increase in dose proportional manner from 100-400 mg of KAR5585 (Part 2, Cohorts 2-4) in the fed state.
  • TABLE 16
    (Summary of Dose Proportionality Analysis of Plasma KAR5417 and
    KAR5585 Pharmacokinetic Parameters AUC0-12, AUC0-inf, and Cmax Following
    100 to 400 mg of KAR5585 Administered as Repeat Oral Doses under
    Fed Conditions (Pharmacokinetic Evaluable Population))
    95%
    PK Day Degrees of Standard Confidence
    Parameter (AM) Analyte Effect Estimate Freedom Error Interval
    AUC0-12 1 KAR5417 Intercept 0.828 25 NC NC
    Slope (β) 1.38 25 0.161  1.05-1.71
    KAR5585 Intercept 0.969 20 NC NC
    Slope (β) 0.964 20 0.245 0.453-1.47
    7 KAR5417 Intercept 2.63 25 NC NC
    Slope (β) 1.29 25 0.114  1.05-1.52
    KAR5585 Intercept 1.51 24 NC NC
    Slope (β) 0.952 24 0.0950 0.756-1.15
    14 KAR5417 Intercept 5.18 23 NC NC
    Slope (β) 1.11 23 0.127 0.846-1.37
    KAR5585 Intercept 2.37 21 NC NC
    Slope (β) 0.832 21 0.0951 0.634-1.03
    AUC0-inf 1 KAR5417 Intercept 1.12 25 NC NC
    Slope (β) 1.36 25 0.159  1.03-1.69
    KAR5585 Intercept 0.817 20 NC NC
    Slope (β) 1.01 20 0.255 0.474-1.54
    Cmax 1 KAR5417 Intercept 0.167 25 NC NC
    Slope (β) 1.37 25 0.169  1.03-1.72
    KAR5585 Intercept 0.198 25 NC NC
    Slope (β) 1.03 25 0.193 0.636-1.43
    7 KAR5417 Intercept 0.393 25 NC NC
    Slope (β) 1.29 25 0.118  1.05-1.54
    KAR5585 Intercept 0.688 25 NO NC
    Slope (β) 0.809 25 0.121 0.561-1.06
    14 KAR5417 Intercept 0.877 23 NC NC
    Slope (β) 1.11 23 0.153 0.794-1.43
    KAR5585 Intercept 0.705 23 NC NC
    Slope (β) 0.794 23 0.139 0.508-1.08
    Abbreviations: AM, before noon (ante meridiem); AUC0-12, area under the concentration versus time curve from time 0 to 12 hours after dosing, using the trapezoidal rule; AUC0-24, area under the concentration versus time curve from time 0 to 24 hours after dosing, using the trapezoidal rule; AUC0-inf, area under the concentration versus time curve from time 0 extrapolated to infinity; NC, not calculated; PK, pharmacokinetic.
    • Discussion of Pharmacokinetics Results:
  • Following KAR5585 administration, KAR5585 was rapidly absorbed. For doses of 100, 200 and 400 mg KAR5585, Part 2, Cohorts 2-4 (fed state), the median time to peak plasma concentrations of KAR5585 ranged from 0.75-4 hours, 1.5 to 6 hours, and 1.5 to 6 hours, respectively, on all dosing days and times. There was some evidence for delayed absorption of KAR5585 on Day 7 for the evening dose, where the median time to peak plasma concentrations of KAR5585 were 4 hours, 6 hours, and 6 hours, for the 100, 200 and 400 mg doses, respectively. The Day 7 PM tmax values were on the upper end of the tmax values determined in
  • Day 1, Day 7 and Day 14. This was not observed on Day 1.
  • Peak plasma KAR5585 concentrations, as measured by mean Cmax, increased in a dose proportional manner from 100-400 mg (Part 2, Cohort 2-4, fed state). Mean Cmax values increased 4.4-fold over the 4-fold increase in dose between the 100 mg dose (Cohort 2) and the 400 mg dose (Cohort 4) on Day 1. Mean Cmax values increased ˜3.0-fold over the 4-fold increase in dose between the 100 mg dose (Part 2, Cohort 2) and the 400 mg dose (Part 2, Cohort 4) on Day 14.
  • Systemic exposure to KAR5585, as measured by mean AUC0-12 and AUC0-24, appeared to increase in a dose-proportional manner between the 100 and 400 mg dose levels, with a 5.1-fold and 3.6-fold increase in mean AUC0-12 and mean AUC0-24 estimates, respectively, for a 4-fold increase in dose between the 100 mg dose (Part 2, Cohort 2) and the 400 mg dose (Part 2, Cohort 4) on Day 1. Mean AUC0-12 and mean AUC0-24 estimates, increased 3.1-fold and 3.63-fold respectively, for a 4-fold increase in dose between the 100 mg dose (Part 2, Cohort 2) and the 400 mg dose (Part 2, Cohort 4) on Day 14.
  • The mean apparent elimination half-life of KAR5585 increased with increasing dose levels studied, and the mean values were 2.73, 4.08 and 6.45 hrs on Day 14 after oral administration of repeat dose twice-daily administration of 100, 200 and 400 mg of KAR5585 (Part 2, Cohort 2-4,fed state), respectively. The half-life of KAR5585 was 2.49 hrs on Day 14 after oral administration of repeat dose twice-daily administration of 100 mg in the fasted state, and was comparable to the half-life in the fed state (2.73 hrs) for the 100 mg dose.
  • Peak plasma KAR5417 concentrations, as measured by mean Cmax, appeared to increase in a greater that dose proportional manner from 100-400 mg (Part 2, Cohort 2-4, fed state). Mean Cmax values increased 6.9-fold over the 4-fold increase in dose between the 100 mg dose (Cohort 2) and the 400 mg dose (Cohort 4) on Day 1. Day 14 mean Cmax values increased in an approximately dose proportional manner with an ˜4.5-fold increase in Cmax over the 4-fold increase in dose between the 100 mg dose (Part 2, Cohort 2) and the 400 mg dose (Part 2, Cohort 4).
  • Mean extent of systemic exposure to KAR5417, as measured by mean AUC0-12 and AUC0-24, appeared to increase in a greater than dose-proportional manner between the 100 and 400 mg dose levels, with a 7.0-fold and 6.45-fold increase in mean AUC0-12 and mean AUC0-24 estimates, respectively, for a 4-fold increase in dose between the 100 mg dose (Part 2, Cohort 2) and the 400 mg dose (Part 2, Cohort 4) on Day 1. Day 14 mean AUC0-12 and mean AUC0-24 estimates, increased 4.6-fold and 4.45-fold respectively, for a 4-fold increase in dose between the 100 mg dose (Part 1, Cohort 2) and the 400 mg dose (Part 2, Cohort 4).
  • Overall, the mean extent of systemic exposure to KAR5417, as measured by mean AUC0-12 and AUC0-24, appeared to be comparable under fasted conditions (Part 2, Cohort 1; Day 1 AUC0-12=741 hr*ng/mL; Day 14 AUC0-24=1650 hr*ng/mL,) relative to fed conditions (Part 2, Cohort 2; Day 1 AUC0-12=470 hr*ng/mL; Day 14 AUC0-24=1220 hr*ng/mL,). This observation is in contrast to the food effect comparison in Part 1, Cohort 3A and 3B (400 mg KAR5585). In Part 1, a high fat, high calorie meal resulted in AUC0-inf of KAR5417 that was approximately 1.8-fold higher following drug administration of KAR5585 400 mg under fed conditions (AUC0-inf=6710 ng·hr/mL) relative to fasting conditions (AUC0-inf=3650 ng·hr/mL).
  • Steady-state plasma levels of KAR5417 were achieved by Day 7 as assessed by comparison of Day 7 and Day 14 AUC0-12 and C12 hr values following twice daily oral administration of KAR5585 for 14-days. Accumulation ratios for KAR5417 compared RCmax and RAUC0-12 for Day 7/Day 1 and Day 14/Day 1, and verified that steady-state was achieved by Day 7. The RAUC0-12 values for KAR5417 ranged from 2.19-2.57, 1.09-1.34 and 1.65-2.38 for the 100, 200 and 400 mg doses of KAR5585, respectively, suggesting that the PK of KAR5417 was independent of time, and steady-state was achieved on Day 7 following repeated twice-daily administration for 14-days.
    • Pharmacokinetics Conclusions:
  • KAR5585 is a prodrug for the active TPH1 inhibitor KAR5417. Following KAR5585 administration, KAR5585 was rapidly absorbed and converted to KAR5417.
  • Peak plasma KAR5417 concentrations, as measured by mean Cmax, appeared to increase in a greater that dose proportional manner from 100-400 mg (Part 2, Cohort 2-4, fed state). Mean Cmax values increased 6.9-fold over the 4-fold increase in dose between the 100 mg dose (Cohort 2) and the 400 mg dose (Cohort 4) on Day 1. On Day 14, mean Cmax values increased in an approximately dose proportional manner with an ˜4.5-fold increase in Cmax over the 4-fold increase in dose between the 100 mg dose (Part 2, Cohort 2) and the 400 mg dose (Part 2, Cohort 4). For doses of 100, 200 and 400 mg KAR5585, Part 2, Cohorts 2-4 (fed state), the median time to peak plasma concentrations of KAR5417 ranged from 2 to 6 hours, 3 to 8 hours, and 3 to 6 hrs.
  • Mean extent of systemic exposure to KAR5417, as measured by mean AUC0-12 and AUC0-24, appeared to increase in a greater than dose-proportional manner between the 100 and 400 mg dose levels, with a 7.0-fold and 6.45-fold increase in mean AUC0-12 and mean AUC0-24 estimates, respectively, for a 4-fold increase in dose between the 100 mg dose (Part 2, Cohort 2) and the 400 mg dose (Part 2, Cohort 4) on Day 1. Day 14, mean AUC0-12 and mean AUC0-24 estimates, increased 4.6-fold and 4.45-fold respectively, for a 4-fold increase in dose between the 100 mg dose (Part 1, Cohort 2) and the 400 mg dose (Part 2, Cohort 4).
  • Overall, the mean extent of systemic exposure to KAR5417, as measured by mean AUC0-12 and AUC0-24, appeared comparable under fasted conditions (Part 2, Cohort 1; Day 1 AUC0-12=741 hr*ng/mL; Day 14 AUC0-24=1650 hr*ng/mL,) relative to fed conditions (Part 2, Cohort 2; Day 1 AUC0-12=470 hr*ng/mL; Day 14 AUC0-24=1220 hr*ng/mL,). This observation is in contrast to the food effect comparison in Part 1, Cohort 3A and 3B (400 mg KAR5585). In Part 1, a high fat, high calorie meal resulted in AUC0-inf of KAR5417 that was approximately 2-fold higher following drug administration of KAR5585 400 mg under fed conditions (AUC0-inf=6710 ng·hr/mL) relative to fasting conditions (AUC0-inf=3650 ng·hr/mL).
  • The mean apparent elimination half-life of KAR5417 was 19.6, 25.0 and 30.6 hrs on Day 14 after oral administration of repeat dose twice-daily administration of 100, 200 and 400 mg of KAR5585 (Part 2, Cohort 2-4, fed state). The elimination half —life (30.6 hrs) of KAR5417 on repeat dose administration of 400 mg doses of KAR5585, was similar to the elimination half-life of KAR5417 (20.5 hrs) following single-dose administration of 400 mg KAR5585 (Part 1 Cohort 3B).
  • KAR5417 plasma levels achieved steady-state exposure by Day 7 as assessed by comparison of Day 7 and Day 14 AUC0-12 and C12 hr values following twice daily administration of KAR5585 for 14-days. Accumulation ratios for KAR5417 compared RCmax and RAUC0-12 for Day 7/Day 1 and Day 14/Day 1. The RAUC0-12 values for KAR5417 ranged from 2.19-2.57, 1.09-1.34 and 1.65-2.38 for the 100, 200 and 400 mg doses of KAR5585 suggesting that the PK of KAR5417 was independent of time and steady-state was achieved on Day 7 following repeated, twice-daily administration for 14-days.
    • Biomarker Evaluation:
  • Biomarker evaluations were carried out in subjects dosed with KAR5585 or placebo.
  • The biomarker portion of the study was conducted in Part 2 MAD using the Biomarker Population. The biomarkers evaluated were serum 5-HT and plasma 5-HIAA, as well as urine 5-HIAA/24 hours (as measured, adjusted, estimated, and per gram creatinine). Urinary 5-HIAA was determined by a validated (21 C.F.R. 58, GLP-compliant) method using liquid chromatographic separation and tandem mass spectrometry detection.
  • The Biomarker Population consisted of all subjects with evaluable baseline (Day 1 predose) and at least one postdose (Day 7 or Day 14) biomarker measurements.
  • A total of 48 subjects received study drug according to the protocol (Table 22). Two plasma 5 HIAA values were excluded from analyses because Day 7 assessments were lacking. These were values for Subject 001-M036 in the KAR5585 200 mg fed Cohort and Subject 001-M001 in the KAR5585 100 mg fasting Cohort. Tables and figures missing a Day 7 value for one or both these subjects are marked with an “s”. Values excluded were identified based on statistical criteria and clinical sensibility.
    • Baseline Characteristics:
  • Baseline characteristics are presented in Table 23. Baseline levels of the biomarkers serum 5-HT, plasma-5HIAA, the 5-HIAA measured in urine during 24 hours, without adjustment for daily variations in creatinine excretion (measured urine 5-HIAA), the 5-HIAA measured in urine during 24 hours, adjusted for the mean 24-hour creatinine excretion on Days 1, 7, and 14 (adjusted urine 5-HIAA), estimated urine 5-HIAA, and urine 5-HIAA were similar among the 5 treatment groups (placebo, KAR5585 100 mg fasting, KAR5585 100 mg fed, KAR5585 200 mg fed, and KAR5585 400 mg fed).
    • Analysis of Biomarkers: Biomarker Results and Tabulations of Individual Subject Data:
  • Biomarker data were analyzed for each KAR5585 dose separately, for all KAR5585 doses pooled, and for all placebo subjects pooled.
  • Biomarker analyses were performed for:
      • Serum 5-HT
      • Plasma 5-HIAA
      • Urine 5-HIAA/24 hours (as measured, adjusted, estimated, and per gram creatinine)
  • Analyses of biomarker changes and biomarker changes with respect to PK parameters were performed. Linear mixed-effect modeling for combined Day 7 and Day 14 biomarker measurements versus corresponding PK parameters to account for the repeated measures for the same subject had been planned but it was not performed because the relationships between Day 7 and Day 14 versus PK parameters were not consistent with each other.
  • Primary Biomarker Endpoint: Change in Plasma 5 HydroxyindoleaceticAcid from Day 1 to Day 14:
  • Dosing with KAR5585 reduced plasma 5-HIAA concentration. Mean percent change in plasma 5-HIAA was −56.67 from Day 1 to Day 7 and −53.33 from Day 1 to Day 14 in subjects randomized to KAR5575 400 mg under fed conditions. Mean percent change at Day 7 was +19.79 and at Day 14 was +20.12 in subjects randomized to placebo. Mean difference of both absolute and percent changes from Day 1 to Day 14 in plasma 5-HIAA concentration was statistically significant in favor of KAR5585 compared to placebo in each dose group and for all doses combined at Day 14 (Table 17).
  • TABLE 17
    (Differences of Changes from Day 1 Predose between KAR5585 and Placebo
    of Plasma 5-HIAA (ng/ml) by Cohort-Part 2 MAD Biomarker Population)
    Mean Difference of Changes from Day 1 between
    KAR5585 and Placebo
    Absolute Change from Day 1 % Change from Day 1
    Estimate Estimate
    Dose Level/Time (95% CI) P Value (95% CI) P Value
    100 mg Predose Day 7 0.33 0.9531 23.67 0.6330
    Fasting (−10.74, 11.41) (−73.11, 120.45)
    Predose Day 14 −5.92 0.0015 −48.83 <.0001
    (−9.42, −2.41) (−67.43, −30.22)
    100 mg Predose Day 7 −4.56 0.4226 −48.56 0.3284
    Fed (−15.63, 6.52) (−145.34, 48.21)
    Predose Day 14 −4.50 0.0175 −52.70 <.0001
    (−8.13, −0.87) (−71.95, −33.45)
    200 mg Predose Day 7 1.22 0.8293 12.06 0.8077
    Fed (−9.85, 12.30) (−84.72, 108.83)
    Predose Day 14 −5.25 0.0059 −52.46 <.0001
    (−8.88, −1.62) (−71.71, −33.20)
    400 mg Predose Day 7 −11.44 0.0463 −76.47 0.1255
    Fed (−22.52, −0.37) (−173.24, 20.31)
    Predose Day 14 −10.69 <.0001 −73.45 <.0001
    (−14.20, −7.19) (−92.05, −54.85)
    All Predose Day 7 −3.61 0.4005 −22.33 0.5515
    Doses (−11.98, 4.76) (−95.48, 50.83)
    Predose Day 14 −6.69 <.0001 −57.11 <.0001
    (−9.36, −4.02) (−71.27, −42.95)
    Abbreviations: 5-HIAA, 5-hydroxyindoleacetic acid; CI, confidence interval; MAD, multiple ascending dose.
    • Biomarker: Measured Urine 5-Hydroxyindoleacetic Acid:
  • Urine 5 HIAA/24 hour was analyzed in 4 different manners: as measured in the 24-hour collection and (in order to correct for any collection errors) adjusted for creatinine excretion, estimated by the expected creatinine excretion for the subject (as defined in and expressed per gram creatinine. Results were similar for each of the 4 manners and are presented in this report for measured urine. Tables and figures for adjusted, estimated, and per-gram creatinine results are presented in Section 14.
  • Dosing with KAR5585 reduced measured urine 5-HIAA concentration. Mean percent change in measured urine 5-HIAA was −39.97 from Day 1 to Day 7 and −50.85 from Day 1 to Day 14 in subjects randomized to KAR5575 400 mg under fed conditions. Mean percent change at Day 7 was +9.44 and at Day 14 was +3.97 in subjects randomized to placebo.
  • Difference of absolute and relative changes from Day 1 in measured urine 5-HIAA on Days 7 and 14 were statistically significant in favor of KAR5585 in all dose groups except one: the relative change on Day 14 for the KAR5585 100 mg fasting dose group (Table 18).
  • TABLE 18
    (Differences of Changes from Day 1 Predose between KAR5585
    and Placebo of Measureda Urine 5-Hydroxyindoleacetic
    Acid (mg/24 hours), by Cohort (Biomarker Population))
    Mean Difference of Changes from Day 1 between
    KAR5585 and Placebo
    Absolute Change from Day 1 % Change from Day 1
    Estimate Estimate
    Dose Level/Time (95% CI) P Value (95% CI) P Value
    100 mg Predose Day 7 −0.92 .0208 −31.97 .0005
    Fasting (−1.68, −0.16) (−49.29, −14.64)
    Predose Day 14 −0.91 .0007 −17.65 .1113
    (−1.41, −0.40) (−39.12, 3.82)
    100 mg Predose Day 7 −2.09 <.0001 −50.34 <.0001
    Fed (−2.86, −1.33) (−67.66, −33.01)
    Predose Day 14 −1.65 <.0001 −36.03 .0022
    (−2.18, −1.13) (−58.26, −13.81)
    200 mg Predose Day 7 −0.92 .0248 −26.95 .0043
    Fed (−1.71, −0.13) (−44.89, −9.02)
    Predose Day 14 −1.58 <.0001 −37.11 .0016
    (−2.10, −1.06) (−59.33, −14.89)
    400 mg Predose Day 7 −1.68 <.0001 −49.41 <.0001
    Fed (−2.44, −0.92) (−66.73, −32.08)
    Predose Day 14 −2.04 <.0001 −54.82 <.0001
    (−2.55, −1.54) (−76.29, −33.35)
    All Predose Day 7 −1.42 <.0001 −40.03 <.0001
    Doses (−2.00, −0.84) (−53.17, −26.89)
    Predose Day 14 −1.54 <.0001 −36.39 <.0001
    (−1.93, −1.16) (−52.74, −20.05)
    aMeasured is as measured in 24-hour 5HIAA excretion without adjustment for variations in daily creatinine excretion.
    Abbreviations: 5-HIAA, 5-hydroxyindoleacetic acid, CI, confidence interval.
  • Both absolute and percent changes from Day 1 in creatinine-normalized urine 5-HIAA on Days 7 and 14 were statistically significant in favor of KAR5585 versus placebo in all dose groups.
    • Serum 5-Hydroxytryptamine:
  • Mean difference of both absolute and relative changes from Day 1 to Day 14 in serum 5-HT concentration was statistically significant in favor of KAR5585 compared to placebo for the 400 mg fed and all KAR5585 doses pooled (Table 19).
  • Mean difference of percent changes from Day 1 in serum 5-HT concentration was statistically significant compared to placebo on Day 7 in favor of the 200 mg fed dose group.
  • TABLE 19
    Differences of Changes from Day 1 Predose between KAR5585 and Placebo of
    (Serum 5-HT (ng/ml) by Cohort-Part 2 MAD Biomarker Population)
    Mean Difference of Changes from Day 1 between
    KAR5585 and Placebo
    Absolute Change from Day 1 % Change from Day 1
    Estimate Estimate
    Dose Level/Time (95% CI) P Value (95% CI) P Value
    100 mg Predose Day 7 −12.97 .4642 −10.97 .2567
    Fasting (−47.53, 21.59) (−29.80, 7.85)
    Predose Day 14 −17.39 .3285 −15.92 .1598
    (−52.04, 17.26) (−37.90, 6.06)
    100 mg Predose Day 7 −15.75 .3745 −11.02 .2549
    Fed (−50.31, 18.81) (−29.84, 7.81)
    Predose Day 14 5.08 .7820 −0.47 .9678
    (−30.79, 40.95) (−23.22, 22.28)
    200 mg Predose Day 7 −28.53 .1097 −21.64 .0270
    Fed (−63.09, 6.03) (−40.47, −2.82)
    Predose Day 14 −5.79 .7525 −11.43 .3279
    (−41.66, 30.08) (−34.18, 11.32)
    400 mg Predose Day 7 16.47 .3531 2.09 .8282
    Fed (−18.09, 51.03) (−16.73, 20.91)
    Predose Day 14 −84.50 <.0001 −50.02 <.0001
    (−119.15, −49.85) (−72.00, −28.04)
    All Predose Day 7 −10.19 .4467 −10.39 .1566
    Doses (−36.32, 15.93) (−24.61, 3.84)
    Predose Day 14 −27.14 .0475 −20.26 .0203
    (−53.52, −0.75) (−36.99, −3.52)
    • Analysis of Biomarkers in Relation to Pharmacokinetic Parameters:
  • All subjects were dosed with KAR5585 or placebo. Following dosing, KAR5585 was rapidly absorbed and the active moiety KAR5417 appeared rapidly in plasma.
  • Only those subjects with all biomarker results and results for the PK parameters AUC0-24, Cmin, concentration, obtained 12 hr after an administered dose (C12 hr), and AUC0-12 were included in the PK-Biomarker analyses. The PK parameters AUC0-24, Cmin, C12 hr, and AUC0-12 were adjusted from those stated in the protocol (AUC0-24, Cmin, and Cmax) to account for the double daily dosing.
  • All subjects in Part 2 (MAD) were eligible for biomarker analyses. Only the subset of the Biomarker Population randomized to active drug were included in PK-Biomarker analyses.
    • Pharmacokinetic Parameters and Plasma 5-Hydroxyindoleacetic Acid, the Primary Biomarker Endpoint:
  • On Day 14, the absolute and relative changes from baseline in plasma 5-HIAA were significantly correlated with KAR5417 AUC0-24, Cmax, C12, and AUC0-12 (P≤0.0010).
  • Greater values for the PK parameters were associated with greater decreases in plasma 5-HIAA concentrations, as illustrated in FIG. 23 , which shows the relationship between relative changes from baseline in plasma 5-HIAA and KAR5417 AUC0-24.
  • FIG. 23 discloses absolute and relative changes at day 14 of Plasma 5-HIAA from Day 1 Predose vs. AUC[0-24] in subjects who received KAR5585—Part 2 MAD Biomarker Population.
  • While there were no significant correlations on Day 7 between absolute or relative change from baseline in serum 5-HT concentration and AUC0-24, Cmax, C12, or AUC0-12 for KAR5417, both absolute and relative changes on Day 14 were correlated (P<0.0010).
  • While there were no significant correlations between absolute or relative change from baseline in measured urine 5-HIAA and KAR5417 AUC0-24, Cmax, C12, or AUC0-12 on Day 7, both absolute and relative changes were significantly correlated for Day 14 (P≤0.0067). Greater values for the PK parameters were associated with greater decreases in measured urine 5-HIAA concentrations, which shows the relationship between relative change in measured urine 5-HIAA (mg/24 hours) from Day 1 to Day 14 and KAR5417 AUC0-24.
  • The relationships between adjusted and estimated urine 5-HIAA and KAR5417 PK parameters were similar to those for measured urine 5-HIAA: though there were no significant correlations on Day 7 between absolute or relative change from baseline in urine 5-HIAA and KAR5417 PK parameters, the correlations were significant on Day 14 for both absolute and relative changes in urine 5-HIAA and KAR5417 PK parameters (adjusted urine 5-HIAA, P≤0.0007; estimated urine 5-HIAA, P≤0.0110).
    • Discussion of Biomarker Results:
  • There was a strong association between plasma 5-HIAA (pre-established as the primary biomarker endpoint) and both KAR5585 dose and the duration of dosing. The mean reduction from Day 1 to Day 14 in plasma 5-HIAA was greater for the highest dose (
    Figure US20240041877A1-20240208-P00002
    53.33%, 400 mg fed) than for the lowest dose (−28.71%, 100 mg fasting; −32.58%, 100 mg fed). The mean percent difference of change from Day 1 between KAR5585 and placebo was significant (P<0.0001) for each dose group and all doses pooled at Day 14 but not significant at Day 7 for any dose group.
  • There was also a strong association between urine 5-HIAA/24 hours and KAR5585 dose. At the highest KAR5585 dose, 400 mg, mean percent change in measured urine 5-HIAA was 1150.85 from Day 1 to Day 14, whereas mean percent change in subjects randomized to placebo was +3.97. Mean differences of absolute and relative changes from Day 1 to Day 14 were statistically significant in favor of KAR5585 in all dose groups except one (the relative change on Day 14 for the KAR5585 100 mg fasting dose group). Results were comparable in urine 5-HIAA/24 hours as adjusted, estimated, and per gram creatinine.
  • Serum 5-HT did not reveal the strong association between the biomarker of serotonin and KAR5585 dose or duration of dosing. The differences of changes from Day 1 between KAR5585 and placebo were statistically significant for the highest dose group (400 mg fed) and for all KAR5585 doses pooled.
  • A strong relationship was seen between KAR5417 exposure and 5-HIAA reductions. A strong relationship between both plasma and urine 5-HIAA is supported by the observation that higher exposure to KAR5417, as measured by the PK parameters AUC0-24, Cmax, C12, and AUC0-12, was associated with greater reduction in 5-HIAA.
    • Biomarker Conclusions:
  • Dose- and time-dependent reductions were observed in 5-HIAA (a PD marker of 5-HT synthesis) in both plasma and urine.
  • At the highest KAR5585 dose, 400 mg, mean percent change in plasma 5-HIAA concentration was −53.33 from Day 1 to Day 14, whereas mean percent change in subjects randomized to placebo was +20.12.
  • At the highest KAR5585 dose, 400 mg, mean percent change in measured urine 5-HIAA was −50.85 from Day 1 to Day 14, whereas mean percent change in subjects randomized to placebo was +3.97. Results were comparable in urine 5-HIAA/24 hours as adjusted, estimated, and per gram creatinine.
  • A strong relationship was seen between KAR5417 exposure and 5-HIAA reductions.
    • OVERALL CONCLUSIONS
  • The study was divided into 2 parts: SAD (Part 1) and MAD (Part 2). Part 1 (SAD) was further divided into Period 1 (fasting administration) and Period 2 (fed administration, food effect). The KAR5585 doses administered were the following:
      • In Part 1 (SAD) Period 1 (fasting): 100 mg, 200 mg, 400 mg, 700 mg, 1200 mg, or 2000 mg in Cohorts 1 through 6, respectively
      • In Part 1 (SAD) Period 2 (fed, high-fat food effect): 400 mg in Cohort 3 only
      • In Part 2 (MAD): 100 mg (fasting), 100 mg (fed), 200 mg (fed), and 400 mg (fed) or matching placebo administered BID (approximately every 12 hours) for 27 doses in Cohorts 1 through 4, respectively.
  • Pharmacokinetics: Following administration of KAR5585 (prodrug), KAR5417 (active TPH1 inhibitor) appeared rapidly in plasma, an observation consistent with rapid absorption of KAR5585 and efficient conversion to KAR5417.
  • Administration of the KAR5585 under fed conditions in Part 1, Period 2, increased the extent and peak of exposure of both KAR5585 and KAR5417. This was considered to be a clinically-relevant change in exposure. In Part 2, the mean extent of systemic exposure to KAR5417, as measured by mean AUC0-12 and AUC0-24, appeared comparable under fasted conditions. This observation is in contrast to the food-effect comparison in Part 1.
  • Biomarkers: Dose- and time-dependent reductions were observed in 5-HIAA (a PD marker of 5-HT synthesis) in both plasma and urine.
  • At the highest KAR5585 dose, 400 mg, mean percent change in plasma 5-HIAA concentration was −53.33 from Day 1 to Day 14, whereas mean percent change in subjects randomized to placebo was +20.12.
  • At the highest KAR5585 dose, 400 mg, mean percent change in measured urine 5-HIAA was −50.85 from Day 1 to Day 14, whereas mean percent change in subjects randomized to placebo was +3.97. Results were comparable in urine 5-HIAA/24 hours as adjusted, estimated, and per gram creatinine.
  • A strong relationship was seen between KAR5417 exposure and 5-HIAA reductions.
  • Following administration of KAR5585 (prodrug), KAR5417 (active TPH1 inhibitor) appeared rapidly in plasma, an observation consistent with rapid absorption of KAR5585 and efficient conversion to KAR5417. A strong relationship was seen between KAR5417 exposure and 5-HIAA reductions. Neither the prodrug (KAR5585) nor the active drug (KAR5417) showed any tendency to increase QTcF in a dose-dependent manner.
  • It should be understood that the foregoing description is only illustrative of the present disclosure. Various alternatives and modifications can be devised by those skilled in the art without departing from the present disclosure. Accordingly, the present disclosure is intended to embrace all such alternatives, modifications and variances which fall within the scope of the appended claims.

Claims (24)

What is claimed is:
1. A daily dosage regimen for treating pulmonary arterial hypertension, comprising two discrete dosage forms, wherein the dosage forms each include an amount of about 600 mg to about 800 mg of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.
2. The daily dosage regimen of claim 1, wherein the dosage forms each include RVT-1201, wherein the (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate is substantially as depicted in FIG. 1 .
3. The daily dosage regimen of claim 1, wherein the dosage forms are oral dosage forms.
4. The daily dosage regimen of claim 1, wherein each of the dosage forms further include an amount of a pharmaceutically acceptable excipient.
5. A daily dosage regimen for treating pulmonary arterial hypertension, comprising an amount of 1200 mg to 1600 mg of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.
6. The daily dosage regimen of claim 5, wherein the (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate is substantially as depicted in claim 1.
7. The daily dosage regimen of claim 6, wherein the amount further includes a pharmaceutically acceptable excipient.
8. A method for treating pulmonary arterial hypertension, comprising administering to a human patient in need thereof an amount of 1200 mg to 1600 mg of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate per day.
9. The method of claim 8, wherein the (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate is substantially as depicted in FIG. 1 .
10. The method of claim 8, wherein the amount is administered orally.
11. The method of claim 8, wherein the amount is administered at 600 mg to 800 mg BID.
12. A method for reducing the level of serotonin biosynthesis by at least 50% within 14 days after commencement of treatment, comprising administering to a human patient in need thereof an amount of about 800 mg to about 1600 mg of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate per day.
13. The method of claim 12, wherein the (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate is substantially as depicted in FIG. 1 .
14. The method of claim 12, wherein the amount is administered orally.
15. The method of claim 12, wherein the amount is administered is about 400 mg to about 800 mg BID.
16. The method of claim 12, wherein the amount is administered at dosages selected from the group consisting of about 400 mg BID, 600 mg BID, and 800 mg BID.
17. A method for achieving an AUC0-tau of ≥2530 ng.hr/mL of (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid within 14 days after administration, comprising administering daily to a human patient an effective amount of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.
18. The method of claim 17, wherein the amount administered is about 800 mg to about 1600 mg per day.
19. The method of claim 18, wherein the amount is administered is about 400 mg to about 800 mg BID.
19. A method of achieving a >50% reduction in urinary 5-HIAA within 14 days after administration, comprising administering daily to a human patient an effective amount of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.
20. The method of claim 19, wherein the amount administered is about 800 mg to about 1600 mg per day.
21. The method of claim 20, wherein the amount is administered is about 400 mg to about 800 mg BID.
22. A method for treating pulmonary arterial hypertension, comprising administering daily to a human patient in need thereof an amount of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate sufficient to achieve an AUC0-tau of ≥2530 ng.hr/mL of (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid within 14 days after commencement of administration.
23. A method for treating pulmonary arterial hypertension, comprising administering daily to a human patient in need thereof an amount of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate effective to achieve a >50% reduction in urinary 5-HIAA within 14 days after commencement of administration.
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