EP2023923A2 - Utilisation de l'ixabépilone en combinaison avec des inhibiteurs du cyp3a4 en tant que produits pharmaceutiques - Google Patents

Utilisation de l'ixabépilone en combinaison avec des inhibiteurs du cyp3a4 en tant que produits pharmaceutiques

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Publication number
EP2023923A2
EP2023923A2 EP07784137A EP07784137A EP2023923A2 EP 2023923 A2 EP2023923 A2 EP 2023923A2 EP 07784137 A EP07784137 A EP 07784137A EP 07784137 A EP07784137 A EP 07784137A EP 2023923 A2 EP2023923 A2 EP 2023923A2
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EP
European Patent Office
Prior art keywords
ixabepilone
cancer
ketoconazole
cyp3a4
administered
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EP07784137A
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German (de)
English (en)
Inventor
Marvin Barry Cohen
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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Publication of EP2023923A2 publication Critical patent/EP2023923A2/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Ixabepilone is a semisynthetic analog of epothilone B. It is [IS- [lR*,3R*(E),7R*,10S*,HR*,12R*,16S*]]-7,l l-Dihydroxy-8, 8,10,12,16- pentamethyl-3 -[ 1 -methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza- 17- oxabicyclo[14.1.0]heptadecane-5,9-dione, having the structure:
  • Ixabepilone stabilizes microtubules, induces apoptosis, and has demonstrated high anti-tumor activity.
  • Ixabepilone, processes for preparing ixabepilone, and formulations and methods of treatment or Use comprising ixabepilone are disclosed in U.S. Patent 6,365,749; U.S. Patent 6,518,421; U.S. Patent 6,605,599; U.S. Patent 6,670,384; U.S. Patent 6,686,380; U.S. Patent 6,689,803; U.S. Patent 6,982,276; U.S. Patent 7,008,936; U.S. Patent 7,022,330; and U.S. Patent Application Publication 2003/0073677 Al, each of which is incorporated herein by reference in its entirety.
  • Ixabepilone is a cytotoxic compound and administration of the compound presents adverse effects of the human patient while treating the cancer.
  • adverse reactions in monotherapy include peripheral sensory neuropathy and fatigue.
  • Uses of ixabepilone are sought that provide efficacious medicaments for treatment at lower administered dosages.
  • ixabepilone in combination with inhibitors of CYP3A4/5 enzymes, provides a medicament that has an enhanced beneficial anti-cancer effect as compared with when ixabepilone is administered unaccompanied by ketoconazole at the same dose.
  • use of ixabepilone to treat cancer can be effectively achieved with a dose that is substantially less than the recommended dose for treating cancer when ixabepilone is administered alone.
  • the CYP3A4/5 inhibitor for example, ketoconazole or lapatinib, inhibits the removal of the ixabepilone by the CYP3A4/5 enzymes, thus allowing treatment of cancer using lower amounts of ixabepilone than the treatment using ixabepilone in the absence of ketoconazole or lapatinib.
  • the Use may also be employed to prolong the exposure of the cancer cells to higher levels of ixabepilone, by inhibiting the removal of the ixabepilone by CYP3A4/5 enzymes, when compared to ixabepilone administered in the absence of the CYP3A4/5 inhibitor(s).
  • FIGS. 1A-1B are tables (Tables 1A-1B) respectively, showing results of a clinical study directed to the interaction of ixabepilone and a CYP3A4/5 inhibitor, namely ketoconazole, and pharmacokinetic parameters for ixabepilone, as follows:
  • IA Summary Statistics for ixabepilone PK parameters.
  • the C ma ⁇ and AUC 0 _ ⁇ values are geometric means (%CV) and the remaining parameters are means (+ SD).
  • the sample size (n) represents number of patients assessed;
  • FIG. 2 illustrates an alternative embodiment showing the maximum percentage of microtubule bundles (MTB) bundling in peripheral blood mononuclear cells where ixabepilone is administered at reduced in combination with ketoconazole (Cycle 1) and where ixabepilone is administered at full dose (Cycle 2);
  • MTB microtubule bundles
  • FIG. 3 A shows concentration-dependent metabolism of ixabepilone in human livermicrosomes
  • FIG. 3B shows concentration-dependent metabolism of ixabepilone in human cDNA expressed CYP3A4/5 enzymes
  • FIG. 3 C shows clinical results of the relationship of percent PBMCs with microtubule bundles and ixabepilone plasmaconcentration.
  • Ixabepilone is a semi-synthetic analog of epothilone B that binds tubulin and induces formation of microtubule bundles in cells which can be measured in the laboratory.
  • Mani S et ah "The clinical development of new mitoticinhibitors that stabilize the microtubule," Anticancer Drugs 2004; 15(6):553-8.
  • Mani S, et ah "Phase I clinical and pharmacokinetic studyof BMS-247550, a novel derivative of epothilone B, in solid tumors," Clin. Cancer Res 2004; 10(4): 1289-98.
  • Cytochrome P450 enzymes include a number of human cytochrome P450 enzymes, including the CYP3A family of enzymes, i.e., CYP3A4 and CYP3A5. References to "CYP3A4/5" are intended to include either or both of CYP3A4 and CYP3A5. This family of enzymes catalyzes oxidative and reductive reactions and has activity towards a chemically diverse group of substrates.
  • cytochrome P450 enzymes are the major catalysts of drug biotransformation reactions and also serve an important detoxification role in the body.
  • Inhibitors of the cytochrome P450 enzymes particularly, CYP3A4/5 inhibitors, interfere with the body's ability to detoxify.
  • developing pharmaceuticals for human consumption that inhibit CYP3A4/5, and/or that may effectively and safely be used in combination with compounds that inhibit CYP3A4/5 presents particular challenges. See, for example, the Guidance for Industry: In Vivo Drug Metabolism/Drug Interaction Studies— Study Design, Data Analysis, and Recommendations for Dosing and Labeling prepared by the Food and Drug Administration (November 1999).
  • CYP3A4/5 inhibition may be considered an undesirable activity, and efforts are directed in research to develop compound that do not inhibit
  • CYP3A4/5 See, e.g., US 6,992,193 B2, "Sulfonylamino phenylacetamide derivatives and methods of their use.”
  • Commonly-known CYP3A4/5 inhibitors include HIV protease inhibitors (indinavir, nelfmavir, ritonavir), amiodarone, cimetidine, clarithromycin, diltiazen, erythromycin, fluvoxamine, grapefruit juice, itraconazole, ketoconazole, mibefradil, nefazodone, troleandomycin, and verapamil.
  • Lapatinib an FDA approved tyrosine kinase inhibitor available from Glaxosmith Kline, is also a CYP3A4/5 inhibitor.
  • CYP3A4/5 inhibitors as used herein include each of these substances, as well as any other CYP3A4/5 inhibitors well known in the field. See, e.g., WO 2005/007631.
  • Potent CYP3A4/5 inhibitors which are of particular interest in view of their potency, include ketoconazole, itraconazole, ritonavir, amprenavir, indinavir, nelfmavir, delavirdine, and voriconazole.
  • Ketoconazole one of the potent CYP3A4/5 inhibitors, is an imidazole compound used as an antifungal agent.
  • Ketoconazole is cis-l-acetyl-4-[4-[[2-(2,4-di- chlorophenyl)-2-( 1 H-imidazol- 1 -ylmethyl)- 1 ,3 -dioxolan-4- yl]methoxy]phenyl]piperazine, and has the structure:
  • Ketoconazole was originally described in US Pat. 4,335,125, incorporated herein, with its principal utility being as an antifungal agents. Ketoconazole and formulations are well known and widely described, for example, see US Pat.
  • CYP3A4/5 inhibitors in combination with ixabepilone provides surprisingly advantageous results, enabling a reduction in the dose of ixabepilone.
  • a clinical study was performed in patients with cancer evaluating the impact of ketoconazole (inhibitor of CYP3A4) on pharmacokinetics, drug-target interactions and pharmacodynamics of ixabepilone.
  • ketoconazole co- administration resulted in substantial reduction in dose as the maximum dose, for
  • ixabepilone when compared to single agent therapy (40 mg/m ).
  • Co-administration of ketoconazole with ixabepilone resulted in a 79% increase in AUC 0 ⁇ and the relationship of microtubule bundle formation in peripheral blood mononuclear cells (MT-PBMC) to plasma ixabepilone concentration was well described by the Hill Equation.
  • MT-PBMC correlated with neutropenia.
  • Ixabepilone is oxidatively metabolized by enzymes CRP3A4/5 in the human body.
  • Inhibitors of CYP3A4/5 may be used in the context of ixabepilone dosing with reduced dosage of ixabepilone as compared with monotherapy.
  • CYP3A4/5 plays a major role in the oxidative metabolism of ixabepilone at concentrations of 0.1 to 25 ⁇ M in native human liver microsomes.
  • the clinical study validates in vitro findings that inhibition of CYP3 A4/5 by ketoconazole significantly increase the exposure to ixabepilone, and that inhibition of its metabolism directly alters its blood exposure.
  • In vitro microsomal studies show that ixabepilone is selectively metabolized by CYP3A4/5 and not by other cytochromes tested.
  • ketoconazole and ixabepilone clearly indicate that inhibition of CYP3 A4/5 by ketoconazole significantly increases the exposure of ixabepilone in the blood and alters drug-target effect.
  • the invention herein is directed to combined use of ixabepilone and CYP3A4/5 inhibitors, particularly lapatinib and ketoconazole, where the ixabepilone is administered at a substantially reduced dose to achieve the same effect that would be obtainable from a higher dose recommended for administration of ixabepilone in the absence of CYP3A4/5 inhibitors.
  • the discoveries and data herein herein support Uses of ixabepilone in combination with other CYP3A4/5 inhibitors, at reduced doses of ixabepilone.
  • ketoconazole is one of the most potent inhibitors of CYP3A4, other clinically important inhibitors of CYP3A4/5 are described above, and are commonly used in cancer patients. See, Marechal, et ah, "In silico and in vitro screening for inhibition of cytochrome P450 CYP3A4 by comedications commonly used by patients with cancer," Drug Metab Dispos
  • a technically straightforward assay ( ⁇ ⁇ 8hr performance time) is used to visually quantitate tubulin bundles and predict both neutropenia and blood levels of ixabepilone.
  • Applicants have discovered there is a direct relationship between ixabepilone pharmacokinetics, neutrophil counts, and microtubule bundles in PBMCs.
  • a count of microtubule bundles in PBMCs serve as a validated surrogate for assessing ixabepilone toxicity.
  • the CYP3A4/5 inhibitor is co-administered with ixabepilone, also in co-administration with a compound that is an activator of the human pregnane x receptor.
  • co-administration of the CYP3A4/5 inhibitor and ixabepilone is advantageous in both protecting against inadvertent metabolism and drug interactions with ixabepilone and aiding in its anti-tumor effects.
  • Co-medications e.g., dexamethasone
  • routinely used in cancer patients can serve as potent activators of the human pregnane x receptor (PXR).
  • ketoconazole regulates CYP3A4/5 at the level of transcription, which could alter drug metabolism by inducing its expression.
  • Ketoconazole can inhibit PXR mediated CYP3 A4/5 transcription and normalize transcriptional regulation of CYP3A4/5 across the patient population.
  • PXR can also regulate tumor drug metabolism and resistance and ketoconazole may inhibit this process also.
  • co-administration of ketoconazole may be advantageous. Supporting these findings are the observation that ketoconazole can augment cytotoxicity of drugs (e.g., nocodazole) in cancer cells. DEFINITIONS
  • ixabepilone or “ixa” encompasses the aza-epothilone B analog ixabepilone, as described above on page 1, or a pharmaceutically-acceptable solvate, clathrate, hydrate, and/or prodrugs thereof (including mixtures of any of the foregoing).
  • Processes for making ixabepilone are described in the art, for example, US Pat. 6,365,749, U.S. Pat. 6,518,421, and US patent application publication 2004/0132146Al (Serial No. 10/668,032), all of which are assigned to the present assignee and incorporated herein by reference.
  • prodrug denotes a compound which, upon administration to a subject undergoes chemical conversion by metabolic or chemical processes to yield the active ingredient, i.e., ixabepilone.
  • solvate refers to a form of compound that further comprises a solvent, such as for example, an alcohol such as ethanol.
  • clathrate refers to a form having a crystalline structure with voids or channels that may optionally comprise solvent or water.
  • hydrate refers to a form of ixabepilone that further comprises water.
  • substantially reduced dose or a “substantial reduction in dose” means a reduction in dose, i.e., for ixabepilone, that is at least twenty-five percent less than the standard recommended dose, more preferably at least thirty -percent less, and most more preferably more than 40% less, and most preferably about 40-50% less.
  • standard recommended dose or “standard dose” for ixabepilone is 40 mg/m administered intraveneously over three hours every three weeks.
  • AUC is the area under the curve
  • MRT is the mean residence time
  • Vss is the volume of distribution at steady state
  • MTD is maximum tolerated dose
  • DLT is dose limiting toxicity
  • SEM is standard error of the mean
  • PET is a form of well known scan, i.e., position emission tomography.
  • a method for the treatment of cancer comprising administering to a human a therapeutically-effective combination of CYP3A4/5 inhibitors (e.g., lapatinib, ketoconazole) and ixabepilone. Also disclosed are Uses for preparing medicaments for treatment of human patients, comprising a combination of
  • CYP3A4/5 inhibitors e.g., lapatinib, ketoconazole and ixabepilone.
  • the CYP3A4/5 inhibitors can be administered daily.
  • the CYP3A4/5 inhibitor(s) e.g., lapatinib, ketoconazole
  • the ixabepilone for example, starting at least one day prior to the administration of the ixabepilone.
  • CYP3A4/5 inhibitors e.g., lapatinib, ketoconazole
  • the administration of the CYP3A4/5 inhibitors can be continued for one or more days after completion of the ixabepilone administration.
  • the cycle of CYP3A4/5 inhibitors (e.g., lapatinib, ketoconazole) and ixabepilone administration can be repeated one or more times, as appropriate to treat the patient.
  • the suitable amount of ixabepilone (i.e., reduced dose) to be administered according to the invention includes at least about 15 mg/m 2 , and preferably, at least about 20-25 mg/m 2 .
  • suitable ranges for Use in the invention include from about 10 to about 35 mg/m 2 , more preferably from about 15 to about 30 mg/m 2 , and most preferably at from about 20 to about 30 mg/m 2 .
  • particular doses include about 20 mg/m 2 , about 25 mg/m 2 , and about 30 mg/m 2 .
  • the ixabepilone may be administered on different cycles and over different time spans but in one embodiment is administered over a period of 1 to 3 hours, once every 21 days.
  • oral administration of ixabepilone for example, in the form of an enteric coated bead used to prepare a tablet or capsule, as described in WO 2006/055740, published May 26, 2006, incorporated herein.
  • suitable ranges to be administered include at least about 100 mg per day, at least about 200 mg per day, and at least about 300 mg per day.
  • suitable ranges include from about 100 to 400 mg per day, about 200 to about 400 mg per day, and about 300 to about 400 mg per day.
  • Ketoconazole administration may be once daily, or divided into two or more dosages given over a 24 hour period.
  • a method of treating cancer in a human comprising administering to the human a therapeutically-effective combination of (1) an amount of a CYP3A4/5 inhibitor (e.g., lapatinib, ketoconazole) and (2) at least about 15-30 mg/m of ixabepilone wherein the ixabepilone is administered intravenously every three weeks, preferably over the course of a 3 hour infusion.
  • a CYP3A4/5 inhibitor e.g., lapatinib, ketoconazole
  • ixabepilone is administered intravenously every three weeks, preferably over the course of a 3 hour infusion.
  • the Use or method of treatment involves about 20 mg/m 2
  • the Use or method of treatment involves about 25 mg/m .
  • a method of treating cancer in a human comprising administering to the human a therapeutically-effective combination of (1) at least about 100 mg per day of ketoconazole and (2) at least about 15 mg/m 2 of ixabepilone.
  • Alternate variations of this embodiment include administration of about 200 mg per day ketoconazole, as well as about 300 mg per day, and also about 400 mg per day, of ketoconazole.
  • at least about 20-25 mg/m 2 of ixabepilone is administered intravenously every three weeks.
  • Another embodiment encompasses the administration of at least about 300 mg per day of ketoconazole and at least about 20-25 mg/m 2 of ixabepilone.
  • a method of treating cancer in a human comprising administering to the human a therapeutically-effective combination of (1) an amount of a CYP3A4/5 inhibitor (e.g., lapatinib, ketoconazole) and (2) an amount of ixabepilone, wherein the combined administration provides an enhanced anti-cancer effect as compared with when ixabepilone is administered unaccompanied by a CYP3A4/5 inhibitor (e.g., lapatinib, ketoconazole).
  • a CYP3A4/5 inhibitor e.g., lapatinib, ketoconazole
  • enhanced anticancer effect it is meant that the dose of ixabepilone can be substantially reduced, wherein the term substantially reduced is as defined above, and includes reduction in dose of at least about 25%, and also up to about 40-50%, while achieving the same microtubule stabilizing effect, e.g., when the CYP3A4/5 inhibitor (e.g., lapatinib, ketoconazole) is administered in combination with the ixabepilone, the dose of ixabepilone can be reduced while achieving the same microtubule stabilizing effect and thus, the same anti-cancer effect.
  • the CYP3A4/5 inhibitor e.g., lapatinib, ketoconazole
  • Ixabepilone is useful as a microtubule-stabilizing agent. Ixabepilone is useful in the treatment of a variety of cancers and other proliferative diseases including, but not limited to, the following:
  • - carcinoma including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid, and skin, including squamous cell carcinoma;
  • - hematopoietic tumors of lymphoid lineage including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, lymphomas including B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, and Burketts lymphoma;
  • - hematopoietic tumors of myeloid lineage including acute and chronic myelogenous leukemias and promyelocytic leukemia;
  • tumors including melanoma, seminoma, teratocarcinoma, neuroblastoma, and glioma;
  • tumors of the central and peripheral nervous system including astrocytoma, neuroblastoma, glioma, and schwannomas;
  • tumors of mesenchymal origin including fibrosarcoma, rhabdomyoscaroma, and osteosarcoma;
  • tumors including melanoma, xeroderma pigmentosum, keratoacanthoma, seminoma, thyroid follicular cancer, and teratocarcinoma.
  • Ixabepilone is useful for treating patients who have been previously treated for cancer, as well as those who have not previously been treated for cancer.
  • the methods and compositions of this invention can be used in first-line and second-line cancer treatments and in the adjuvant setting. Furthermore, the methods of the invention can be applied for treating refractory or resistant cancers.
  • Ixabepilone will induce or inhibit apoptosis, a physiological cell death process critical for normal development and homeostasis. Alterations of apoptotic pathways contribute to the pathogenesis of a variety of human diseases.
  • the subject compounds, as modulators of apoptosis, will be useful in the treatment of a variety of human diseases with aberrations in apoptosis including, but not limited to, cancer and precancerous lesions, immune response related diseases, viral infections, kidney disease, and degenerative diseases of the musculoskeletal system.
  • the recommended dosage of ixabepilone in the absence of the CYP3A4/5 inhibitor(s) is 40 mg/m administered intravenously over 3 hours every 3 weeks.
  • Body surface area may be considered as a factor in determining the recommended dose for a particular patient. Doses for patients with BSA (body surface area) greater
  • 2 2 than 2.2 m can be calculated based on 2.2 m . Additionally, dose adjustments may be made, or treatment delayed or discontinued, if toxicities are present. Additionally, dose reduction is recommended when administering ixabepilone for monotherapy to patients with hepatic impairment. Based upon a population pharmacokinetic analysis in human patients, gender, race and age do not have meaningful effects on the phamacokinetics of ixabepilone.
  • Ixabepilone may be administered parenterally as described in U.S. Patent 7,022,330, U.S. Patent 6,670,384, U.S. Patent Application Publication 2005/0171167 Al, WO 2005/110407, and PCT/US2006/011920, each of which is incorporated herein by reference in its entirety.
  • Ixabepilone may be administered orally as described in U.S. Patent 6,576,651 and U.S. Patent Application 11/281,855, each of which is incorporated herein by reference in its entirety.
  • Ixabepilone may be administered in combination with other agents, such as those described in US 2003/0073677, including capecitabine (XelodaTM), cetuximab (ErbituxTM), trastuzumab (HerceptinTM), and/or bevacizumab (AvastinTM).
  • capecitabine XelodaTM
  • cetuximab ErbituxTM
  • trastuzumab HerceptinTM
  • AvastinTM bevacizumab
  • ixabepilone and CYP3A4/5 inhibitor(s) described herein also contemplates use of one or more of these additional anti -cancer agents.
  • Ixabepilone can be prepared for intraveneous administration and/or oral administration by methods known in the field.
  • One approach to formulate ixabepilone for pharmaceutical use involves preparing a lyophilized product which then can be packaged and transported in a solid state. With this formulation, the lyophilized product may be reconstituted with a vehicle and then further diluted with an infusion fluid prior to administration to the patient.
  • U.S. Patent No. 6,670,384 discloses a process for obtaining a lyophilized product using a tertiary butanohwater mixture, which then can be packaged and transported in a freeze-dried solid state. With this product, the intravenous formulation is typically prepared by medical professionals at the site of administration before the start of the infusion.
  • the constitution vehicle may comprise a mixture of Dehydrated Alcohol (e.g., ethanol) and a nonionic surfactant, such as a polyoxyethylated castor oil (e.g., Cremophor ® ).
  • a nonionic surfactant such as a polyoxyethylated castor oil (e.g., Cremophor ® ).
  • Cremophor R a nonionic surfactant
  • Cremophor ® may be used for solubility reasons, e.g., in view of ixabepilone's relatively low water solubility.
  • the reconstituted ixabepilone solution may then diluted with an infusion fluid and administered via IV administration.
  • Lactated Ringer's Injection is a preferred diluent for ixabepilone.
  • LRI has a pH range of about 6.0 to 7.5.
  • Lactated Ringer's Injection contains Sodium Chloride USP 0.6 g, Sodium Lactate 0.31 g, Potassium chloride USP 0.03 g and Calcium Chloride-2H 2 O USP 0.02g.
  • Ixabepilone is provided as a two-vial system, with the lyophilized drug in one vial, and a vehicle for reconstitution in a second vial; instructions are provided when the drug is supplied for reconstituting the ixabepilone and administering it to a human patient.
  • ixabepilone is constituted with a solution vehicle, wherein the solution vehicle includes (in addition to solvent) at least one buffer and at least one pH adjusting ingredient, e.g., a base.
  • the constituted solution may be diluted with an infusion fluid to provide a formulation for administration.
  • EXAMPLE 1 Clinical Ketaconazole-Ixabepilone Interaction Study A clinical study was conducted to evaluate the effects of co-administration of ixabepilone and potent CYP3A4/5 inhibitor(s), i.e., ketoconazole, as compared with when ixabepilone is administered in the absence of the CYP3A4/5 inhibitor(s).
  • ixabepilone and potent CYP3A4/5 inhibitor(s) i.e., ketoconazole
  • Ketoconazole 400 mg/d was given orally with a meal on day -1 (24 hours before the infusion of ixabepilone), on day 1 (2 hours prior to the infusion of ixabepilone) and on days 2 to 5 (six doses).
  • any dose level could be expanded to at least six patients based on the observation of one or more dose-limiting toxicities.
  • the maximum tolerated dose (MTD) was exceeded when defined by the dose at which at least 33% of six patients had dose-limiting toxicity(ies).
  • MTD maximum tolerated dose
  • additional subjects could be enrolled to obtain additional safety data.
  • Blood samples (4 ml per sample) were collected from an indwelling catheter or by direct venipuncture using tubes containing K 3 EDTA as the anticoagulant. Every reasonable attempt was made to obtain a dedicated peripheral catheter on the opposite arm or side of body from that used for drug infusion.
  • the collection times were predose, at 90 and 180 minutes from start of dosing, then at 0.25, 0.5, 1.0, 3.0, 5.0, 22, 45, 69, 93 and 117 hours from the end of infusion.
  • plasma was collected by centrifugation (10 minutes at 1000 x g at 4°C) and stored at - 20 0 C till analysis.
  • the number of chemotherapy regimens used were two and three in 10 (37%) and 13 (48%) patients, respectively.
  • the most common diagnosis was gynecologic malignancy (carcinoma of ovaries, cervix, endometrium) followed by prostatic adenocarcinoma. Liver metastases was observed in 2 patients ( ⁇ 7%) and the median (range) pretreatment bilirubin (mg/dl), SGPT (IU/L) and albumin (g/dl) levels were 22 (14-43), 19 (8-60), 3.8 (2.8-4.3). The main reason for discontinuation of treatment was disease progression/relapse (12 patients, 44%).
  • the erythromycin breath test a measure of hepatic CYP3 A activity, was administered to subjects prior to treatment for exploratory evaluation as a marker of
  • ixabepilone clearance is affected by co-administration of ketoconazole (See Figures IA- IB, Tables IA and B). Specifically, ixabepilone clearance decreased in 19 of 22 patients when co-administered with ketoconazole. As shown in Figure IB (Table IB), co-administration of ketoconazole with ixabepilone resulted in an increase of approximately 7% in ixabepilone C ma ⁇ . However, the 90% confidence interval indicates that this effect is not statistically different from no change. Co-administration of ketoconazole with ixabepilone resulted in a 79% increase in AUC 0 ⁇ . The 90% confidence interval indicates that this effect is statistically different from no change.
  • the Hill equation with E 0 fixed at zero was the best model compared to the Hill equation with E 0 as a model parameter, the Emax model with E 0 fixed to zero, the Emax model with E 0 as a model parameter, the linear model or the log-linear model, based on Objective function, Akaike criteria and Schwartz criteria.
  • Table 1C lists the cycle 1 dose-limiting toxic events following administration of ixabepilone and ketoconazole. During the administration of ketoconazole dose alone, there were no grade 2 or greater toxic events observed. Most patients complained of grade 1 abdominal discomfort (bloating/nausea) for the duration of this treatment period. The initial dose level of ixabepilone administered for cycle 1 was 10
  • Figure 2 reflects results of an alternate embodiment.
  • the graph represents the percentage of MTB bundling in PBMCs in two cycles of treatment - one cycle, with 8 patients, involving co-administration of ixabepilone at substantially reduced dose (50% of dose recommended for monotherapy) and ketoconazole (Cycle 1), and a second cycle with 17 patients involving monotherapy at the standard recommended dose.
  • ixabepilone at substantially reduced dose (50% of dose recommended for monotherapy)
  • ketoconazole Cycle 1
  • the anti-cancer effect achievable with ixa at reduced dose and ketoconazole in combination s substantially the same as that achieved with ixabepilone at full dose.
  • the protein concentration of human liver microsomes was 0.24 mg/ml (for 0.1 and 0.3 ⁇ M ixabepilone concentrations) or 0.5 mg/mL (for 1-25 ⁇ M ixabepilone concentrations).
  • the CYP3A4 concentration was 25 pmole/mL (for 0.1 and 0.3 ⁇ M ixabepilone concentrations) and 50 pmole/mL (for 1-100 ⁇ M ixabepilone concentrations).
  • the incubation time was 5 min for incubations at 0.1-2.5 ⁇ M ixabepilone concentrations and 10 min for 5-100 ⁇ M ixabepilone concentrations.
  • Metabolites were identified by analyzing C-ixabepilone (20 ⁇ M) incubation of samples from pooled human liver microsomes using LC -MS/MS. The results from these analyses demonstrated that ixabepilone was mainly metabolized to oxidative metabolites. In addition to parent drug ixabepilone, the identified metabolites
  • Human cDNA-expressed enzymes (CYP1A2, 2A6, 2C8, 2C9, 2C19, 2D6 and 3A4) were incubated with ixabepilone.
  • the incubation mixtures consisted of 100 pmole/mL of CYP enzymes, 0.5 ⁇ M of ixabepilone, 1 mM NADPH, and 0.1 M phosphate buffer containing 0.5 mM Of MgCl 2 , pH 7.4 in duplicate.
  • the final volumes of the incubation mixtures were 0.5 mL. After 10 min of incubation at 37°C in a water shaker bath, 0.5 mL of ice cold acetonitrile was added to each tube to stop the reaction.
  • the samples were centrifuged for 5 min at 3000 rpm. Aliquots (150 ⁇ L) from the supernatants were mixed with 150 ⁇ L of acetonitrile containing 0.5 ⁇ M of the internal standard, followed by vortex mixing for 2 min. The supernatants were then separated from the precipitated proteins after a 10-min centrifugation at 3000 rpm and analyzed by LC/MS analysis against a standard curve to determine the concentration of ixabepilone.
  • CYP inhibitors and antibodies were incubated with human liver microsomes and ixabepilone (0.5 ⁇ M) in triplicate.
  • Human liver microsomes were incubated with 0.5 ⁇ M of ixabepilone in the presence of the respective CYP inhibitors, furafylline (CYP1A2, 10 ⁇ M), tranylcypromine (CYP2A6, 2 ⁇ M), sulfaphenazole (CYP2C9, 10 ⁇ M), benzylnirvanol (CYP2C19, 1 ⁇ M), quinidine (CYP2D6, 1 ⁇ M), ketoconazole (CYP3A4, 1 ⁇ M), and montelukast (CYP2C8, 3 ⁇ M).
  • Each 0.5 mL incubation mixture contained 430 ⁇ L of 0.1 M phosphate buffer (containing 0.5 mM Of MgCl 2 ; pH 7.4), 50 ⁇ L of 10 mM NADPH solution, 2.5 ⁇ L of selective chemical inhibitor solution, 5 ⁇ L of 0.05 mM ixabepilone solution, and 12.5 ⁇ L of human liver microsomes (20 mg/mL).
  • the metabolism-dependent inhibitor of CYPl A2, furafylline was pre-incubated with human liver microsomes in the presence of NADPH for 15 min in a shaking water bath before ixabepilone was added. After substrate addition, the samples were then incubated for 10 min at 37°C.
  • acetonitrile was added to each incubation mixture to stop the reaction.
  • the samples were centrifuged for 10 min at 3000 rpm. Aliquots (150 ⁇ L) from the supernatants were mixed with 150 ⁇ L of acetonitrile containing 0.5 ⁇ M of the internal standard, followed by vortex mixing for 2 min. The supernatants were then separated from the precipitated proteins after a 10-min centrifugation at 3000 rpm and analyzed by LC/MS against a standard curve to determine the concentration of ixabepilone.
  • Monoclonal anti-human CYP antibodies (anti-lA2, anti-2C8, anti-2C9, anti- 2Cl 9, anti-2D6, and anti-3A4) were from NIH, Bethesda, Maryland (19). A mixture containing human liver microsomes, 0.1 M potassium phosphate buffer (containing 0.5 mM of MgCl 2 ), pH 7.4 and monoclonal anti-CYP antibody (anti-CYPlA2, anti-
  • the consumption of ixabepilone in human liver microsomes and in human cDNA expressed CYP enzymes can be characterized by monophasic Michaelis- Menten kinetics.
  • the K m values for the oxidative metabolism of ixabepilone were 8.2 and 4.3 ⁇ M in human liver microsomes and CYP3A4, respectively.
  • V values were 1399 nmol/mg protein/min (approximately 13 nmol/pmol CYP3A4 in human liver microsome /min) and 17.9 nmol/pmol CYP/min for human liver microsomes and CYP3A4, respectively ( Figures 3A and B).
  • Ly VT Everett D, et al. Metabolism of C-Ixabepilone in mouse,rat, dog, monkey and human liver microsomes. Drug Metabolism Reviews2006;38(suppl 2): 173.
  • ixabepilone was consumed in appreciable amounts (>90%) only by CYP3A4.
  • CYP3A4 cDNA-expressed CYP enzymes
  • Ketoconazole (25 ⁇ M) alone has no effect on formation of microtubule bundles.
  • ketoconazole (25 ⁇ M) did not inhibit tubulin bundle formation in HepG2 cells.
  • ixabepilone is administered as a 3 hour iv infusion on day 1 of a 21 day cycle.
  • Lapatinib is administered oral, continuously, every day (at least one hour before or one hour after a meal), starting on day 1.
  • capecitabine also is administered oral, BID (with food or within 30 minutes after food), on days 1 through 14 of a 21-day cycle.
  • BID with food or within 30 minutes after food
  • the MTD level will be expanded to provide additional safety data. Since both lapatinib and ixabepilone are CYP3A4 substrates, stepwise alternative increase of both drugs is implemented to exclude serious combined-treatment toxicity. In the triple combination arm, capecitabine may be escalated
  • a dose-escalation sequence proceeds as follows:
  • Dose level -1 is provided in case the MTD is exceeded at dose level 1 or for subjects requiring dose reduction on an individual basis. Once the MTD is identified, that dose level may be expanded. For the doublet combination if MTD is not reached by dose level 3, an additional dose level with lapatinib 1500 mg and ixabepilone 40 mg/m 2 may be considered.
  • epothilones and epothilone analogs in development that are metabolized in human patients by the CYP3A4/5 enzymes.
  • epothilones and analogs may include epothilone B (patupilone), ZK-EPO, and epothilone D analogs, including compounds shown below:
  • Such other epothilones and compounds may also include compounds as disclosed in US Pat. 6,242,469 and 6,284,781; EP 091227; WO 03/022844; US2004/0053910; US 2004/0152708; US Serial No. 11/214,988; US Pat. 6,605,726; US 2003/0144523 (No. 09/485292); and Klar et al, Angew Chem. Int. Ed. 2006, 45: 1-7, incorporated herein.
  • G is benzothiazol yl substituted with methyl or a group ;
  • Ri is methyl, lower alkyl, lower alkenyl or lower alkynyl ("lower” in this respect meaning having from one to four, more preferably one to three, carbon atoms); Ri and R 2 are each hydrogen, methyl, or form a bond to provide a double bond; and Q is
  • R 4 is hydrogen or methyl, preferably methyl.

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Abstract

La présente invention concerne des utilisations de l'ixabépilone en combinaison avec des inhibiteurs du CYP3A4 tels que le kétoconazole et le lapatinib pour obtenir un effet pharmacologique amélioré de manière surprenante par comparaison avec l'ixabépilone administré sans inhibiteur du CYP3A4. L'invention concerne également des procédés de traitement du cancer chez un patient humain par l'administration à l'humain d'une combinaison thérapeutiquement efficace d'une quantité d'inhibiteur du CYP3A4 et d'une quantité d'ixabépilone afin d'obtenir un effet pharmacologique amélioré.
EP07784137A 2006-05-25 2007-05-25 Utilisation de l'ixabépilone en combinaison avec des inhibiteurs du cyp3a4 en tant que produits pharmaceutiques Withdrawn EP2023923A2 (fr)

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