EP1608366A1 - Verwendung von ritonavir zur behandlung von unkonjugierter hyperbilirubinämie - Google Patents

Verwendung von ritonavir zur behandlung von unkonjugierter hyperbilirubinämie

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Publication number
EP1608366A1
EP1608366A1 EP04757865A EP04757865A EP1608366A1 EP 1608366 A1 EP1608366 A1 EP 1608366A1 EP 04757865 A EP04757865 A EP 04757865A EP 04757865 A EP04757865 A EP 04757865A EP 1608366 A1 EP1608366 A1 EP 1608366A1
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EP
European Patent Office
Prior art keywords
ritonavir
ugtiai
effective amount
substrate
day
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04757865A
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English (en)
French (fr)
Inventor
Dale J. Kempf
Richard J. Bertz
Jeffrey F. Waring
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Abbott Laboratories
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Abbott Laboratories
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Publication date
Priority claimed from US10/395,772 external-priority patent/US20040192624A1/en
Priority claimed from US10/802,829 external-priority patent/US7320961B2/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP1608366A1 publication Critical patent/EP1608366A1/de
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
    • 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
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/215—IFN-beta
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention is directed to a method for inducing UGTIAI isoform expression for treatment of a disease or disorder or adverse effect caused by an elevated serum concentration of an UGTIAI substrate comprising the step of administering to a subject an effective amount of ritonavir.
  • the present invention is directed to a method of treating unconjugated hyperbilirubinemia by UGTIAI induction comprising the step of administering to a subject an effective amount of ritonavir.
  • Glucuronidation is a major metabolic pathway that determines the disposition of several endogenous substrates, such as for example, estriol and bilirabin, as well as exogenous substrates such as ethinylestradiol.
  • the UDP-glucuronosyltransferases are a superfamily of enzymes which catalyze these reactions with UDG-glucuronic acid as a cofactor.
  • the UGT superfamily comprises at least ten isozymes in rat and more than ten isozymes in humans. In fact, a total of 15 human UGT isozymes have been identified each with distinct substrate specificities, UGTIAI being a bilirabin-specific isozyme.
  • Bilirabin is the principal product of heme catabolism, and is cleared from circulation by the liver where it undergoes glucuronidation, i.e., conjugation with glucuronic acid to form water-soluble metabolites such as mono- and diglucuronides which are ultimately excreted in the feces.
  • Indinavir (Merck & Co. Inc., New Jersey, USA) is a potent and commonly used protease inhibitor that has been shown to be highly effective against HIV when used in combination with reverse transcriptase inhibitors.
  • indinavir therapy is associated with a 6-25% incidence of asymptomatic, unconjugated hyperbilirubinemia in the absence of histologic liver injury. Id Patients in whom excessive accumulation of bilirabin leads to the development of clinical jaundice have been subjected to treatment interruption and additional clinical investigation.
  • PK Steady State Pharrnacokinetic (PK) Interaction Study of Atazanavir (ATV) with Ritonavir (RTV) in Healthy Subjects, poster presented at the 42 nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, California, September 27-30 th , 2002. It has been found that atazanavir in both an in vitro system of human microsomes and in human cells transfected with the UGTIAI isoform inhibits bilirubin conjugation in the micromolar range. O'Mara, E., Mummaneni, V. et al.
  • Uridine Diphosphate-Glucuronosyl Transferase UDP-GT 1A1 Genotype and Total Bilirubin Elevations in Healthy Subjects Receiving BMS-232632 and Saquinavir, poster presented at the 40 th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada, September 17-20, 2000.
  • Unconjugated hyperbilirubinemia is also an adverse effect associated with medicaments or combinations of medicaments such as, for example, amphotericin B/cholesteryl sulfate complex, testosterone, interferon beta- lb, bicalutamide, ciprofloxacin, oxaliplatin, floxuridine, gemcitabine hydrochloride, sargramostim, gemtuzumab ozogamicin, vinorelbine tartrate, carboplatin, peginterferon alfa-2B, tacrolimus, aldesleukin, dalfopristin/quinupristin, didanosine and capecitabine.
  • medicaments or combinations of medicaments such as, for example, amphotericin B/cholesteryl sulfate complex, testosterone, interferon beta- lb, bicalutamide, ciprofloxacin, oxaliplatin, floxuridine, gemcitabine hydrochloride, sar
  • UGTIAI substrates such as, for example, unconjugated hyperbilirubinemia it is desirable to induce UGTIAI.
  • HIV infection and AIDS with potent HIV protease inhibitors such as, for example, indinavir and atazanavir without having to discontinue treatment because of elevations in serum bilirabin caused by inhibition of UGTIAI.
  • potent HIV protease inhibitors such as, for example, indinavir and atazanavir
  • medicaments such as, for example, amphotericin B/cholesteryl sulfate complex, testosterone, interferon beta- lb, bicalutamide, ciprofloxacin, oxaliplatin, floxuridine, gemcitabine hydrochloride, sargramostim, gemtuzumab ozogamicin, vinorelbine tartrate, carboplatin, peginterferon alfa-2B, tacrolimus, aldesleukin, dalfopristin/quinupristin, didanosine and capecitabine without having to discontinue treatment because of elevations in seram bilirubin.
  • medicaments such as, for example, amphotericin B/cholesteryl sulfate complex, testosterone, interferon beta- lb, bicalutamide, ciprofloxacin, oxaliplatin, floxuridine, gemcitabine hydrochloride, sargramostim, gemtuzumab
  • the present invention provides a method for inducing UGTIAI isoform expression for treatment of a disease or disorder or adverse effect caused by an elevated serum concentration of UGTIAI substrates comprising the step of administering to a subject an effective amount of ritonavir.
  • the present invention provides a method for treating unconjugated hyperbilirubinemia comprising the step of administering an effective amount of ritonavir to a subject in need thereof.
  • the effective amount of ritonavir is in a range of about 25 to about 1200 mg daily.
  • FIG. 1 shows the mean ( ⁇ SD) seram bilirabin over time for the three groups of Gunn rats, wherein Group I received 500/100 mg/kg/day atazanavir/ritonavir, Group II received 100 mg/kg/day ritonavir, and Group HI received only vehicle.
  • FIG. 2 shows the mean ( ⁇ SD) seram bilirabin over time for the three groups of Gunn rats, wherein Group I received 500/100 mg/kg/day indinavir/ritonavir, Group II received 100 mg/kg/day ritonavir, and Group IE received only vehicle.
  • FIG. 3 shows mean ( ⁇ SD) seram ethinylestradiol concentrations after administration of ethinylestradiol alone and with ritonavir.
  • FIG. 4 shows individual and mean ( ⁇ SD) ethinylestradiol Cmax after administration of ethinylestradiol alone and with ritonavir.
  • FIG. 5 shows individual and mean ( ⁇ SD) ethinylestradiol AUC ⁇ after administration of ethinylestradiol alone and with ritonavir.
  • FIG. 6 shows individual and mean ( ⁇ SD) ethinylestradiol elimination rate constant ( ⁇ ) after administration of ethinylestradiol alone and with ritonavir.
  • Unconjugated hyperbilirubinemia is an undesirable disease or disorder or adverse effect which is caused by administration to a subject of medicaments or combinations of medicaments such as, for example, indinavir, atazanavir, amphotericin B/cholesteryl sulfate complex, testosterone, interferon beta- lb, bicalutamide, ciprofloxacin, oxaliplatin, floxuridine, gemcitabine hydrochloride, sargramostim, gemtuzumab ozogamicin, vinorelbine tartrate, carboplatin, peginterferon alfa-2B, tacrolimus, aldesleukin, dalfopristin/quinupristin, didanosine and capecitabine.
  • medicaments or combinations of medicaments such as, for example, indinavir, atazanavir, amphotericin B/cholesteryl sulfate complex, testosterone, interferon beta- lb, bicalu
  • ritonavir can be co- administered with indinavir, atazanavir, amphotericin B/cholesteryl sulfate complex, testosterone, interferon beta- lb, bicalutamide, ciprofloxacin, oxaliplatin, floxuridine, gemcitabine hydrochloride, sargramostim, gemtuzumab ozogamicin, vinorelbine tartrate, carboplatin, peginterferon alfa-2B, tacrolimus, aldesleukin, dalfopristin/quinupristin, didanosine and capecitabine to induce UGTIAI isoform expression, and, in turn, lower seram bilirabin concentration.
  • the present invention provides a method for inducing UGTIAI for treatment of a disease or disorder or adverse effect caused by an elevated serum concentration of an UGTIAI substrate comprising the step of administering to a subject an effective amount of ritonavir.
  • the present invention provides a method for treating unconjugated hyperbilirubinemia comprising the step of administering an effective amount of ritonavir to a subject in need thereof.
  • the present invention provides a method for treating a disease or disorder or adverse effect caused by an elevated serum concentration of an UGTIAI substrate upon administration of an active pharmaceutical ingredient comprising the step of co-administering ritonavir in an effective amount with the active pharmaceutical ingredient to a subject in need thereof.
  • the active pharmaceutical ingredient is selected from the group consisting essentially of indinavir, atazanavir, amphotericin B/cholesteryl sulfate complex, testosterone, interferon beta- lb, bicalutamide, ciprofloxacin, oxaliplatin, floxuridine, gemcitabine hydrochloride, sargramostim, gemtuzumab ozogamicin, vinorelbine tartrate, carboplatin, peginterferon alfa-2B, tacrolimus, aldesleukin, dalfopristin/quinupristin, didanosine and capecitabine.
  • the active pharmaceutical ingredient is indinavir.
  • the active pharmaceutical ingredient is atazanavir.
  • the disease or disorder caused by an elevated serum concentration of an UGTIAI substrate is unconjugated hyperbilirubinemia.
  • the present invention provides a method for increasing glucuronidation of an UGTIAI substrate comprising the step of administering an effective amount of ritonavir.
  • the UGTIAI substrate is bilirubin.
  • the present invention provides a method for increasing excretion of an UGTIAI substrate comprising the step of administering an effective amount of ritonavir.
  • the UGTIAI substrate is bilirubin.
  • the present invention provides a method for inducing UGTIAI for treatment of a disease or disorder or adverse effect caused by an elevated seram concentration of an UGTIAI substrate comprising the step of administering to a subject a composition comprising an effective amount of ritonavir.
  • the present invention provides a method for treating unconjugated hyperbilirubinemia comprising the step of administering a composition comprising an effective amount of ritonavir to a subject in need thereof.
  • the composition may further comprise an effective amount of lopinavir in addition to the ritonavir. Examples of such a composition is disclosed in U.S. Patent No. 6,458,818.
  • co-administration and “co-adminstering” refer to administering to a subject ritonavir and another active pharmaceutical ingredient as separate dosage forms which are administered at same or different times, or together as a single dosage form.
  • subject refers to a mammal, and, more particularly to a human.
  • the phrase "effective amount" is an amount of ritonavir which is sufficient to induce UGTIAI isoform expression or to increase glucuronidation of an UGTIAI substrate or to increase excretion of an UGTIAI substrate.
  • the effective amount of ritonavir is an amount in a range of about 25 mg to about 1200 mg daily.
  • the amount of ritonavir that may be combined with carrier materials to produce a single dosage form will vary depending upon the subject treated and the particular mode of administration.
  • Ritonavir is represented structurally as formula (I) below.
  • Ritonavir is also known to be an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase, especially, CYP3A4 as disclosed in U.S. Patent No. 6,037,157.
  • Ritonavir may be administered orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
  • sterile injectable preparations for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Suppositories for rectal administration of ritonavir can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
  • ritonavir may be admixed with at least one inert diluent such as sucrose lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
  • Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • Ritonavir can also be administered in the form of liposomes.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically aceptable and metabolizable lipid capabale of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natureal and synthetic.
  • a second set of rats received ritonavir at a total daily dosage of 100 mg/kg/day.
  • a third group of rats was administered vehicle only.
  • Atazanavir was formulated in a vehicle consisting of 5% EtOH:95% propylene glycol (PG):1 molar equivalent of p-toluene sulfonic acid.
  • Ritonavir was formulated in a vehicle consisting of 5% EtOH:95% propylene glycol (PG): 2 molar equivalents of p-toluene sulfonic acid. Formulations were prepared so that all rats received a total constant volume of 2 ml/kg with each treatment. Rats were dosed twice daily on Day 0 approximately twelve hours apart, and a third time in the morning on Day 1, for a total of three doses. A sample of blood (approximately 0.5 ml) was collected from each rat via the jugular vein into a plain microcentrifuge tube (no anticoagulant) 4 hours following the first and third dose, and used for analysis of total bilirubin. The mean ( ⁇ SD) serum bilirabin over time for the three groups of rats is shown in FIG. 1. Serum bilirubin markedly increased after the first dose, then declined after three doses.
  • PG propylene glycol
  • RNA preparation and analysis was done according to the Affymetrix Inc. protocol. The integrity of the RNA from the pooled samples was determined using an Agilent 2100 Bioanalyzer.
  • cDNA was prepared from 15 ug of RNA using the Superscript Choice system from Gibco BRL Life Technologies (Cat. No. 18090-019). The Gibco protocol was followed exactly, with the exception that the primer used for the reverse transcription reaction was a modified T7 primer with 24 thymidines at the 5' end. The sequence was: 5'-GGCCAGTGAATTGTAATACGACTCACTATAGGGAGGCGG-(dT)24-3'. Following this, labeled cRNA was synthesized from the cDNA using the Enzo RNA Transcript Labeling ICit (Cat. No.
  • cRNA was then fragmented in a solution of 40 mM Tris acetate, pH 8.1, 100 mM KOAc, and 30 mM MgOAc at 94o for 35 minutes. Following this, cRNA was hybridized to the Affymetrix Rat U34 Chip which contains approximately 9000 gene sequences. The cRNA was hybridized overnight at 45 °C. The microarray data was analyzed using the Rosetta Resolver v2.0 Expression Data
  • the Affymetrix U34A chip contains 5 different probe sequences which correspond to UDP-glucuronosyltransf erase 1A (UGTl A).
  • UGTl A UDP-glucuronosyltransf erase 1A
  • Ritonavir was prepared as 7.5 and 25 mg/mL solutions in 5% ethanol, 95% propylene glycol and 2 molar equivalents of p-toluenesulfonic acid. Rats in the control group received vehicle consisting of 5% ethanol, 95% propylene glycol and 37.6 mg/mL p-toluenesulfonic acid. Sodium phenobarbital dose solution was prepared in normal saline at a concentration of 25 mg base/ml.
  • VAF Crl:CD@ (SD)BR Sixteen male and female Sprague-Dawley rats (VAF Crl:CD@ (SD)BR) weighing about 250 g were obtained from Charles River Laboratories, Inc. (Portage, MI). The rats were randomly divided into four treatment groups shown in Table 2.
  • the animals were given free access to Certified Rodent Chow* #5002 pellets (Purina Mills, Inc., St. Louis, MO.) and water.
  • the rats were housed individually in stainless steel cages and were identified by a unique identifier number. Body weights were recorded on Day 0, Day 7 and at the end of the study.
  • the rats in treatment Groups T 0 , Ti and T 2 were sacrificed at approximately 48 hours after the last dose.
  • the rats in treatment Group T 3 were sacrificed at approximately 24 hours after the last dose.
  • the livers were removed, blotted dry and weighed individually. The livers were then homogenized individually in ice-cold 1.15% potassium chloride containing 10 mM potassium phosphate buffer (pH 7.4) using a tissue homogenizer. Microsomes were prepared by differential centrifugation and were stored at -70 °C in 0.1 M potassium phosphate buffer (pH 7.4) containing 20% (v/v) glycerol and 1.0 mM EDTA.
  • Microsomal protein content was determined using a bicinchoninic acid (BCA) assay kit (Pierce Chemical), with bovine seram albumin as the standard.
  • Total cytochrome P450 content was determined by means of ferrous carbon monoxide complex formation.
  • the microsomes were characterized for the following cytochrome P450-mediated reactions: 7-pentoxyresorafin O-dealkylase, chlorzoxazone 6- hydroxylase, benzphetamine N-demethylase and erythromycin N-demethylase.
  • Hepatic 17 -ethinylestradiol and 1-naphthol glucuronidation activities are summarized in Table 3 below.
  • Ritonavir was found to significantly increase the glucuronidation of 17 ⁇ - ethinylestradiol, a UGTIAI substrate, in both male and female rats.
  • the increase in glucuronidation of 17 -ethinylestradiol was 2-fold in both male and female rats treated with 50 mg kg/day of ritonavir.
  • the second dose of oral contraceptive was administered during ritonavir dosing, on Day 29.
  • Blood samples for ethinylestradiol concentrations were collected for 48 h after each of the oral contraceptive doses.
  • Blood samples for ritonavir concentrations were collected at baseline, i.e., prior to dosing on Day 1 (0 h), and at steady state on Day 29, at 0 and 4 h after the morning dose. Twenty-seven subjects were enrolled in the study. Four subjects failed to complete the study and did not receive the oral contraceptive dose administered during ritonavir dosing. Data from these four subjects were therefore excluded from summary statistics.
  • the mean ⁇ SD age of the 23 subjects who completed the study was 34 ⁇ 10 yrs (range 19 to 45 yrs), the mean ⁇ SD weight was 67.3 ⁇ 10.9 kg (range 50.8 to 90.3 kg), and the mean ⁇ SD height was 167 ⁇ 7 cm (range 155 to 180 cm).
  • Ethinylestradiol was supplied as Demulen® 1/50-21 tablets (G.D. Searle & Co.) containing 50 ⁇ g of ethinylestradiol and 1 mg of ethynodiol diacetate and was administered at 8:00 a.m. on Day 1 and Day 29 with approximately 240 mL of water and within 15 minutes of a meal or snack.
  • Ritonavir (Abbott Laboratories) was supplied as a liquid formulation (80 mg/mL solution) and was administered as 300 mg (3.75 mL) every 12 hours on Day 15, 400 mg (5.0 mL) every 12 hours on Day 16, and 500 mg (6.25 mL) every 12 hours on Days 17 to 30, at approximately 8:00 a.m. and 8:00 p.m. on Days 15 to 30.
  • Subjects were confined for 64 hours from Day -1 (day prior to the initial dose) through the first 48 hour blood collection (morning of Day 3) and for 64 hours from Day 28 through the second 48 hour blood collection (morning of Day 31).
  • subjects came to the clinical testing unit as outpatients for meals, dosing and other study activities twice daily for a total of 14 consecutive days, starting on Day 15. Strenuous activity during confinement was not permitted.
  • subjects abstained from all food and beverages except for the scheduled meals and snacks provided in the study. Water was available ad libitum. All meals were standardized with regard to content during confinement. Breakfast, lunch, and dinner were served at approximately 7:30 a.m., 1:00 p.m. and 7:30 p.m.
  • Blood samples (7 mL) were collected for seram ethinyl estradiol concentrations at the following times relative to the dose on Day 1 and Day 29: prior to (0 h) and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 18, 24, 30, 36, and 48 h post-dose.
  • blood samples (7 mL) were collected for plasma ritonavir concentrations prior to dosing on Day 1 (0 h) and at steady state on Day 29, at 0 h (prior to morning dosing) and 4 h after the morning dose. All plasma and serum samples were packed with dry ice and shipped to the analytical sites.
  • Seram samples were analyzed for ethinylestradiol concentrations at Pharmaco LSR, Richmond, VA. Plasma samples were stored frozen until analyzed for ritonavir concentrations at Oneida Research Services (ORS), Inc., Whitesboro, NY.
  • ORS Oneida Research Services
  • the derivatized extract was stored at -20 °C until analysis. Analysis was by capillary GC/MS using negative chemical ionization with selected ion monitoring. This method has been validated over 17 ⁇ -ethinylestradiol concentrations ranging from 2.00 to 256 pg/mL for a 1.0 mL seram volume, with a minimum quantitation limit of 2.00 pg/mL.
  • the seram samples of the study were assayed with 17 ⁇ -ethinylestradiol calibration curves ranging from 2.00 to 256 pg/mL and the mean correlation coefficient was 0.9994.
  • serum samples were supplemented with low, medium and high concentrations of ethinyl estradiol, and were assayed with the unknowns.
  • the low, medium and high quality controls were 6.00, 24.0 and 144 pg/mL, respectively.
  • the mean calculated concentration values for ethinylestradiol at the end of the analyses were 5.31, 21.4 and 131 pg/mL for the low, medium and high quality controls, respectively.
  • the corresponding coefficients of variation were 11.4, 8.1 and 7.1 %.
  • Ritonavir plasma concentrations were determined using a validated reverse-phase high performance liquid chromatographic (HPLC) method with UV detection.
  • HPLC reverse-phase high performance liquid chromatographic
  • the extraction procedure involved the addition of an internal standard to a 500 ⁇ L aliquot of sample, extraction of this aliquot under neutral conditions with ethyl acetate:hexane; 9:1 (v/v), evaporation of the organic phase to dryness, and reconstitution of the sample in mobile phase, followed by two washes of the reconstituted extract with hexane.
  • An aliquot of the reconstituted extract was then analyzed by reverse phase high performance liquid chromatography with ultraviolet detection at 205 nm. The lower limit of quantitation was 0.010 ⁇ g/mL.
  • the mobile phase consisted of 0.1% trifluoroacetic acid (TFA) in 0.01 M tetramethylammonium perchlorate:acetonitile:methanol (55:40:5; v:v:v).
  • TFA trifluoroacetic acid
  • tetramethylammonium perchlorate:acetonitile:methanol 55:40:5; v:v:v.
  • the procedure was validated at ORS and had been shown to produce linear calibration curves in plasma.
  • the mean correlation coefficient for calibration curves with standards ranging from 0.100 to 15.00 ⁇ g/mL was 0.998.
  • the within-day coefficients of variation (CVs) were below 4.85% at all concentrations.
  • the inter-day CVs for plasma were below 5.66% at all concentrations.
  • An abbreviated validation was performed to demonstrate a lower limit of quantitation of 0.010 ⁇ g/mL in non-HIV positive plasma.
  • the plasma samples of the study were assayed with calibration curves ranging from 0.010 to 15.00 ⁇ g/mL and the mean correlation coefficient was 0.9993.
  • plasma samples were supplemented with low (0.150 ⁇ g/mL), medium (7.500 ⁇ g/mL) and high (12.00 ⁇ g/mL) concentrations of ritonavir, and were assayed with the unknowns.
  • the mean calculated concentration values at the end of the analyses were 0.158, 6.511 and 10.64 ⁇ g/mL and the corresponding coefficients of variation were 3.99, 12.9 and 2.88%, for the low, medium and high quality controls, respectively.
  • Ethinylestradiol pharmacokinetic parameters were estimated following two single doses, on Day 1 and Day 29, using noncompartmental methods. The pharmacokinetic parameters were calculated using the intended sampling times; all samples were collected within 10% of intended sampling times. Maximal plasma concentration (Cmax,) and time to reach Cmax (Tmax) were obtained directly from individual concentration vs. time profiles. The area under the plasma concentration-time curve (AUC ⁇ ) was calculated as the sum of AUCt, the area up to the last measurable concentration computed using the linear trapezoidal rule, and the extrapolation to infinity, calculated as the quotient of the last measurable concentration (Ct) and the terminal elimination rate constant ( ⁇ ).
  • the terminal elimination rate constant was calculated as the negative of the slope of the regression of the logarithms of the plasma concentrations vs. time, starting at 18 h post- dose.
  • the half-life of the terminal phase (tl/2) was obtained by dividing the natural logarithm of 2 (In 2) by ⁇ .
  • Serum concentrations of ethinylestradiol and plasma concentrations of ritonavir for each time of sampling were tabulated and summary statistics computed.
  • the paired t-test was performed using PROC UNIVARIATE of SAS version 6.09 on a UNIX operating system. A p value ⁇ 0.050 was considered statistically significant.
  • ethinyl estradiol pharmacokinetic parameters determined after administration of the oral contraceptive alone and those determined during 500 mg ql2h ritonavir administration, with the exception of Tmax.
  • ethinyl estradiol mean Cmax and mean AUC decreased by 32% and 41 %, respectively, while an increase in the mean terminal elimination rate constant was observed (+3 1%).
  • the harmonic mean half life of ethinyl estradiol decreased from 17.0 h after administration of the oral contraceptive alone to 13.0 h after administration of the oral contraceptive with ritonavir.

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EP04757865A 2003-03-24 2004-03-19 Verwendung von ritonavir zur behandlung von unkonjugierter hyperbilirubinämie Withdrawn EP1608366A1 (de)

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Application Number Priority Date Filing Date Title
US802829 1997-02-19
US10/395,772 US20040192624A1 (en) 2003-03-24 2003-03-24 Method for treating a disease, disorder or adverse effect caused by an elevated serum concentration of an UGT1A1 substrate
US395772 2003-03-24
US10/802,829 US7320961B2 (en) 2003-03-24 2004-03-18 Method for treating a disease, disorder or adverse effect caused by an elevated serum concentration of an UGT1A1 substrate
PCT/US2004/008415 WO2004084892A1 (en) 2003-03-24 2004-03-19 Use of ritonavir for the treatment of unconjugated hyperbilirubinemia

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US7320961B2 (en) 2003-03-24 2008-01-22 Abbott Laboratories Method for treating a disease, disorder or adverse effect caused by an elevated serum concentration of an UGT1A1 substrate

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JPH04188068A (ja) * 1990-11-22 1992-07-06 Eiken Chem Co Ltd ビリルビン検出用試験片
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GUIDANCE FOR INDUSTRY (Q7A GOOD MANUFACTURING PRACTICE GUIDANCE FOR ACTIVE PHARMACEUTICAL INGREDIENTS), Retrieved from the Internet <URL:http://www.fda.gov/cder/guidance/4286fnl.htm> *
RANDOMINSKA-PANDYA A A, CZERNIK P J, LITTLE J M, BATTAGLIA E, MACKENZIE P I: "Structural and functional studies of UDP-glucuronosyltransferases", DRUG METABOLISM REVIEWS, vol. 31, no. 4, 1999, pages 817 - 899 *
See also references of WO2004084892A1 *
TUKEY R H, STRASSBURG CH P: "Human UDP-glucuronosyltransferases: Metabolism, expression and disease", ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, vol. 40, 2000, pages 581 - 616 *

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