Inhibition of cyp3a drug metabolism

A technique of drug and pharmacokinetics, applied in metabolic diseases, drug combinations, medical preparations containing active ingredients, etc., can solve problems such as increasing the risk of drug-drug interactions

Inactive Publication Date: 2013-05-15
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, ritonavir is also a potent inhibitor of CYP enzymes that metabolize other drugs, such as CYP2D6 (in the case of dextromethorphan-O-demethylase, IC 50 = 2.5μM) and CYP2C9 / 10 (IC50 = 8.0μM for tolbutamide methylhydroxylase) (Kumar, G.N., et al., J. Pharmacol. Exp. Ther. 277:423-431 (1996)), which increases the risk of unwanted drug-drug interactions

Method used

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  • Inhibition of cyp3a drug metabolism
  • Inhibition of cyp3a drug metabolism
  • Inhibition of cyp3a drug metabolism

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0138] Example 1: In vitro evaluation of boceprevir as an inhibitor of human cytochrome P450 enzymes

[0139] 1.1 Introduction and Purpose.

[0140] This study was designed to evaluate the ability of boceprevir to inhibit major CYP enzymes in human liver microsomes, with the aim of determining the potential of boceprevir to inhibit the metabolism of other drugs. The inhibitory capacity of boceprevir was determined in vitro by measuring the activity of each CYP enzyme in human liver microsomes in the presence or absence of boceprevir. These in vitro experiments were designed to measure the inhibition constant (IC) of boceprevir for direct inhibition of each human CYP enzyme examined. 50 value), and was designed to determine whether boceprevir is a time-dependent inhibitor of the enzyme. K for direct inhibition of CYP3A4 / 5 determined i Value and mechanism of inhibition (measured by midazolam 1'-hydroxylation). Experiments were also performed to determine whether the observed...

Embodiment 2

[0232] Example 2: Clinical evaluation of boceprevir (BOC) as an inhibitor of human cytochrome P450 enzymes

[0233] A clinical study was conducted to determine the effect of boceprevir on the pharmacokinetic (PK) profile of midazolam (MDZ) by monitoring the effect of boceprevir on MDZ, a sensitive CYP3A4 / 5 Substrate) metabolism to assess the ability of boceprevir to inhibit CYP3A4 / 5 in vivo.

[0234] 2.1 General methodology

[0235] The study was performed in healthy adult subjects (7 male and 5 female subjects) at a single center according to good clinical practice. This study used a fixed-sequence design (boceprevir alone followed by MDZ + boceprevir). Determine the PK profile of MDZ and its metabolite (1-hydroxymidazolam [1-OH-MDZ]) when administered alone and after coadministration with boceprevir and with boceprevir The PK characteristics after the 7-day washout period after Weiwei were compared.

[0236] 2.2 Test product, dose, administration mode

[0237] Administe...

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Abstract

The present invention provides methods, pharmaceutical compositions, medicaments, and pharmaceutical kits that employ the use of boceprevir as a CYP3A4 / 5 inhibitor to improve the pharmacokinetics of therapeutic compounds metabolized by cytochrome P450 3A4 / 5 (CYP3A4 / 5) enzymes.

Description

technical field [0001] The present application relates generally to improving the pharmacokinetics of drugs metabolized by CYP3A enzymes by coadministration of compounds that inhibit cytochrome P450 3A (CYP3A) enzymes. Background technique [0002] Oxidative metabolism by the CYP3A4 and CYP3A5 members of the CYP3A subfamily of enzymes plays a major role in the elimination of a large number of drugs, and it is difficult to maintain therapeutically effective plasma levels of drugs that are rapidly metabolized by these enzymes. Also, for some drugs, the metabolic by-products of CYP3A-mediated metabolism are highly toxic and can produce serious side effects. [0003] In humans, CYP3A4 is usually the most abundant CYP3A isoform in the adult liver and intestine, but polymorphically expressed CYP3A5 may account for more than 50% of the total hepatic CYP3A in CYP3A5-expressing individuals. See, e.g., Granfors, M. T. et al., Basic & Clinical Pharmacology & Toxicology 98:79-85 (200...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/21A01N37/18
CPCA61K38/07A61K45/06A61P1/00A61P1/04A61P1/08A61P13/00A61P13/08A61P15/10A61P25/04A61P25/08A61P25/14A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/36A61P3/04A61P31/04A61P31/10A61P31/12A61P31/18A61P33/06A61P35/00A61P35/02A61P43/00A61P9/12A61K2300/00A61K38/06
Inventor A.霍萨尔S.古普塔N.基什纳尼C.卡塞拉E.奥马拉
Owner MERCK & CO INC
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