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Clin Pharmacokinet. 2017 May;56(5):525-536. doi: 10.1007/s40262-016-0454-8.

Evaluation of Concomitant Antiretrovirals and CYP2C9/CYP2C19 Polymorphisms on the Pharmacokinetics of Etravirine.

Author information

1
Model Answers Pty Ltd, Level 5, 99 Creek Street, 4000, Brisbane, QLD, Australia. modelanswers@gmail.com.
2
Janssen R&D, Beerse, Belgium.
3
Alios BioPharma, South San Francisco, CA, USA.

Abstract

BACKGROUND:

Etravirine is a non-nucleoside reverse transcriptase inhibitor indicated in combination with other antiretrovirals for treatment-experienced HIV patients ≥6 years of age. Etravirine is primarily metabolized by cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A. This analysis determined the impact of concomitant antiretrovirals and CYP2C9/CYP2C19 phenotype on the pharmacokinetics of etravirine.

METHODS:

We used 4728 plasma concentrations from 817 adult subjects collected from four clinical studies to develop the population pharmacokinetic model. The presence of atazanavir/ritonavir, lopinavir/ritonavir, darunavir/ritonavir, tenofovir disoproxil fumarate, or enfuvirtide together with the CYP2C9 and CYP2C19 phenotype and other demographics were evaluated.

RESULTS:

A one-compartment model with first-order input and a lag-time best described the data. Estimates of apparent total clearance (CL/F), apparent central volume of distribution (V c/F), first-order absorption rate constant (k a), and absorption lag-time were 41.7 L/h, 972 L, 1.16 h, and 1.32 h, respectively. Estimates of between-subject variability on CL/F, V c/F, and relative bioavailability (F) were 39.4 %CV (percentage coefficient of variation), 35.9 %CV and 35.5 %CV, respectively. Between-occasion variability on F was estimated to be 30.0 %CV. CL/F increased non-linearly with body weight and creatinine clearance (CLCR), and also varied based on CYP2C9/CYP2C19 phenotype.

CONCLUSIONS:

In this analysis, body weight, CLCR, and CYP2C9/CYP2C19 phenotype were found to describe some of the variability in CL/F. It was not possible to show an impact of concomitant antiretrovirals on the pharmacokinetics of etravirine for adults predominantly taking coadministered boosted protease inhibitors as a background antiretroviral regimen.

PMID:
27665573
DOI:
10.1007/s40262-016-0454-8
[Indexed for MEDLINE]

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