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



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.



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 (Vc/F), first-order absorption rate constant (ka), 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, Vc/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.



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.
Model Answers Pty Ltd, Level 5, 99 Creek Street, 4000, Brisbane, QLD, Australia. modelanswers@gmail.com.
Bruce
0000-0001-8622-4272
B
Green
Janssen R&D, Beerse, Belgium.
Herta
H
Crauwels
Alios BioPharma, South San Francisco, CA, USA.
Thomas N
TN
Kakuda
Janssen R&D, Beerse, Belgium.
Simon
S
Vanveggel
Janssen R&D, Beerse, Belgium.
Anne
A
Brochot
D000328:Adult; D044966:Anti-Retroviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002986:Clinical Trials as Topic / Q000379:methods; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics* / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics* / Q000378:metabolism; D004347:Drug Interactions / Q000502:physiology; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D009570:Nitriles; D011110:Polymorphism, Genetic / Q000235:genetics; D011724:Pyridazines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics
D044966:Anti-Retroviral Agents; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19
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