Bruce Green (1), Herta Crauwels (2), Thomas N. Kakuda (3), Simon Vanveggel (2), Magda Opsomer (2), Anne Brochot (2)
(1) Model Answers Pty Ltd, Brisbane, Australia, (2) Janssen R&D, Mechelen, Belgium, (3) Janssen R&D, Titusville, USA
Background: HIV type-1 infected patients are routinely treated with multiple drugs. Etravirine is a non-nucleoside reverse transcriptase inhibitor indicated in combination with other antiretrovirals (ARV) for treatment-experienced patients >=6 years of age. The purpose of this analysis was to determine if any covariates, including concomitant ARVs, could explain any of the variability in the PK of etravirine.
Methods: 4728 plasma concentrations from 817 adult subjects across 4 clinical studies were used to develop a population PK model for etravirine. Covariates evaluated were baseline age, total bodyweight (WT), creatinine clearance (CRCL), sex, race, CYP2C9 and CYP2C19 phenotypes, and the presence of the following concomitant medications: atazanavir/ritonavir, lopinavir/ritonavir, darunavir/ritonavir, tenofovir disoproxil fumarate or enfuvirtide. A mixture model was used to assign CYP2C9 or CYP2C19 phenotype for subjects where this was unknown (UNK).
Results: 0.2%, 3.2%, 10.8% and 85.5% of subjects were poor (PM), intermediate (IM), extensive (EM) and UNK CYP2C9 metabolisers, respectively. 0.4%, 2.6%, 6.7%, 3.2%, 0.6%, and 86.5% were PM, IM, EM, rapid, ultra-rapid, and UNK CYP2C19 metabolisers, respectively. WT ranged from 34.5-160kg. A 1-compartment model with first-order input and a lag-time best described the data. Estimates of CL/F, Vc/F, Ka and ALAG1 were 41.7 L/hr, 972 L, 1.16 /hr, and 1.32 hr, respectively. Estimates of between-subject variability on CL/F, Vc/F and relative bioavailability (F) were 39.4 %CV, 35.9 %CV and 35.5 %CV, respectively. Between-occasion variability on F was estimated to be 30.0 %CV. There were no apparent effects of age, sex, race or concomitant ARVs. CL/F increased non-linearly with increasing WT and CRCL where:
CL/F = 41.7x(WT(kg)/71)0.291x(CRCL(L/hr)/6)0.246
and the exponent of 0.291 on WT aligns with allometric theory by approximating a value of 0.75 on lean bodyweight.[1,2] CL/F for known PM was 15.2 L/hr, with CL/F for subjects of UNK CYP2C9 or CYP2C19 phenotype either the same as the population value (41.7 L/hr) or 9.42 L/hr, depending upon the mixture model allocation.
Conclusions: WT, CRCL, and CYP2C9 or CYP2C19 phenotype were found to describe some of the variability in etravirine CL/F, although the effects were not considered clinically relevant. Also, there were no apparent clinically relevant differences in the effect of concomitant ARVs on the PK of etravirine for adult subjects predominantly taking co-administered boosted protease inhibitors (PIs) as a background ARV regimen.
References:
[1] McLeay SC, Morrish GA, Kirkpatrick CMJ, and Green B. The relationship between drug clearance and body size: systematic review and meta-analysis of the literature published from 2000 to 2007. Clin Pharmacokinet 2012, 51(5):319–30
[2] Janmahasatian S, Duffull SB, Ash S, Ward LC, Byrne NM, Green B. Quantification of lean bodyweight. Clin Pharmacokinet 2005, 44(10):1051-1065
Reference: PAGE 24 (2015) Abstr 3491 [www.page-meeting.org/?abstract=3491]
Poster: Drug/Disease modeling - Infection