Pharmacokinetic and pharmacodynamic comparison of once-daily efavirenz (400 mg vs. 600 mg) in treatment-naïve HIV-infected patients

results of the ENCORE1 Study

L. Dickinson*, J. Amin, L. Else, M. Boffito, D. Egan, A. Owen, S. Khoo, D. Back, C. Orrell, A. Clarke, M. Losso, P. Phanuphak, D. Carey, D. A. Cooper, S. Emery, R. Puls

*Corresponding author for this work

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Daily efavirenz 400 mg (EFV400) was virologically noninferior to 600 mg (EFV600) at 48 weeks in treatment -naïve patients. We evaluated EFV400 and EFV600 pharmacokinetics (NONMEM v. 7.2), assessing patient demographics and genetic polymorphisms (CYP2B6, CYP2A6, CYP3A4, NR1I3) as covariates and explored relationships with efficacy (plasma HIV € RNA (pVL) <200 copies/mL) and safety outcomes at 48 weeks in 606 randomized ENCORE1 patients (female = 32%, African = 37%, Asian = 33%; EFV400 = 311, EFV600 = 295). CYP2B6 516G>T/983T>C/CYP2A6∗9B/∗17 and weight were associated with efavirenz CL/F. Exposure was significantly lower for EFV400 (geometric mean ratio, GMR; 90% confidence interval, CI: 0.73 (0.68-0.78)) but 97% (EFV400) and 98% (EFV600) of evaluable pVL was <200 copies/mL at 48 weeks (P = 0.802). Four of 20 patients with mid € dose concentrations <1.0 mg/L had pVL ≥200 copies/mL (EFV400 = 1; EFV600 = 3). Efavirenz exposure was similar between those with and without efavirenz € related side effects (GMR; 90% CI: 0.95 (0.88-1.02)). HIV suppression was comparable between doses despite significantly lower EFV400 exposure. Comprehensive evaluation of efavirenz pharmacokinetics/pharmacodynamics revealed important limitations in the accepted threshold concentration.

Original languageEnglish
Pages (from-to)406-416
Number of pages11
JournalClinical Pharmacology and Therapeutics
Volume98
Issue number4
DOIs
Publication statusPublished - 1 Oct 2015
Externally publishedYes

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