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; DA Cooper; S Emery; D. Nolan

doi:10.1002/cpt.156

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Pharmacokinetic and pharmacodynamic comparison of Once-daily efavirenz (400 mg vs. 600 mg) in Treatment-Naïve HIV-Infected Patients: Results of the ENCORE1 study

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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, …

Clinical Pharmacology & Therapeutics, Vol.98(4), pp.406-416

2015

DOI: https://doi.org/10.1002/cpt.156

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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.

Details

Title: Pharmacokinetic and pharmacodynamic comparison of Once-daily efavirenz (400 mg vs. 600 mg) in Treatment-Naïve HIV-Infected Patients: Results of the ENCORE1 study
Authors/Creators: L Dickinson (Author/Creator)
J Amin (Author/Creator)
L Else (Author/Creator)
M Boffito (Author/Creator)
D Egan (Author/Creator)
A Owen (Author/Creator)
S Khoo (Author/Creator)
D Back (Author/Creator)
C Orrell (Author/Creator)
A Clarke (Author/Creator)
M Losso (Author/Creator)
P Phanuphak (Author/Creator)
D Carey (Author/Creator)
DA Cooper (Author/Creator)
S Emery (Author/Creator)
D. Nolan (Author/Creator)
Publication Details: Clinical Pharmacology & Therapeutics, Vol.98(4), pp.406-416
Publisher: Nature Publishing Group
Identifiers: 991005543390707891
Copyright: © 2015 The Authors.
Murdoch Affiliation: Murdoch University
Language: English
Resource Type: Journal article
Additional Information: David Nolan appears courtesy of the ENCORE1 Study Group

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.66 HIV; 1.66.1372 HIV Comorbidities
Web Of Science research areas: Pharmacology & Pharmacy
ESI research areas: Pharmacology & Toxicology