Pharmacokinetic and Pharmacodynamic Comparison of Once-Daily Efavirenz (400 mg vs. 600 mg) in Treatment-Naive HIV-Infected Patients: Results of the ENCORE1 Study

Dickinson, L., Amin, J., Else, L., Boffito, M., Egan, D., Owen, A., Khoo, S., Back, D., Orrell, C., Clarke, A., Losso, M., Phanuphak, P., Carey, D., Cooper, D. A., Emery, S. and Puls, R. (2015) Pharmacokinetic and Pharmacodynamic Comparison of Once-Daily Efavirenz (400 mg vs. 600 mg) in Treatment-Naive HIV-Infected Patients: Results of the ENCORE1 Study. Clinical Pharmacology and Therapeutics, 98 4: 406-416. doi:10.1002/cpt.156

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Author Dickinson, L.
Amin, J.
Else, L.
Boffito, M.
Egan, D.
Owen, A.
Khoo, S.
Back, D.
Orrell, C.
Clarke, A.
Losso, M.
Phanuphak, P.
Carey, D.
Cooper, D. A.
Emery, S.
Puls, R.
Title Pharmacokinetic and Pharmacodynamic Comparison of Once-Daily Efavirenz (400 mg vs. 600 mg) in Treatment-Naive HIV-Infected Patients: Results of the ENCORE1 Study
Journal name Clinical Pharmacology and Therapeutics   Check publisher's open access policy
ISSN 1532-6535
0009-9236
Publication date 2015-10-01
Year available 2015
Sub-type Article (original research)
DOI 10.1002/cpt.156
Open Access Status File (Publisher version)
Volume 98
Issue 4
Start page 406
End page 416
Total pages 11
Place of publication Hoboken, NJ, United States
Publisher Nature Publishing Group
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Faculty of Medicine
 
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