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Randomized Controlled Trial
. 2015 Oct;98(4):406-16.
doi: 10.1002/cpt.156. Epub 2015 Jul 14.

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  1 , J Amin  2 , L Else  1 , M Boffito  3 , D Egan  1 , A Owen  1 , S Khoo  1 , D Back  1 , C Orrell  4 , A Clarke  5 , M Losso  6 , P Phanuphak  5 , D Carey  2 , D A Cooper  2 , S Emery  2 , R Puls; ENCORE1 Study Group
Collaborators, Affiliations
Randomized Controlled Trial

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 et al. Clin Pharmacol Ther. 2015 Oct.

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.

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Figures

Figure 1
Figure 1
Flow diagram summarizing (a) the data included in the population PK model and (b) genetic data available for analysis. EFV: efavirenz; PK: pharmacokinetics; WK: week; LLQ: lower limit of qualification; ITT: intent to treat.
Figure 2
Figure 2
Efavirenz concentrations on a log‐linear scale following 400 mg once daily (gray), 600 mg once daily (white), and 800 mg once daily (black) dosing (n = 1,491 concentrations; n = 606 patients). Black lines connect the points of the full pharmacokinetic profiles of those patients with intensive sampling included in the pharmacokinetic substudy (n = 46 patients).
Figure 3
Figure 3
Mean individual predicted efavirenz concentrations at 12 hours postdose (C12) on a log scale stratified for metabolizer status (extensive, intermediate, slow) and dose (400 and 600 mg once daily; n = 295 and n = 273, respectively). The black dashed line illustrates the recommended minimum effective concentration for efavirenz (MEC) of 1.0 mg/L. Each point represents an individual patient and the solid black line the median concentrations. Numbers of patients with C12 below the MEC or with detectable or missing viral load at 48 weeks are shown. C12: concentration 12 hours post‐dose representing the mid‐dose interval concentration; VL: viral load.
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References

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