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The objectives of this study were to characterize the population pharmacokinetics (PK) of efavirenz (EFV) and 8-hydroxy-efavirenz (8OHEFV) in plasma and peripheral blood mononuclear cells (PBMCs) and to explore covariates affecting the PK parameters. Fifty-one patients had steady-state 0-to-24-h concentrations of EFV and 8OHEFV in plasma with corresponding concentrations in PBMCs, while 261 patients had one or two sparse concentrations at 16 ± 1 h postdose at weeks 4 and/or 16. The pharmacogenetic markersCYP2B6*6 ,CYP3A5*3 ,CYP3A5*6 ,UGT2B7*2 ,ABCB1 (3435C→T, 3842A→G),OATP1B1*1B , andOATP1B1*5 , the presence of a rifampin-based antituberculosis (anti-TB) regimen, baseline body weight and organ function values, and demographic factors were explored as covariates. EFV concentration data were well described by a two-compartment model with first-order absorption (Ka ) and absorption lag time (A lag ) (Ka = 0.2 h−1 ;A lag = 0.83 h; central compartment clearance [CLc /F ] forCYP2B6*1/*1 = 18 liters/h, forCYP2B6*1/*6 = 14 liters/h, and forCYP2B6*6/*6 = 8.6 liters/h) and PBMCs as a peripheral compartment. EFV transfer from plasma to PBMCs was first order (CLp /F = 32 liters/h), followed by capacity-limited return (V max = 4,400 ng/ml/h;Km = 710 ng/ml). Similarly, 8OHEFV displayed a first-order elimination and distribution to PBMCs, with a capacity-limited return to plasma. No covariate relationships resulted in a significant explanation of interindividual variability (IIV) on the estimated PK parameters of EFV and 8OHEFV, except forCYP2B6*6 genotypes, which were consistent with prior evidence. Both EFV and 8OHEFV accumulated to higher concentrations in PBMCs than in plasma and were well described by first-order input and Michaelis-Menten kinetics removal from PBMCs.CYP2B6*6 genotype polymorphisms were associated with decreased EFV and 8OHEFV clearance.

antimicrobial agents and chemotherapy

Population Pharmacokinetic Model Linking Plasma and Peripheral Blood Mononuclear Cell Concentrations of Efavirenz and Its Metabolite, 8-Hydroxy-Efavirenz, in HIV Patients