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

Abstract

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 Ϯ 1 h postdose at weeks 4 and/or 16. The pharmacogenetic markers CYP2B6*6, CYP3A5*3, CYP3A5*6, UGT2B7*2, ABCB1 (3435C¡T, 3842A¡G), OATP1B1*1B, and OATP1B1*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 (K a ) and absorption lag time (A lag ) (K a ϭ 0.2 h Ϫ1 ; A lag ϭ 0.83 h; central compartment clearance [CL c /F] for CYP2B6*1/*1 ϭ 18 liters/h, for CYP2B6*1/*6 ϭ 14 liters/h, and for CYP2B6*6/*6 ϭ 8.6 liters/h) and PBMCs as a peripheral compartment. EFV transfer from plasma to PBMCs was first order (CL p /F ϭ 32 liters/h), followed by capacity-limited return (V max ϭ 4,400 ng/ml/h; K m ϭ 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 for CYP2B6*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.KEYWORDS efavirenz, 8-hydroxy-efavirenz, peripheral blood mononuclear cells, population pharmacokinetics E favirenz (EFV)-based antiretroviral therapy remains the preferred first-line treatment option in important international guidelines, including those of the World Health Organization (1). EFV displays a wide between-patient pharmacokinetic (PK) variability (2, 3). This is ascribed partially to genetic variation of the CYP2B6 enzyme, which is primarily responsible for the metabolism of efavirenz to 8-hydroxy-efavirenz (8OHEFV) (4, 5). Efavirenz is described to have a narrow safety margin (6-8). In addition, a couple

Genetic and non‐genetic factors influencing efavirenz population pharmacokinetics among human immunodeficiency virus‐1‐infected children in Ethiopia

“…Furthermore, the finding indicates that the impact of CYP2B6*6 on EFV PKs is higher in children compared to adult Ethiopians, as Habtwolde et al estimated, about two-fold lower EFV CL for adults with CYP2B6*6/*6. 37 Second, consistent with previous studies in adult subjects, 11,22,23 this study finds that ABCB1 c.4036A>G (rs3842) genetic polymorphism has a significant impact on EFV PKs, a finding which to our knowledge has not been reported previously in pediatric subjects. Third, consistent with results from previous pediatric and adult studies, 5,6,15 this study demonstrates EFV autoinduction phenomenon in pediatric subjects.…”

Early or deferred initiation of efavirenz during rifampicin‐based TB therapy has no significant effect on CYP3A induction in TB‐HIV infected patients

“…The determination of plasma efavirenz by LC‐MS/MS was performed as described previously (Burhenne et al, 2010 ; Habtewold et al, 2016 ; Habtewold et al, 2017 ). The method was validated according to the FDA validation guidelines and fulfilled all criteria concerning accuracy, precision, recovery, linearity, and stability.…”

An Integrated Spatial Dynamics—Pharmacokinetic Model Explaining Poor Penetration of Anti-retroviral Drugs in Lymph Nodes

“…The reaction dynamics describing HIV infection are adapted directly from the basic HIV model (Ho et al, 1995 ; Wei et al, 1995 ; Perelson et al, 1997 ; Nowak and May, 2000 ; Perelson and Ribeiro, 2013 ). Published pharmacokinetic studies have been used for modeling the dynamics of anti-retroviral drugs in both plasma and lymphoid lobule (Dixit and Perelson, 2004 ; Hurwitz et al, 2007 ; Arab-Alameddine et al, 2012 ; Habtewold et al, 2017 ). Modeling assumptions concerning transport of T cells and antiretroviral drugs are as follows:…”

“…Currently five different NNRTIs have been approved by FDA for antiretroviral therapy. For our current study we chose to use efarivenz due to the availability of a previously published intracellular pharmacokinetic model by Habtewold et al ( 2017 ) as shown in Figure 5 . Efarivenz (EFV) is usually prescribed once daily in doses of 600mg single pill.…”