Population pharmacokinetic model linking plasma and peripheral blood mononuclear cells (PBMCs) concentrations of efavirenz and its metabolite, 8-hydroxy-efavirenz in HIV patients [PublishAheadOfPrint]

Objectives: To characterize the population PK of EFV and 8-hydroxy-efavirenz (8OHEFV) in plasma and peripheral blood mononuclear cells (PBMCs) and explore covariates affecting the PK parameters.

Methods: Fifty-one patients had steady-state 0-24h plasma with corresponding PBMC concentrations of EFV and 8OHEFV, while 261 patients had 1 or 2 sparse concentrations at 16±1h post-dose at weeks 4 and/or 16. Pharmacogenetic markers CYP2B6*6, CYP3A5 (*3 &*6);, UGT2B7*2, ABCB1 (3435C<T, 3842A<G), OATP1B1 (*1B & *5), presence of rifampicin-based anti-TB regimen, baseline body weight and organ function values; and demographic factors were explored as covariates.

Results: EFV concentration data were well described by a 2-compartment model with first-order absorption and absorption lag time (K_a = 0.2h^-1; ALAG = 0.83h; CL_c/F for CYP2B6*1/*1 = 18L/h, CYP2B6*1/*6 = 14L/h, and CYP2B6*6/*6 = 8.6L/h) and PBMCs as a peripheral compartment. EFV transfer from plasma to PBMCs was first-order (CL_p/F = 32L/h), followed by capacity-limited return (V_max = 4400ng/mL/h; K_m = 710ng/mL). Similarly, 8OHEFV displayed a first-order elimination and distribution to PBMCs, with a capacity-limited return to plasma. No covariate relationships resulted in significant explanation of IIV on the estimated PK parameters of EFV and 8OHEFV, except for CYP2B6*6 genotypes, which were consistent with prior evidence.

Conclusions: Both EFV and 8OHEFV accumulated to higher concentrations in PBMCs than in plasma, and were well described by first-order input and Michaelis-Menten removal from PBMCs. CYP2B6*6 genotype polymorphisms were associated with decreased EFV and 8OHEFV clearance.

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