Pharmacogenetic-Based Efavirenz Dose Modification: Suggestions for an African Population and the Different CYP2B6 Genotypes

Abstract

BackgroundPharmacogenetics contributes to inter-individual variability in pharmacokinetics (PK) of efavirenz (EFV), leading to variations in both efficacy and toxicity. The purpose of this study was to assess the effect of genetic factors on EFV pharmacokinetics, treatment outcomes and genotype based EFV dose recommendations for adult HIV-1 infected Ugandans.MethodsIn total, 556 steady-state plasma EFV concentrations from 99 HIV infected patients (64 female) treated with EFV/lamivudine/zidovidine were analyzed. Patient genotypes for CYP2B6 (*6 & *11), CYP3A5 (*3,*6 & *7) and ABCB1 c.4046A>G, baseline biochemistries and CD4 and viral load change from baseline were determined. A one-compartment population PK model with first-order absorption (NONMEM) was used to estimate genotype effects on EFV pharmacokinetics. PK simulations were performed based upon population genotype frequencies. Predicted AUCs were compared between the product label and simulations for doses of 300 mg, 450 mg, and 600 mg.ResultsEFV apparent clearance (CL/F) was 2.2 and 1.74 fold higher in CYP2B6*6 (*1/*1) and CYP2B6*6 (*1/*6) compared CYP2B6*6 (*6/*6) carriers, while a 22% increase in F1 was observed for carriers of ABCB1 c.4046A>G variant allele. Higher mean AUC was attained in CYP2B6 *6/*6 genotypes compared to CYP2B6 *1/*1 (p<0.0001). Simulation based AUCs for 600 mg doses were 1.25 and 2.10 times the product label mean AUC for the Ugandan population in general and CYP2B6*6/*6 genotypes respectively. Simulated exposures for EFV daily doses of 300 mg and 450 mg are comparable to the product label. Viral load fell precipitously on treatment, with only six patients having HIV RNA >40 copies/mL after 84 days of treatment. No trend with exposure was noted for these six patients.ConclusionResults of this study suggest that daily doses of 450 mg and 300 mg might meet the EFV treatment needs of HIV-1 infected Ugandans in general and individuals homozygous for CYP2B6*6 mutation, respectively.

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

“…Besides, Rotger et al identified intracellular EFV concentration as a predictor of neuropsychological toxicity induced by EFV (21). Efforts to predict safety and efficacy of EFV have focused on characterizing the systemic pharmacokinetics (12,22,23). Borand et al (24) found no association between treatment failure and the recommended efavirenz concentrations in plasma below 1 mg/liter (6).…”

“…Compartmental models for EFV and 8OHEFV were parameterized as volumes (V c EFV, V p EFV, V c 8OHEFV, and V p 8OHEFV) and transfer rate constants (k 20 , k 23 , k 32 , k 45 , and k 54 ), with derived clearances (CL c EFV and CL p EFV are first-order clearance terms for EFV, while CL c 8OHEFV and CL p 8OHEFV represent clearances for 8OHEFV from the central to peripheral compartments, respectively). Since the absolute oral bioavailability (F) of EFV cannot be determined in the absence of intravenous administration, the fraction of metabolic conversion of EFV to 8OHEFV also cannot accurately be determined, and clearance and volume of distribution terms for both EFV and 8OHEFV represent apparent values, such as CL/F and V/F.…”

“…Since the absolute oral bioavailability (F) of EFV cannot be determined in the absence of intravenous administration, the fraction of metabolic conversion of EFV to 8OHEFV also cannot accurately be determined, and clearance and volume of distribution terms for both EFV and 8OHEFV represent apparent values, such as CL/F and V/F. The rate constant terms k 23 and k 45 describe first-order transfer processes, while k 32 and k 54 represent nonlinear transfer rates defined by the Michaelis-Menten equation (equations 1 and 2). In these equations, V max EFV and V max 8OHEFV represent the maximum rates of transfer of EFV and 8OHEFV, respectively, and K m EFV and K m 8OHEFV are concentrations associated with half of the respective V max values.…”

Efavirenz: A review of the epidemiology, severity and management of neuropsychiatric side-effects

“…[7][8][9] This enzyme is highly susceptible to polymorphism and these polymorphs play a role in the variability of efavirenz plasma concentrations. [9] Functionally deficient alleles may result in higher plasma levels of efavirenz in patients receiving a standard dose of 600 mg daily because of decreased metabolism of efavirenz.…”

Incidence of neuropsychiatric side effects of efavirenz in HIV-positive treatment-naïve patients in public-sector clinics in the Eastern Cape

“…8,9 The plasma levels of efavirenz as well as genetic polymorphisms in certain populations are thought to be the cause of these neuropsychiatric side effects. 3,10,11 There have been several studies 7,12,13,14,15 comparing efavirenz with various other treatments such as nevirapine, protease inhibitors, etravirine and raltegravir. In all instances, efavirenz was seen to induce neuropsychiatric side effects more frequently than these other treatments.…”