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.
Highlights
Efavirenz (EFV) is currently the most widely used nonnucleoside reverse transcriptase inhibitor (NNRTI) for HIV patients, during co-treatment with rifampicin [1]
EFV exhibits significant inter-individual pharmacokinetic variability as well as a narrow therapeutic window, with plasma concentrations .4 mg/mL being associated with more central nervous system (CNS) toxicity while the rate of virologic failure increases with concentrations,1 mg/mL [2]
The dataset contained 556 EFV concentration values collected from 99 HIV/ AIDS patients (64 females) over 252 days from the 14th day of initiation of EFV based highly active antiretroviral therapy (HAART)
Summary
Efavirenz (EFV) is currently the most widely used nonnucleoside reverse transcriptase inhibitor (NNRTI) for HIV patients, during co-treatment with rifampicin [1]. Despite extensive clinical experience with EFV, unpredictable inter-individual variability in efficacy and toxicity remain important limitations associated with its use. EFV exhibits significant inter-individual pharmacokinetic variability as well as a narrow therapeutic window, with plasma concentrations .4 mg/mL being associated with more central nervous system (CNS) toxicity while the rate of virologic failure increases with concentrations ,1 mg/mL [2]. EFV therapeutic drug monitoring has been recommended [3]. Among the factors affecting EFV pharmacokinetics are ethnicity, host genetic factors, gender, body weight, drug interactions, binding to plasma proteins, hepatic impairment, disease status and pregnancy [4,5,6,7]. Pharmacogenetics 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
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