CYP2B6*6, CYP2B6*18, Body weight and sex are predictors of efavirenz pharmacokinetics and treatment response: population pharmacokinetic modeling in an HIV/AIDS and TB cohort in Zimbabwe.

Milcah Dhoro,Bernard Ngara,Gerald Kadzirange,Prosper Chonzi,Charles Nhachi,Simbarashe Zvada,Collen Masimirembwa

doi:10.1186/s40360-015-0004-2

Abstract

BackgroundEfavirenz (EFV) therapeutic response and toxicity are associated with high inter-individual variability attributed to variation in its pharmacokinetics. Plasma concentrations below 1 μg/ml may result in virologic failure and above 4 μg/ml, may result in central nervous system adverse effects. This study used population pharmacokinetics modeling to explore the influence of demographic and pharmacogenetic factors including efavirenz-rifampicin interaction on EFV pharmacokinetics, towards safer dosing of EFV.MethodsPatients receiving an EFV-based regimen for their antiretroviral therapy and a rifampicin-containing anti-TB regimen were recruited. EFV plasma concentrations were measured by HPLC and genomic DNA genotyped for variants in the CYP2B6, CYP2A6 and ABCB1 genes. All patients were evaluated for central nervous system adverse effects characterised as sleep disorders, hallucinations and headaches using the WHO ADR grading system. A pharmacokinetic model was built in a forward and reverse procedure using nonlinear mixed effect modeling in NONMEM VI followed by model-based simulations for optimal doses.ResultsCYP2B6*6 and *18 variant alleles, weight and sex were the most significant covariates explaining 55% of inter-individual variability in EFV clearance. Patients with the CYP2B6*6TT genotype had a 63% decrease in EFV clearance despite their CYP2B6*18 genotypes with females having 22% higher clearance compared to males. There was a 21% increase in clearance for every 10 kg increase in weight. The effect of TB/HIV co-treatment versus HIV treatment only was not statistically significant. No clinically relevant association between CYP2B6 genotypes and CNS adverse effects was seen, but patients with CNS adverse effects had a 27% lower clearance compared to those without. Model- based simulations indicated that all carriers of CYP2B6*6 TT genotype would be recommended a dose reduction to 200 mg/day, while the majority of extensive metabolisers may be given 400 mg/day and still maintain therapeutic levels.ConclusionThis study showed that screening for CYP2B6 functional variants has a high predictability for efavirenz plasma levels and could be used in prescribing optimal and safe EFV doses.

Highlights

Efavirenz (EFV) therapeutic response and toxicity are associated with high inter-individual variability attributed to variation in its pharmacokinetics
Treatment success with Efavirenz (EFV) requires maintenance of an optimal plasma concentration to ensure a balance between adverse drug reactions (ADRs) and possible treatment failure
Steady state concentrations below 1 μg/ml in plasma have been reported to be associated with an increased risk for virological failure and drug resistance, while concentrations above 4 μg/ml have been reported to be associated with an increased risk for the development of central nervous system (CNS) adverse effects, hepatic toxicity, and necessity for treatment discontinuation [1,2]

Summary

Introduction

Efavirenz (EFV) therapeutic response and toxicity are associated with high inter-individual variability attributed to variation in its pharmacokinetics. Plasma concentrations below 1 μg/ml may result in virologic failure and above 4 μg/ml, may result in central nervous system adverse effects. Steady state concentrations below 1 μg/ml in plasma have been reported to be associated with an increased risk for virological failure and drug resistance, while concentrations above 4 μg/ml have been reported to be associated with an increased risk for the development of central nervous system (CNS) adverse effects, hepatic toxicity, and necessity for treatment discontinuation [1,2]. High rates of CNS adverse effects characterized by hallucinations, vivid dreams and insomnia have been reported in more than 50% of the patients who initiate EFV with up to a fifth of all individuals on an EFV based regimen discontinuing the drug and switching therapy primarily due to the unbearable neurotoxicity [3]. Zimbabwe is ranked among high burden countries for both TB and HIV [10]

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