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Background  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. 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.    Methods  Patients 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.    Results   CYP2B6*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 C YP2B6*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.    Conclusion  This 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.

bmc pharmacology and toxicology

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