Population Pharmacokinetics of Efavirenz and MDR-1, CY2B6, and CYP3A5 Polymorphisms
Jackson K. Mukonzo (1), Paul Waako (1), Daniel Röshammar (3), Maria Andersson (2), Jan-Olov Svensson (2), Jasper Ogwal-Okeng (1), Lars L Gustafsson (2), Eleni Aklillu (2)
(1) Department of Pharmacology & Therapeutics, Makerere University, Kampala Uganda; (2) Department of Clinical Pharmacology, Karolinska Institute, Stockholm, Sweden; (3) Department of Pharmacology, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
Objectives: Efavirenz, an antiretroviral drug metabolized by polymorphic enzymes, exhibits between-subject pharmacokinetic variability causing varied clinical response. Lower and higher plasma concentration among HIV patients' results into virologic failure and central nervous system related toxicities, respectively. Factors for efavirenz pharmacokinetic variability ranging from sex to ethnicity are poorly understood. We examined the effect of genetic polymorphism in CYP2B6, CYP3A5 and MDR-1 on the efavirenz population pharmacokinetics among Ugandans.
Methods: A total of 402 efavirenz concentrations from 121 healthy volunteers were determined by HPLC. Study participants were genotyped for 26 single nucleotide polymorphisms in CYP2B6 (n =7), CYP3A5 (n =5) and MDR1 (n =14) genes by mini-sequencing and PCR-RFLP. To explore the influence of covariates on the efavirenz pharmacokinetics, the data was analyzed using a non-linear mixed effects modeling approach in NONMEM.
Results: The pharmacokinetics of efavirenz were described by a two-compartment model with zero- followed by first-order absorption. The inclusion of CYP2B6 (516G>T, *11) polymorphisms in the model explained 11%, and 3 % of the between-subject variability (CV %) in efavirenz clearance and 'poor metabolisers' were observed to have 22 and 19% lower clearance than 'extensive metabolisers', respectively. Sex as a covariate reduced unexplained between-subject variability in the peripheral volume of distribution from 41 to 24%, while MDR-1 (rs exon 29) explained 10% of the variability in oral efavirenz bioavailability which was 20% higher in mutant subjects. The peripheral volume of distribution was two-fold higher in females compared to males.
Conclusions: The results indicate that CYP2B6 (516G>T, *11), as well as MDR-1 (rs exon 29) polymorphisms and sex influence efavirenz pharmacokinetics. Presence of MDR-1 at absorptive and secretory sites explains its polymorphic effect on efavirenz bioavailability. The big peripheral volume of distribution in females could be due to a high body fat content in female subjects.