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[6, 8] The CYP2B6 gene is highly polymorphic, with 38 alleles and multiple sub-alleles and single nucleotide polymorphisms identified (http://www.cypalleles.ki.se/cyp2b6.htm; accessed October 2013). Among these variants, the CYP2B6*6 allele is the most frequent across different populations and is functionally relevant.[9, 10] Several studies in healthy volunteers and HIV patients have demonstrated that this variant is associated with increased EFV exposure, higher incidence of CNS and hepatic toxicity as well as treatment discontinuation.[2, 11-15] The contribution of CYP2A6, CYP3A, and UGT2B7 and their potential impact on the overall pharmacokinetic variability in EFV in vivo seems relatively small, with some studies demonstrating an effect while others do not.[6, 7, 16-20] The inter-individual variability in EFV pharmacokinetics http://www.selleckchem.com/products/Imatinib-Mesylate.html may also be attributed to differences in the ability of EFV to induce its own metabolism, via induction of CYP2B6 and possibly other enzymes involved in its metabolism.[21-24] The effects of genetics and covariates on the variability of EFV pharmacokinetics and exposure have been explored previously.[18, 25-29] However, there are no reports that incorporate the hydroxyl http://www.selleckchem.com/products/AP24534.html metabolites of EFV into a pharmacogenetic-based covariate analysis. Incorporation of the hydroxyl EFV metabolites into a covariate model may increase the sensitivity to identify relevant CYP enzymes that contribute to the inter-individual variability in the pharmacokinetics of EFV and provide mechanistic information regarding the in vivo contributions of the enzymes catalyzing efavirenz metabolism. Therefore, the objectives of this study were to develop a pharmacogenetic-based pharmacokinetic model that simultaneously describes disposition of EFV and its major metabolites as well as characterize the contribution of demographic and pharmacogenomic covariates to inter-patient variability in EFV pharmacokinetics. Consequently, the model based prediction of EFV steady state concentrations were generated using this final covariate model among different CYP genotype groups following the conventional (600?mg) and reduced (200 and 400?mg) EFV dosage regimens. Ultimately, adequate prediction of EFV steady-state concentrations from pharmacogenetic information may aid in optimizing EFV therapeutic outcomes through managing inter-patient variability in its http://en.wikipedia.org/wiki/MERTK exposure. This population pharmacokinetic analysis was performed using data from a randomized cross-over drug interaction study of EFV with clopidogrel, and itraconazole in healthy, Korean volunteers.[30] The study was approved by the Institutional Review Board of Inje University Busan Paik Hospital, Korea, and each subject signed a written informed consent. Subjects were excluded from the study for any of the following reasons: allergy to EFV, intake of prescription or non-prescription medications or herbal supplements for the duration of the study, hemoglobin concentration