Cytochrome P450 2B6 516G→T is associated with plasma concentrations of nevirapine at both 200mg twice daily and 400mg once daily in an ethnically diverse population

Abstract

Objectives: The aim of the study was to characterize the impact of the cytochrome P450 2B6 (CYP2B6), CYP3A4, CYP3A5 and ATP-binding cassette sub-family B member 1 (ABCB1) polymorphisms on nevirapine plasma concentrations. Methods: A total of 104 patients (82% male; 26% non-Caucasian) were genotyped for eight single nucleotide polymorphisms at four loci (CYP2B6, CYP3A4, CYP3A5 and MDR1). Nevirapine plasma concentrations were determined using high-performance liquid chromatography. Results: Non-Caucasian ethnicity [5609 ng/mL (n = 27) for non-Caucasians vs. 3771 ng/mL (n = 77) for Caucasians; P < 0.0001] and CYP2B6 516G → T [GG, 3574 ng/mL (n = 50); GT, 4634 ng/mL (n = 50); TT, 8170 ng/mL (n = 4); Panalysisofvariance(ANOVA) = 0.001] were significantly associated with a higher nevirapine trough concentration (Ctrough). The latter association was maintained with both 200 mg twice daily (bid) and 400 mg once daily (qd) dosing [GG, 3527 ng/mL (n = 30); GT, 4525 ng/mL (n = 32); TT, 7020 ng/mL (n = 2); PANOVA = 0.05 and GG, 3645 ng/mL (n = 20); GT, 4861 ng/mL (n = 17); TT, 9508 ng/mL (n = 2); PANOVA = 0.01, respectively]. In a multivariable analysis, CYP2B6 516G → T and non-Caucasian ethnicity remained significant predictors of nevirapine C trough but CYP2B6 516G → T homozygosity had the greatest effect (108% higher, 46% higher). No associations were found between nevirapine Ctrough and the remaining polymorphisms. Conclusion: In this population, both non-Caucasian ethnicity and carriage of the variant allele of CYP2B6 516G → T were significant predictors of nevirapine Ctrough. The association between CYP2B6 516G → T and higher plasma nevirapine exposure was maintained at both bid and qd dosing. © 2009 British HIV Association.