Cytochrome P450 2B6 516G→T is associated with plasma concentrations of nevirapine at both 200 mg twice daily and 400 mg once daily in an ethnically diverse population |
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Authors: | TW Mahungu CJ Smith F Turner D Egan M Youle MA Johnson S Khoo DJ Back A Owen |
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Institution: | Department of HIV Medicine, Royal Free NHS Trust, London, UK,;Department of Pharmacology and Therapeutics, University of Liverpool, School of Biomedical Sciences, Liverpool, UK and;Research Department of Infection and Population Health, University College Medical School, London, UK |
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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); Panalysis of variance (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 Ctrough 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. |
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Keywords: | drug disposition metabolism pharmacogenetics pharmacokinetics |
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