Journal
HIV MEDICINE
Volume 10, Issue 5, Pages 310-317Publisher
WILEY
DOI: 10.1111/j.1468-1293.2008.00689.x
Keywords
drug disposition; metabolism; pharmacogenetics; pharmacokinetics
Categories
Funding
- UK NIHR Biomedical Research Centre for Microbial Diseases in Liverpool
- Boehringer Ingelheim
- MRC [G0800247] Funding Source: UKRI
- Medical Research Council [G0800247] Funding Source: researchfish
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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. 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. 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); P-analysis of variance (anova)=0.001] were significantly associated with a higher nevirapine trough concentration (C-trough). 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); P-anova=0.05 and GG, 3645 ng/mL (n=20); GT, 4861 ng/mL (n=17); TT, 9508 ng/mL (n=2); P-anova=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 C-trough and the remaining polymorphisms. In this population, both non-Caucasian ethnicity and carriage of the variant allele of CYP2B6 516G -> T were significant predictors of nevirapine C-trough. The association between CYP2B6 516G -> T and higher plasma nevirapine exposure was maintained at both bid and qd dosing.
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