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.
OBJECTIVE
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); 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.


CONCLUSIONS
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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Department of HIV Medicine, Royal Free NHS Trust, London, UK. wambura@gmail.com
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Johnson
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D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000368:Aged; D000483:Alleles; D000704:Analysis of Variance; D044383:Black People / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D015331:Cohort Studies; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000008:administration & dosage / Q000097:blood*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000097:blood*; D044465:White People / Q000235:genetics
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018894:Reverse Transcriptase Inhibitors; D003577:Cytochrome P-450 Enzyme System; D019829:Nevirapine; C585599:CYP2B6 protein, human; C510164:CYP3A5 protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human