Pharmacogenetics of plasma efavirenz exposure in HIV-infected adults and children in South Africa

作者：Sinxadi Phumla Z; Leger Paul D; McIlleron Helen M; Smith Peter J; Dave Joel A; Levitt Naomi S; Maartens Gary; Haas David W^*

来源：British Journal of Clinical Pharmacology, 2015, 80(1): 146-156.

DOI：10.1111/bcp.12590

• pharmacogenetics
• efavirenz
• CYP2B6
• HIV therapy
• South Africa

AimsGenetic factors, notably CYP2B6 516GT [rs3745274] and 983TC [rs28399499], explain much of the interindividual variability in efavirenz pharmacokinetics, but data from Africa are limited. We characterized relationships between genetic polymorphisms and plasma efavirenz concentrations in HIV-infected Black South African adults and children.
MethodsSteady-state mid-dosing interval efavirenz concentrations were measured. We genotyped 241 polymorphisms in genes potentially relevant to efavirenz metabolism and transport, including ABCB1, CYP2A6, CYP2B6, CYP3A4, CYP3A5, NR1I2 and NR1I3.
ResultsAmong 113 participants (59 adults and 54 children), minor allele frequencies for CYP2B6 516GT, 983TC, and 15582CT [rs4803419] were 0.36, 0.07, and 0.09, respectively. Based on composite CYP2B6 15582/516/983 genotype, there were 33 extensive metabolizer, 62 intermediate metabolizer and 18 slow metabolizer genotypes. Median (IQR) mid-dose efavirenz concentrations were 1.44 (1.21-1.93) mu g ml(-1), 2.08 (1.68-2.94) mu g ml(-1) and 7.26 (4.82-8.34) mu g ml(-1) for extensive, intermediate and slow metabolizers, respectively. In univariate analyses, a model that included composite genotype best predicted efavirenz concentrations ( = 0.28, 95% CI 0.21, 0.35, P=2.4 x 10(-11)). Among individual CYP2B6 polymorphisms, 516GT best predicted efavirenz concentrations (=0.22, 95% CI 0.13, 0.30, P=1.27 x 10(-6)). There was also associations with 983TC ( = 0.27, 95% CI 0.10, 0.44, P=0.002) and 15582CT (=0.11, 95% CI 0.01, 0.22, P=0.04). Associations were consistent in adults and children. No other polymorphisms were independently associated with efavirenz concentrations.
ConclusionsComposite CYP2B6 genotype based on CYP2B6 516GT, 983TC, and 15582CT best described efavirenz exposure in HIV-infected Black South African adults and children.

• 出版日期2015-7