Measuring the overall genetic component of nevirapine pharmacokinetics and the role of selected polymorphisms: Towards addressing the missing heritability in pharmacogenetic phenotypes?

OBJECTIVE: Nevirapine is an important component of highly active antiretroviral therapy used in the treatment of HIV infection. There is a considerable variation in the pharmacokinetics of nevirapine and this variation can impact the efficacy and toxicity of nevirapine. Although some of this variation can be attributed to environmental factors, the degree to which heritability influences nevirapine pharmacokinetics is unknown. This study aims to estimate how much variation in nevirapine pharmacokinetics is due to genetic factors and to investigate the contribution of selected polymorphisms to this variability. METHODS: Two doses of immediate-release nevirapine were administered to European (n=11) and African American (n=6) participants recruited from the Research in Access to Care in the Homeless cohort. A repeated drug administration method was then used to determine the relative genetic contribution (r_GC) to variability in nevirapine AUC_{0-6 h}. Nevirapine plasma levels were quantified using LC/MS/MS. Patients were also genotyped for selected polymorphisms in candidate genes that may influence nevirapine pharmacokinetics. RESULTS: A significant r_GC for nevirapine AUC_{0-6 h} was found in Europeans (P=0.02) and African Americans (P=0.01). A trend toward higher nevirapine AUC_{0-6 h} for the CYP2B6 516TT (rs3745274; Q172H) genotype was observed in European Americans (P=0.19). CONCLUSION: This study demonstrates that there is a significant genetic component to variability in nevirapine pharmacokinetics. Although genetic variants such as CYP2B6 polymorphisms attributed to some of this variation, these data suggest that there may be additional genetic factors that influence nevirapine pharmacokinetics.