title: Measuring the overall genetic component of nevirapine pharmacokinetics and the role of selected polymorphisms: towards addressing the missing heritability in pharmacogenetic phenotypes?
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors: Departments of aBioengineering and Therapeutic Sciences bEpidemiology cMedicine dThe Institute for Human Genetics, University of California, San Francisco, California eRagon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Massachusetts General Hospital Center for Global Health, Harvard Medical School, Boston, Massachusetts, USA.
authors: Janine E
authors: JE
authors: Micheli
authors: Leslie W
authors: LW
authors: Chinn
authors: Sarah B
authors: SB
authors: Shugarts
authors: Ashish
authors: A
authors: Patel
authors: Jeffrey N
authors: JN
authors: Martin
authors: David R
authors: DR
authors: Bangsberg
authors: Deanna L
authors: DL
authors: Kroetz
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D044465:White People / Q000235:genetics
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019380:Anti-HIV Agents; D019829:Nevirapine; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6
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