title: Pregnancy affects nevirapine pharmacokinetics: evidence from a CYP2B6 genotype-guided observational study.
abstract: Previous studies on nevirapine pharmacokinetics during pregnancy reported contradictory findings.
  
  
  
  The magnitude of pregnancy-induced changes in nevirapine pharmacokinetics was investigated in a genotype-guided study preceded by a pharmacogenetic association study of six genes involved in its disposition.
  
  
  
  CYP2B6 516 G>T and 983 T>C were associated independently with plasma nevirapine concentrations in pregnant (n=110) and postpartum (n=122) women and were used for stratification. NR1I3 540C>T and P450 oxidoreductase 1508C>T were associated with lower and higher plasma concentrations in pregnant and postpartum women, respectively. In the intensive pharmacokinetic phase, apparent clearance (CL/F) was higher in pregnant (n=31) than postpartum (n=28) women (P=0.022) and AUC0-12, Cmax and Cmin were significantly lower. When stratified on the basis of composite CYP2B6 516 G>T and 983 T>C genotypes, CL/F was similar between pregnant (n=6) and postpartum (n=9) women with no variant alleles, but Cmin was below target (3400 ng/ml) in most patients in both groups. In women with one variant allele, clearance was 40.6% higher (P=0.0009) and Cmin was below target in 58% (11/19) of pregnant and 0% (0/10) of postpartum women. Similarly, clearance was 51.7% higher (P=0.008) in pregnant compared with postpartum women with two variant alleles. Cmin was below target in 50% (3/6) of pregnant and 0% (0/10) of postpartum women.
  
  
  
  Nevirapine exposure is significantly reduced during pregnancy. The pharmacodynamic consequences in patients at risk of suboptimal exposure and potential dose optimization strategies warrant further investigation.
authors.affiliation: aDepartment of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK bFaculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria.
authors.forename: Adeniyi
authors.initials: A
authors.lastname: Olagunju
authors.forename: Oluseye
authors.initials: O
authors.lastname: Bolaji
authors.forename: Megan
authors.initials: M
authors.lastname: Neary
authors.forename: David
authors.initials: D
authors.lastname: Back
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D015415:Biomarkers / Q000378:metabolism*; D000090702:Constitutive Androstane Receptor; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D019829:Nevirapine / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D049590:Postpartum Period; D011247:Pregnancy; D014018:Tissue Distribution
chemical_list: D019380:Anti-HIV Agents; D015415:Biomarkers; D000090702:Constitutive Androstane Receptor; C000716327:NR1I3 protein, human; D019829:Nevirapine; D065702:Cytochrome P-450 CYP2B6