title: Integration of population pharmacokinetics and pharmacogenetics: an aid to optimal nevirapine dose selection in HIV-infected individuals.
abstract: BACKGROUND
  Nevirapine is metabolized by CYP2B6 and polymorphisms within the CYP2B6 gene partly explain inter-patient variability in pharmacokinetics. The aim of this study was to model the complex relationship between nevirapine exposure, weight and genetics (based on combined analysis of CYP2B6 516G > T and 983T > C single nucleotide polymorphisms).
  
  
  METHODS
  Non-linear mixed-effects modelling was used to estimate pharmacokinetic parameters from 275 patients. Simulations of the nevirapine concentration profile were performed with dosing regimens of 200 mg twice daily and 400 mg once daily for individuals with body weights of 50, 70 and 90 kg in combination with CYP2B6 genetic variation.
  
  
  RESULTS
  A one-compartment model with first-order absorption best described the data. Population clearance was 3.5 L/h with inter-patient variability of 24.6%. 516T homozygosity and 983C heterozygosity were associated with 37% and 40% lower clearance, respectively. Body weight was the only significant demographic factor influencing clearance, which increased by 5% for every 10 kg increase. For individuals with higher body weight, once-daily nevirapine was associated with a greater risk of sub-therapeutic drug exposure than a twice-daily regimen. This risk was offset in individuals who were 516T homozygous or 983C heterozygous in which drug exposure was optimal for  >  95% of patients with body weight of ≤ 70 kg.
  
  
  CONCLUSIONS
  The data suggest that a 400 mg once-daily dose could be implemented in accordance with CYP2B6 polymorphism and body weight. However, the use of nevirapine once daily (immediate release; off-label) in the absence of therapeutic drug monitoring is not recommended due to the risk of inadequate exposure to nevirapine in a high proportion of patients. There are different considerations for the extended-release formulation (nevirapine XR) that demonstrate minimal peak-to-trough fluctuations in plasma nevirapine levels.
authors: Department of Pharmacology and Therapeutics, School of Biomedical Sciences, University of Liverpool, Liverpool, UK.
authors: Alessandro
authors: A
authors: Schipani
authors: Christoph
authors: C
authors: Wyen
authors: Tabitha
authors: T
authors: Mahungu
authors: Heidy
authors: H
authors: Hendra
authors: Deirdre
authors: D
authors: Egan
authors: Marco
authors: M
authors: Siccardi
authors: Gerry
authors: G
authors: Davies
authors: Saye
authors: S
authors: Khoo
authors: Gerd
authors: G
authors: Fätkenheuer
authors: Michael
authors: M
authors: Youle
authors: Jürgen
authors: J
authors: Rockstroh
authors: Norbert H
authors: NH
authors: Brockmeyer
authors: Margaret A
authors: MA
authors: Johnson
authors: Andrew
authors: A
authors: Owen
authors: David J
authors: DJ
authors: Back
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001835:Body Weight; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D005787:Gene Frequency; D005828:Genetics, Population; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D019829:Nevirapine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D010597:Pharmacogenetics; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D019829:Nevirapine; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating