title: Impact of age, gender and CYP2C9/2C19 genotypes on dose-adjusted steady-state serum concentrations of valproic acid-a large-scale study based on naturalistic therapeutic drug monitoring data.
abstract: OBJECTIVE
  Valproic acid (VPA) has an extensive interindividual pharmacokinetic variability. Published data regarding the impact of gender, age, and CYP2C9/2C19 genetics on VPA variability are conflicting, and the purpose of present study is to clarify the effect of these factors on dose-adjusted steady-state serum VPA concentration (C:D ratio) in a large, naturalistic patient material.
  
  
  METHODS
  In patients who had been subjected to cytochrome P450 (CYP) genotyping and therapeutic drug monitoring of VPA, information about serum concentrations, dose, gender, age, and CYP2C9/2C19 genotypes was retrospectively collected from a routine TDM database during the period 2008-2012. The effects of age, gender, and CYP2C9/CYP2C19 genotypes on C:D ratios of VPA were investigated by multivariate analyses (mixed model) including sampling time as covariate.
  
  
  RESULTS
  In total, 857 serum concentrations from 252 patients were included. A significant gender effect was observed with a 1.3-fold higher estimated C:D ratio in females than in males, i.e., geometric means 0.34 vs. 0.27 μM/mg/day, respectively (p < 0.001). A similar and significant difference in estimated geometric means was found between patients >65 vs. ≤65 years, i.e., 0.36 vs. 0.26 μM/mg/day (p < 0.001), respectively. Finally, no association between the various CYP2C9/2C19 variant genotypes and C:D ratio of VPA was observed (p > 0.1).
  
  
  CONCLUSIONS
  The present study shows that age and gender significantly influence VPA serum concentration. In order to obtain similar drug exposure, our findings suggest that older female patients would generally require 30-50 % lower dosing of VPA compared to younger males. Moreover, we conclude that CYP2C9/2C19 genotype is not relevant for variability in VPA exposure.
authors.affiliation: Center for Psychopharmacology, Diakonhjemmet Hospital, PO Box 85, Vinderen, 0319, Oslo, Norway. Robert.lovsletten.smith@gmail.com.
authors.forename: R L
authors.initials: RL
authors.lastname: Smith
authors.affiliation: Center for Psychopharmacology, Diakonhjemmet Hospital, PO Box 85, Vinderen, 0319, Oslo, Norway.
authors.forename: T
authors.initials: T
authors.lastname: Haslemo
authors.affiliation: Center for Psychopharmacology, Diakonhjemmet Hospital, PO Box 85, Vinderen, 0319, Oslo, Norway.
authors.forename: H
authors.initials: H
authors.lastname: Refsum
authors.affiliation: Center for Psychopharmacology, Diakonhjemmet Hospital, PO Box 85, Vinderen, 0319, Oslo, Norway.|Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway.
authors.forename: E
authors.initials: E
authors.lastname: Molden
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000097:blood* / Q000493:pharmacokinetics; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D016903:Drug Monitoring; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D012737:Sex Factors; D014635:Valproic Acid / Q000097:blood* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D014635:Valproic Acid; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19
keywords: CYP2C19; CYP2C9; Elderly; Gender; Pharmacogenetics; Pharmacokinetics; Valproic acid