Effects of CYP2C19 and CYP2C9 genotypes on pharmacokinetic variability of valproic acid in Chinese epileptic patients: nonlinear mixed-effect modeling

Eur J Clin Pharmacol. 2009 Dec;65(12):1187-93. doi: 10.1007/s00228-009-0712-x. Epub 2009 Sep 16.


Purpose: To evaluate the effects of CYP2C19 and CYP2C9 genotypes on the pharmacokinetic variability of valproic acid (VPA) in epileptic patients using a population pharmacokinetic (PPK) approach.

Methods: VPA concentrations were measured in 287 epileptic patients, who were genotyped for CYP2C19*2/*3 and CYP2C9*3. Patients who were on monotherapy with VPA were divided into two groups, a PPK-model group (n = 177) and a PPK-valid group (n = 110). The PPK parameter values for VPA were calculated in the PPK-model group by using the NONMEM software. Ultimately, a biological model and a final model were established. Each model was then used to independently predict the concentrations of the PPK-valid group to validate the two models.

Results: There was a significant effect of the CYP2C19 and CYP2C9 genotypes on the pharmacokinetic (PK) variability (P < 0.01) in the final PPK model of CL/F. The interindividual CL was calculated according to the final model: CL/F = 0.0951 x (1 + e(0.0267 x (3 - genotype))) + 0.0071 x age (L/h). The coefficient of variation (CV) (omega CL/F) of the final model was 29.3%, while that of the biological model was 31.7%. Based on the genotype, the individual PK parameters can be calculated more accurately than before.

Conclusion: The CYP2C19 and CYP2C9 genotypes significantly influenced the PK variability of VPA, as quantified by NONMEM software.

MeSH terms

  • Adult
  • Aged
  • Antimanic Agents / pharmacokinetics*
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • China
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP2C9
  • Epilepsy / blood
  • Epilepsy / drug therapy*
  • Epilepsy / enzymology*
  • Epilepsy / genetics
  • Female
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Nonlinear Dynamics
  • Population
  • Valproic Acid / pharmacokinetics*
  • Young Adult


  • Antimanic Agents
  • Valproic Acid
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19