Landmark CJ, et al. – In order to elucidate the variable relationship between dose and serum concentrations with the ultimate aim of facilitating safer use of valproic acid (VPA), the clinicians examined the pharmacokinetic variability of VPA in women of childbearing age by therapeutic drug monitoring (TDM) data. Among women of childbearing age, this study showed the extensive pharmacokinetic variability of VPA, which was most pronounced at low doses. In future studies, rather than dosage, serum concentrations of VPA had to be used as a guide for exposure of VPA and possible risks of teratogenicity to assess safety aspects of VPA in women.

• The clinicians used anonymized retrospective data from the TDM database (2006-2015) at the National Center for Epilepsy in Norway.
• Trough total concentrations of VPA at assumed steady state in women aged 14–46 years were examined.

• The clinicians included data from 643 nonpregnant women of childbearing age (mean age = 27 years).
• In this study, mean dose and serum concentration of VPA were 968 (standard deviation [SD] = 453) mg/day and 411 (SD = 138) μmol/L, respectively, and 59% used polytherapy.
• The pharmacokinetic variability in serum concentration/dose (C/D) ratios between women was extensive.
• Mean serum concentration was 336 μmol/L and variability in C/D ratio was 10-fold for doses <700 mg/day (n = 202; 32%; 150-625 mg/day).
• With increasing dose to eightfold, the variability decreased (≥700 to <1,500 mg/day, n = 358) and fourfold (≥1,500 mg/day, n = 96).