Abstracts

The development of specific epilepsy subtypes may be gender specific ([italic]Epilepsia[/italic] 2005; 46: 956-60), and it has been speculated that response to antiepileptic drug (AED) treatment is potentially influenced by gender. Gender influences the pharmacokinetic disposition of drugs in general ([italic]Clin Pharmacokinet[/italic] 2003; 42: 107-21); this concern extends to AEDs ([italic]Epilepsia[/italic] 2005; 46-Suppl 6: 46). While gender is associated with alterations in rat valproic acid (VPA) glucuronidation ([italic]Drug Metab Dispos[/italic] 1996; 24: 367-70), limited information exists concerning the impact of gender on VPA disposition in humans. The objective of this analysis was to examine the effect of gender on VPA pharmacokinetics in adults., Plasma VPA pharmacokinetic parameters from 5 published multiple dose studies ([italic]Clin Drug Investigation [/italic]2004, 24 (9): 495-508) in male (N=106) and female (N=64) healthy subjects and epilepsy patients on drug-metabolizing hepatic enzyme-inducing AEDs receiving 875-5000 mg/day doses of conventional delayed-release enteric-coated divalproex sodium (divalproex) and extended-release divalproex sodium (divalproex-ER) tablets were analyzed. Statistical analysis was performed in SAS at a significance level of 0.05. A linear mixed model with heterogeneous compound symmetry structure across studies to account for correlation among multiple observations within a subject was used for assessing the gender effect on the response. The model included effects for study, formulation, gender, dose level, an interaction between gender and formulation; body weight (ranging from 45 to 139 kg) was a covariate. Data for divalproex and divalproex-ER were analyzed separately since interaction between gender and formulation was significant (p[lt]0.0027)., Gender did not have a significant influence on VPA pharmacokinetics following divalproex or divalproex-ER administration. VPA least squares mean values for males vs. females, respectively, were: (a) for exposure (AUC24 [mg.h/L]) 1800 [italic]vs[/italic]. 1762 (p=0.5148) for divalproex and 1593 [italic]vs[/italic]. 1636 (p=0.5284) for divalproex-ER; (b) for maximum concentration (Cmax [mg/L]) 101.8 [italic]vs[/italic]. 102.4 (p=0.8262) for divalproex and 81.0 [italic]vs[/italic]. 83.9 (p=0.3230) for divalproex-ER; (c) for minimum concentration (Cmin [mg/L]) 52.6 [italic]vs[/italic]. 51.9 (p=0.7894) for divalproex and 47.2 [italic]vs[/italic]. 49.1 (p=0.5470) for divalproex-ER; and (d) for degree of peak-trough fluctuation (DFL) 0.635 [italic]vs[/italic]. 0.660 (p=0.3687) for divalproex and 0.439 [italic]vs[/italic]. 0.476 (p=0.2241) for divalproex-ER., No significant differences in VPA pharmacokinetic parameters were observed between male and female participants receiving divalproex or divalproex-ER after accounting for dose, differences in body weight, study effect and multiple observations within a subject/patient., (Supported by Abbott Laboratories.)