Relationship between valproic acid dosage, plasma concentration and clearance in adult monotherapy patients with epilepsy.

Significant variability has been reported in the plasma concentration-dose relationship for the anticonvulsant compound valproic acid (VPA). Several factors may contribute to this observed variability, including heterogeneous patient populations of children and adults, polytherapy, and timing of plasma concentration sampling. To optimally determine the relationship between trough VPA plasma concentration and dose, we evaluated a homogeneous group of adult ambulatory patients with epilepsy receiving VPA monotherapy. Furthermore, we sought to evaluate whether a relationship existed between VPA dosage and plasma clearance for both total and unbound or free drug. Steady-state trough plasma concentrations were determined in thirty-two patients. Mean VPA dose was 22.8 +/- 10.3 mg/kg/day. Mean total and unbound VPA plasma concentrations were 97.9 +/- 34.9 and 13.2 +/- 10.6 micrograms/ml, respectively. Significant correlations between VPA dose and total and unbound plasma concentrations were found (r = 0.82 and r = 0.85, P < or = 0.001, respectively). Significant relationships were also observed between VPA dose and clearance. A positive correlation was noted for dose and total plasma clearance (r = 0.61, P < or = 0.001), while an inverse correlation existed between dose and unbound VPA plasma clearance (r = -0.51, P < 0.01). Although a statistically significant correlation does exist between VPA dosage and both total and unbound plasma concentrations, significant interpatient variability still remains even under 'optimal' therapeutic drug monitoring conditions.