Valproic acid (VPA) may cause impaired platelet function, thrombocytopenia and, occasionally, severe bleeding. Controversy exists both as to the mechanism of this alteration in hemostasis and as to whether these adverse effects are either dose-related or idiosyncratic. Previous investigations have focused primarily on pediatric patients who commonly were receiving multiple anticonvulsant medications. We evaluated a cohort of 27 adult patients with epilepsy who were receiving VPA monotherapy and compared them with age-matched controls to determine whether a correlation exists between platelet count, function, bleeding time, levels of von Willebrand's factor antigen, and VPA dose or plasma concentration. VPA patients had significantly lower platelet counts and longer bleeding times than did controls (p < 0.05). Platelet count was inversely correlated to VPA dose and both free and total VPA concentration (p < 0.01). There was no significant difference in levels of von Willebrand's factor antigen between patients and controls. We assessed platelet aggregation by measurement of whole-blood platelet aggregation and release with agonists including adenosine diphosphate, thrombin, collagen, arachidonic acid, and ristocetin. VPA patients had significant decreases in platelet aggregation values compared with controls. There were significant differences in collagen, arachidonic acid, and adenosine diphosphate release and aggregation between groups that correlated to both VPA dose (p < 0.01) and concentration (p < 0.05). Prolongation of bleeding time was significantly correlated to both VPA dose and concentration. Our data suggest a significant relationship between impaired platelet function and both VPA dose and plasma concentration.

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Opening and mixing the contents of gabapentin capsules does not significantly impair drug absorption. This may be a viable administration option for patients who are unable to swallow intact capsules. Dietary macronutrient composition (i.e., protein) may favorably influence gabapentin oral absorption.

SUMMARY 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 μ/ml, respectively. Significant correlations between VPA dose and total and unbound plasma concentrations were found (r= 0 82 and r= 0 85, P= 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= 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.

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