Abstracts

Rationale: Valproic acid (VPA) is an anticonvulsant drug (AED) available in multiple different formulations and is commonly utilized for a spectrum of neurological and psychiatric disorders over a wide spectrum of ages. It exhibits concentration-dependent clearance due to saturable protein binding processes which is more pronounced in the elderly. A decrease in unbound valproate clearance compared to younger adults has been reported. Changes in pharmacokinetic (pK) parameters of VPA, healthy elderly volunteers aged 65 - 76, have been confirmed only for an enteric-coated divalproex (Depakote DR) formulation for total daily doses of up to 1,500 mg. Divalproex (Depakote-ER) has shown better tolerability no pharmacokinetic nor tolerability information is available for Depakote-ER in elderly patient.Methods: Patients 60+ yo treated with stable doses of valproic acid for neurologic or psychiatric diseases were recruited. Exclusions were presence of unstable medical condition or co-medication with medication that would alter the metabolism of VPA. Pharmacokinetic studies (pKs) were conducted in each patient on two occassions with timed plasma samples drawn over 72 hrs. The patients were taking Depakote DR for the first and Depakote ER for the second pKs. At the start of the pKs the patient received their usual dose of valproic acid and were also given 100 mg of stable labeled valproate intravenously. The samples are to be assayed for both unlabeled and stable labeled isotope valproic acid by GCMS. Between pKs, the patients were randomized converted either over night or over seven days from DR to the ER formulation. Ten patients were enrolled in the pKs. An additional 10 patients were enrolled only in the slow vs rapid conversion portion of the study. Side effect profile was obtained twice in baseline and three times during and after the conversion from DR to ER. A 37 item 4 level scale adverse event profile was used which was completed by the patient. The scores ranged from 1 (never a problem) to 4 (always a problem).Results: The 5 pKs patient were in their 60s and 5 in their 70s. VPA doses ranged from 500 to 3000 mg/day with no plasma level above the therapeutic range. Other than mild tremor, no clinically evident drug effect was present in any patient. All patients completed the study. Adverse event scores ranged from 1.46 (decreased urination) to 2.46 (depression and memory problems). No difference in scores were found (1) between treatment with Depakote DR and Depakote ER, (2) the rapid or the gradual conversion groups or (3) the group in the 60s and the 70s. Assay of unlabeled and labeled VPA and metabolites is in progress but not complete pK profiles for VPA and metabolites will be present. Conclusions: No difference in tolerability was found between Depakote DR and Depakote ER in elderly patients. Overnight conversion was tolerated the same as a seven day gradual conversion. Results of the pharmacokinetic profiles will be presented.