Abstracts

Rationale: The relative oral bioavailability of extended-release divalproex sodium (Depakote-ER®, Abbott Labs, ER) compared to delayed-release divalproex tablets (DR) in healthy young adults is 89%. However, no bioavailability information is available for valproate from the ER formulation in elderly patients. Absolute bioavailability can be obtained by simultaneous administration of a stable isotope. Methods: A dual-center, steady-state, crossover design (DR to ER, randomized) study in 12 patients (age 60-69, n = 6;> 70 years, n = 6) was designed to assess ER bioavailability (F) relative to DR. Patients were initially on DR maintenance therapy. VPA was taken orally at 08:00 h (fasting). Simultaneous with the oral VPA dose, stable-isotope-labeled VPA (13C4-VPA) was administered (250 mg, i.v.) to assess absolute F. Fourteen blood samples were collected over 24 hours and analyzed by GC-MS. AUC was calculated via trapezoidal curve, with F = oral AUC0-24 / i.v. 13C4-VPA AUC0-infinity, normalized for the mg dose difference. Results: The VPA absolute F in 8 elderly patients on maintenance therapy (500-3000 mg daily) were as follows: Mean FDR = 1.12 ± 0.34, Mean FER 0.92 ± 0.24. (Table). The relative F (AUC-ER/AUC-DR) was 0.87 ± 0.31.Full data for 12 patients and relative F data for ER are forthcoming. Conclusions: VPA from divalproex-DR tablets is completely bioavailable in the 8 elderly patients studied thus far. Relative bioavailability was very similar to younger patients (0.89 vs. 0.87). Upward total daily mg dose adjustment is not generally necessary when converting from enteric-coated divalproex to the ER formulation. Supported by NIH/NINDS P50 NS16308 and an investigator-initiated grant from Abbott Labs.