Abstracts

Valproic Acid (VPA) is a widely prescribed antiepileptic medication (AED) exhibiting complex pharmacokinetics (PK). We have developed an investigational, intravenous, stable-labeled [¹³C][sub]4[/sub]-VPA formulation in order to rigorously characterize steady-state VPA PK in adult and elderly patients. Administration of stable-labeled VPA allows for measurement of half-life and absolute bioavailability in patients without interrupting AED therapy. This will be particularly important in the elderly, a group who is receiving VPA therapy for several indications and who are an understudied population. The purpose of the present study is to present preliminary safety information in patients while on steady-state VPA therapy. Adults 18 years or older on maintenance VPA therapy were eligible to participate in the study. Exclusion criteria included the use of potentially interacting co-medications. On the day of the study, patients were given a single 250 mg intravenous (IV) infusion of a [¹³C][sub]4[/sub]-VPA formulation (equivalent to IV Depacon[reg], IND #67163) as part of their morning dose. The remainder of the dose was given orally. Blood samples were collected just prior to and up to 96 hours after [¹³C][sub]4[/sub]-VPA administration. Both VPA and [¹³C][sub]4[/sub]-VPA were measured in plasma by GC-MS. Non-compartmental PK analysis was done with WinNonLin[reg] (Pharsight Corporation, version 4.0). Blood pressure (BP), respiration rate (RR), and heart rate (HR) data were collected prior to infusion, every 2 minutes during infusion, and every 15 minutes for the first hour following the completion of the infusion. Each subject was monitored by ECG before and during the infusion. The study nurse monitored the infusion site for inflammation during the infusion and at the time that the indwelling catheter was removed. Patients were asked to report any discomfort at the infusion site. Three patients (age range 20-39: 1 female and 2 male) have competed the study. VPA daily doses ranged from 1000-2250 mg/day. No changes in HR, RR, or ECG were noted. In one patient, a modest drop in diastolic BP ([sim]5 mm Hg) was noted during infusion. Our preliminary data indicate that [¹³C][sub]4[/sub]-VPA can be safely administered to healthy patients. The use of a parenteral [¹³C][sub]4[/sub]-VPA formulation permits comprehensive characterization of half-life and bioavailability of VPA in patients without interrupting therapy. After the safety phase of this project, determination of PK and bioavailability in elderly patients will be done. Preliminary PK data will be presented in the poster. (Supported by NIH NINDS P50-NS16308 and M01-RR0040, and Abbott Laboratories)