Abstracts

Rationale: A new formulation of fosphenytoin sodium has been developed by CyDex Pharmaceuticals, Inc., to provide enhanced stability and room temperature storage of the drug product. This will allow broader use by emergency personnel and more rapid access to therapy in most situations. The new formulation contains the solubilizing agent, Captisol, a substituted cyclodextrin known to form reversible complexes with phenytoin and to a much lesser extent fosphenytoin. It is critical to understand any effects that the presence of the cyclodextrin might have on therapy so intravenous (IV) and intramuscular (IM) bioavailability (BA) studies were conducted in healthy volunteers comparing the new formulation, Captisol-Enabled Fosphenytoin Sodium (CE-FOS), to equivalent doses of the commercially available reference product, Cerebyx (Parke-Davis). In addition, safety and tolerability of the two formulations was evaluated. Methods: The studies used a single-dose, double-blind, randomized, two-period crossover design with IM doses of 1000 mg PE (phenytoin equivalents) per injection site and IV doses of 10 mg PE/kg infused at 150 mg PE/minute (300 mg/min Captisol). Blood samples were taken over 48h and analyzed for total phenytoin (total and non-protein bound for the IV study) using a validated LC/MS/MS method with isotopic phenytoin-D10 internal standard. Safety monitoring included analysis of 24-hour urine collections obtained prior to, immediately after, and 14 days following IV injection of the test products. The study was conducted at CEDRA Corporation (Austin, Texas). Pharmacokinetic (PK) parameters for phenytoin were calculated using non-compartmental analysis. Analysis of variance (ANOVA) and the Schuirmann s two one-sided t-test procedures at the 5% significance level were applied to the log-transformed pharmacokinetic exposure parameters, Cmax and AUC. The 90% confidence intervals for the ratio of the geometric means (Test/Reference) were calculated and bioequivalence declared if the lower and upper confidence intervals were within 80% to 125%. Results: PK analysis was conducted on 34 of 38, and 50 of 52 subjects completing the IV and IM studies respectively. Results for total phenytoin are presented in Table 1. The 90% confidence interval for comparing ln(Cmax), ln(AUClast) and ln(AUCinf) were determined to be within the accepted 80% to125% limits for both routes of administration. There were no changes in urinary excretion of monitored analytes other than a small increase in urinary chloride and sodium during the first day following administration of the test drugs. Conclusions: CE-FOS is bioequivalent to the Cerebyx formulation following both IV and IM administration, and shows a similar safety profile. This new Room-Temperature stable formulation will allow broader use of fosphenytoin, particularly in the field and emergency situation.