Relative Bioavailability of Orally Administered Fosphenytoin Sodium Injection Compared with Phenytoin Sodium Injection in Healthy Volunteers

Abstract

To describe the pharmacokinetics of fosphenytoin (FPHT) sodium injection when administered orally, and to determine the relative oral bioavailability (FREL ) of FPHT sodium injection compared with PHT sodium injection based on pharmacokinetic modeling in healthy volunteers. Open-label, randomized, single-dose, two-period, two-sequence crossover study. University-affiliated clinical research center funded by the National Center of Research Resources. Ten healthy adult volunteers. Subjects were randomized to receive a single oral dose of either PHT sodium injection or FPHT sodium injection at a dose equivalent to 400mg PHT acid. Blood samples were collected at baseline (just prior to administration) and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72hours after dose administration. After a 7-14-day washout period, the subjects underwent the same study procedures for administration of the other agent (PHT or FPHT). The mean age and weight of the 10 subjects were 37years and 72.5kg, respectively, and the mean dose was 5.6mg/kg based on PHT acid equivalence. The mean FREL of FPHT was 1.21 (95% confidence interval [CI] 1.07-1.35). Serum PHT concentrations were determined by fluorescence polarization immunoassay. The median (range) maximum serum concentration (Cmax ) values were significantly higher after FPHT administration compared with PHT: 10.7 (9.0-19.4) mg/L versus 5.0 (3.2-8.9) mg/L (p=0.002). The PHT concentration after oral administration of FPHT displayed faster absorption compared with PHT, with a median (range) time to reach Cmax of 1.0 (0.5-2.0) hours versus 6.0 (2.0-24.0) hours (p=0.008). All subjects completed the study without any serious adverse events reported. FPHT sodium injection given orally was absorbed more rapidly and to a significantly greater extent than PHT sodium injection given orally to healthy volunteers. Further evaluation of oral FPHT as an alternative in patients requiring enteral feedings is warranted.