Population pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium in pediatric patients, adult patients, and healthy volunteers

Abstract

PurposeWe performed a population pharmacokinetic analysis of phenytoin after intravenous administration of fosphenytoin sodium in healthy, neurosurgical, and epileptic subjects, including pediatric patients, and determined the optimal dose and infusion rate for achieving the therapeutic range.MethodsWe used pooled data obtained from two phase I studies and one phase III study performed in Japan. The population pharmacokinetic analysis was performed using NONMEM software. The optimal dose and infusion rate were determined using simulation results obtained using the final model. The therapeutic range for total plasma phenytoin concentration is 10–20 μg/mL.ResultsWe used a linear two-compartment model with conversion of fosphenytoin to phenytoin. Pharmacokinetic parameters of phenytoin, such as total clearance and central and peripheral volume of distribution were influenced by body weight. The dose simulations are as follows. In adult patients, the optimal dose and infusion rate of phenytoin for achieving the therapeutic range was 22.5 mg/kg and 3 mg/kg/min respectively. In pediatric patients, the total plasma concentration of phenytoin was within the therapeutic range for a shorter duration than that in adult patients at 22.5 mg/kg (3 mg/kg/min). However, many pediatric patients showed phenytoin concentration within the toxic range after administration of a dose of 30 mg/kg.ConclusionsThe pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium could be described using a linear two-compartment model. The administration of fosphenytoin sodium 22.5 mg/kg at an infusion rate of 3 mg/kg/min was optimal for achieving the desired plasma phenytoin concentration.

Allosteric modulation of sigma‐1 receptors elicits anti‐seizure activities

“…At such concentrations the allosteric effect of phenytoin is negligible (Cobos et al, 2005;. At higher phenytoin concentrations, toxic effects are apparent (Tanaka et al, 2013). Moreover, the sigma-1 receptor antagonist, BD1047, did not block the antiseizure effects of phenytoin ( Figure 1C), suggesting that the primary mechanism by which phenytoin exerts its antiseizure effect is more likely to be through its well-known action on voltage-sensitive Na + channels located in the neuronal plasma membrane (Tunnicliff, 1996).…”

Impact of Body Habitus on Phenytoin Levels Following Fosphenytoin Loading Dose in Pediatric Patients

“…6 Various studies in adult and pediatric populations have analyzed the pharmacokinetics of fosphenytoin administration using plasma concentration data, but none have focused on the effects of obesity. 7 There are published pharmacokinetic data for intravenous phenytoin concluding that the distribution was greater in obese adult patients compared with nonobese. Authors recommend use of an adjusted body weight for loading doses, which is the ideal body weight plus the product of 1.33 times the excess body weight over ideal body weight.…”

Safety, Tolerability, and Pharmacokinetics of Fosphenytoin Loading in Patients With Subarachnoid Hemorrhage

“…21 High serum concentrations of free phenytoin, observed in our study, may have resulted from the combined effects of these pharmacokinetic characteristics including displacement of phenytoin from albumin by fosphenytoin, rapid infusion rate, and small volume of distribution of fosphenytoin after rapid intravenous loading of fosphenytoin. A recent population pharmacokinetic analysis of phenytoin after intravenous administration of fosphenytoin recommended a smaller dosage of fosphenytoin at a slower infusion rate; the optimal dose and infusion rate was calculated as 15 mg PE/kg and 2 mg PE/kg/min, respectively, in adults, 22 and on considering the pharmacokinetic characteristics of fosphenytoin, our study also suggests that loading of fosphenytoin at the slower infusion rate than 150 mg PE/min may be sufficient in achieving a rapid therapeutic range of free phenytoin.…”