Fosphenytoin Population Pharmacokinetics in the Acutely Ill Pediatric Population

Objective: The purpose of this study is to describe the pharmacokinetics of phenytoin in pediatric patients receiving fosphenytoin. Design: Retrospective, population pharmacokinetic analysis. Setting: Emergency department or PICU of a large tertiary care children’s hospital. Patients: Patients less than 19 years old who received fosphenytoin in the PICU or emergency center for treatment of seizures from January 2011 to June 2017 were included. Interventions: Population pharmacokinetic analysis was performed with NONMEM v7.3 (Icon Plc, Dublin, Ireland). Simulation was performed to determine optimal loading dose and maintenance dosing regimens. Measurements and Main Results: A total of 536 patients (55.4% male; median age, 3.4 yr [interquartile range, 0.92–8.5 yr]) met study criteria. Fosphenytoin was administered at median 15.1 mg/kg/dose (interquartile range, 6.3–20.7 mg/kg/dose). Mean serum concentrations of 17.5 ± 7.8 mg/L were at a median 4.2 hours (interquartile range, 2.5–7.8 hr) after a dose. A pharmacokinetic model with two compartments, allometrically scaled fat-free mass on all parameters, and serum creatinine and concomitant phenobarbital use on clearance had the best fit. Simulation demonstrated that a 20 mg/kg loading dose followed by 6 mg/kg/dose every 8 hours had the greatest percentage of concentrations in the 10–20 mg/L range, with reduced doses to achieve therapeutic in patients with reduced kidney function. Conclusions: A loading dose of 20 mg/kg followed by 6 mg/kg/dose every 8 hours based on fat-free mass is a reasonable empiric strategy for attainment and maintenance of therapeutic trough concentrations. Concomitant phenobarbital use may increase clearance of phenytoin and fosphenytoin dose reductions should occur in patients with reduced kidney function. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (https://ift.tt/2gIrZ5Y). Dr. Weingarten received funding from Greenwich Pharmaceuticals. Drs. Weingarten and Riviello disclosed off-label product use in the article. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: bsmoffet@texaschildrens.org ©2018The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

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