A fosphenytoin maintenance dose is most efficacious when started 12 hours following the loading dose in pediatric patients with status epilepticus or seizure clusters. The maintenance dose of 5-7.5mg/kg/dose every 12 hours may better than maintenance doses every 24 hours. These are the findings of a study published in Brain and Development.
Researchers sought to assess the dosing regimen of pediatric fosphenytoin and the optimal timing for total serum phenytoin concentration (CPHT) measurement among patients treated for status epilepticus or seizure clusters.
They conducted a retrospective study of pediatric patients treated with fosphenytoin in status epilepticus or seizure clusters between April 2013 and March 2018 at the Tokyo Women’s Medical University, Yachiyo Medical Center. The study involved 12 pediatric patients (at least 2 years of age) with a loading dose of 22.1 (17.2-27.2) mg/kg. CPHT measured 2-4 hours following the loading dose was 13.4 (8.6-18.9) µg/mL. At 12 and 24 hours after the loading dose, CPHT estimated from individual pharmacokinetic parameters was 9.5 (6.7-14.2) and 5.8 (3.7-10.0) µg/mL, respectively.
Body weight was incorporated in the pharmacokinetic model as a covariate for maximum elimination rate. Median patient age was 4 (2-12) years, and median patient weight was 17.0 (9.4-43.7) kg. Among the patients in the study cohort, 6 had status epilepticus and 6 had seizure clusters.
Seizures were caused by pre-existing epilepsy (6 patients), acute encephalopathy (4 patients), febrile convulsion (1 patient), and afebrile convulsion (1 patient). Median duration of treatment was 4 (1-15) days. Among all patients, 7 received concomitant antiepileptic drugs that possibly affected the pharmacokinetics of fosphenytoin. No adverse effects during fosphenytoin treatment were seen.
Researchers noted that if a fosphenytoin loading dose was administered at 22.5mg/kg (the standard pediatric fosphenytoin dosing regimen in Japan) and a maintenance dose of 5 or 7.5mg/kg was administered every 12 hours beginning 12 hours following the loading dose, then day 8 CPHT estimates at 5mg/kg would be 5.74 (2.6-15.4) µg/mL and at 7.5mg/kg the estimates would be 13.9 (5.7-31.0) µg/mL.
Study limitations include underpowered sample size, lack of measurement of free serum phenytoin concentration, use of concomitant antiepileptic drugs affecting measurements, and unaccounted for genetic polymorphisms that might affect interindividual variation.
Researchers concluded that a loading dose of fosphenytoin 22.5mg/kg is appropriate among pediatric patients treated for status epilepticus or seizure clusters, and “a maintenance dose of fosphenytoin should be started 12 h after the loading dose, and a maintenance dose of 5–7.5 mg/kg/dose every 12 h may be better than every 24 h.”
They suggest that in clinical practice to efficaciously adjust the dosage, measurements should be taken of CPHT at 2 and 12 hours following the loading dose.
Okamoto G, Furuya E, Terada K, Yasukawa K, Takanashi JI, Kobayashi E. Fosphenytoin dosing regimen including optimal timing for the measurement of serum phenytoin concentration in pediatric patients. Brain Dev. Published online July 22, 2022. doi:10.1016/j.braindev.2022.06.012