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

• Published in: European journal of clinical pharmacology Vol. 69; no. 3; pp. 489 - 497
• Main Authors: Tanaka, Jun, Kasai, Hidefumi, Shimizu, Kenji, Shimasaki, Shigeki, Kumagai, Yuji
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.03.2013; Springer; Springer Nature B.V
• Subjects: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Anticonvulsants - administration & dosage; Anticonvulsants - adverse effects; Anticonvulsants - blood; Anticonvulsants - pharmacokinetics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Biotransformation; Child; Child, Preschool; Clinical Trials, Phase I as Topic; Clinical Trials, Phase III as Topic; Computer Simulation; Drug Dosage Calculations; Drug therapy; Female; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Health; Humans; Infusions, Intravenous; Japan; Kinetics; Linear Models; Male; Medical sciences; Middle Aged; Models, Biological; Nervous system (semeiology, syndromes); Neurology; Patients; Pediatrics; Pharmacokinetics and Disposition; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Phenytoin - administration & dosage; Phenytoin - adverse effects; Phenytoin - analogs & derivatives; Phenytoin - blood; Phenytoin - pharmacokinetics; Prodrugs - administration & dosage; Prodrugs - adverse effects; Prodrugs - pharmacokinetics; Randomized Controlled Trials as Topic; Retrospective Studies; Software; Young Adult; Japan; Population pharmacokinetics; Fosphenytoin sodium injection; Status epilepticus; Epileptic seizure; Phenytoin; Pediatrics; Intravenous administration; Epilepsy; Infant; Anticonvulsant; Subintrant crisis; Adult; Neurological disorder; Child; Human; Fosphenytoin; Nervous system diseases; Healthy subject; Neuroprotective agent; Injection; Hydantoins; Cerebral disorder; Convulsion; Sodium; Central nervous system disease
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-012-1373-8

Purpose We 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. Methods We 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. Results We 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. Conclusions The 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.