Estimation of population pharmacokinetic parameters of free-phenytoin in adult epileptic patients.
BACKGROUND
Serum concentrations of free-phenytoin (F-PHT) obtained in adult epileptic patients receiving PHT in monotherapy were analyzed to estimate the Michaelis-Menten pharmacokinetic parameters.


METHODS
Steady-state F-PHT serum concentrations, PHT dosing history, and associated information were collected prospectively. The maximum metabolic rate (Vm) and Michaelis-Menten constant (Km) of F-PHT and their interindividual variability data were estimated using nonlinear mixed effects modeling (NONMEM).


RESULTS
Twenty-nine patients with two or more available steady-state F-PHT serum concentrations (total of 63 dose/serum concentration pairs) met the inclusion criteria. Patients were taking PHT (100-500 mg/day) in monotherapy. The population estimates of F-PHT for Vm and Km were 9.1 mg/kg/day and 7.3 mg/L, respectively. The model was prospectively evaluated in a small group (seven) of additional patients.


CONCLUSIONS
The recommended daily dose in this population to achieve a F-PHT concentration of 1.5 mg/L is 6.1 mg/kg.
Deleu
Dirk
D
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK.
Aarons
Leon
L
Ahmed
Ikhlas Ali
IA
D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000097:blood* / Q000493:pharmacokinetics*; D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010672:Phenytoin / Q000097:blood* / Q000493:pharmacokinetics*
D000927:Anticonvulsants; D010672:Phenytoin