Population pharmacokinetics of phenytoin in Japanese patients with epilepsy: analysis with a dose-dependent clearance model.
The population pharmacokinetic parameters of phenytoin were estimated using routine therapeutic drug monitoring data from 116 epileptic patients. The 531 serum concentration values at steady-state after repetitive oral administration were analyzed using a nonlinear mixed effects model (NONMEM) program designed for estimation of population pharmacokinetic parameters. A one-compartment model with dose-dependent clearance was used for the pharmacokinetic analysis of phenytoin. The volume of distribution (V) was estimated to be 1.231/kg in a typical 42-kg patient, assuming that the bioavailability of orally administered phenytoin is 100%. The maximal elimination rate (V(max)) and the Michaelis-Menten constant (K(m)) were 9.80 mg/d/kg and 9.19 micrograms/ml, respectively. The parameter of power function of weight to adjust V and V(max) was estimated to be 0.463. In addition, K(m) for phenytoin appeared to be 16% increased in patients receiving zonisamide concurrently. The population pharmacokinetic parameters of phenytoin will be useful for designing dosage regimens in epileptic patients.
Odani
A
A
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Japan.
Hashimoto
Y
Y
Takayanagi
K
K
Otsuki
Y
Y
Koue
T
T
Takano
M
M
Yasuhara
M
M
Hattori
H
H
Furusho
K
K
Inui
K
K
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000453:epidemiology / Q000378:metabolism*; D005260:Female; D006801:Humans; D007223:Infant; D007564:Japan / Q000453:epidemiology; D008297:Male; D008954:Models, Biological; D010672:Phenytoin / Q000097:blood / Q000493:pharmacokinetics*; D011153:Population; D013223:Statistics as Topic
D000927:Anticonvulsants; D010672:Phenytoin