title: Dose adjustment of phenytoin for comedication in Japanese patients with epilepsy.
abstract: This study sought a suitable physiological parameter related to daily phenytoin (PHT) dose (D) providing a steady-state serum concentration (Ct) and analyzed the influences of coadministered antiepileptic drugs on Ct quantitatively to adjust PHT dose. Data were derived from a total of 368 patients with epilepsy treated with multiple oral administrations of PHT. Phenobarbital, carbamazepine, valproic acid, zonisamide, clonazepam, and ethosuximide were coadministered. For the administration of PHT alone, 4 types of parameter, that is, total body weight, total body water volume, body surface area, and extracellular water volume (VECW) were examined. Then, a Michaelis-Menten kinetic model was postulated including VECW, which was assumed to detect the effect of the coadministered drug quantitatively. Adopting VECW as a transforming factor, the concentration to dose (L:D) ratio [Ct/(D/VECW)] was independent of the patient's age and gender in relation to Ct and expressed as Ct/(D/VECW) = 0.0245 x Ct + 0.076. Analysis clarified that ratios were estimated as 0.90, 0.91, 0.89, and 0.84 for phenobarbital, carbamazepine, valproic acid, and zonisamide, respectively, to maintain the same Ct concentration of PHT. Influences were not detected as the number (> or =2) of coadministered drugs increased, regardless of factor type. PHT clearance changed in an age-dependent manner and was usually poorly correlated with weight-based doses. VECW was more closely correlated with age-dependent changes in physiological parameters such as clearance. VECW was considered to remove the influence of age on clearance, and estimated ratios could be used for all age groups. In the case of the addition or removal of concomitant treatment with antiepileptic drugs in the same patient, the daily PHT dose was calculated using the value of each ratio or its reciprocal. Our results could be helpful in determining PHT dosing.
authors.affiliation: Department of Pharmacy, Kagawa University Hospital, Kagawa, Japan. fukuoka@med.kagawa-u.ac.jp
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Fukuoka
authors.forename: Junji
authors.initials: J
authors.lastname: Uno
authors.forename: Toyohisa
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Houchi
authors.forename: Michio
authors.initials: M
authors.lastname: Kimura
authors.forename: Shushi
authors.initials: S
authors.lastname: Morita
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000378:metabolism; D000465:Algorithms; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001830:Body Surface Area; D001834:Body Water / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000188:drug therapy*; D045604:Extracellular Fluid / Q000378:metabolism; D005260:Female; D016231:Fluorescence Polarization Immunoassay; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D010672:Phenytoin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012044:Regression Analysis; D012727:Sex Characteristics
chemical_list: D000927:Anticonvulsants; D010672:Phenytoin