Previously reported routine phenytoin clinical pharmacokinetic data from Japan, England, and Germany were analysed to estimate population pharmacokinetic parameters. There were 780 steady-state phenytoin concentrations and associated dosage rates (mg/day) from 322 patients. The patient group spanned paediatric and adult ages, mean age being 18.4 +/- 17.3 (SD) years; 53% were males. The data were analysed using NONMEM, a computer programme designed for population pharmacokinetic analysis. Estimates of the influence of age, gender, data source, height and weight on the maximum elimination rate (Vm) and Michaelis-Menten constant (Km) were obtained. The Vm and Km of a 70 kg adult male European were estimated to be 415 mg/day and 5.7 mg/L, respectively. Vm is not influenced by gender, age or data source. The parameters of a power function of height and weight were estimated to adjust Vm for body size. The best function adjusts Vm in proportion to weight to the 0.6 power; height contains no useful information. Km is not influenced by gender. The Km for patients less than 15 years old is 43% less than that of older patients. The Km of Japanese patients appears to be 23% less than that for European patients. Even after adjustments for age, etc., apparent Vm and Km vary unpredictably among individuals with a coefficient of variation between 10 to 20% and approximately 50% respectively.
Clinical effects and pharmacokinetics of once-a-day pediatric zonisamide (ZNS) monotherapy were investigated in 72 children (range, 3 months to 15 years; mean age, 8 years and 3 months) with cryptogenic localization-related epilepsies with simple, complex, or secondarily generalized partial seizures; none had prior epilepsy treatment. ZNS was initiated at 2mg/kg; daily dosage was doubled at weekly intervals to achieve maintenance dosage (8.0 mg/kg; mean, 7.97 +/- 0.55 mg/kg). Blood samples determined trough and peak plasma levels; levels were 27.0 +/- 9.4 microg/ml and 33.8 +/- 10.8 microg/ml, respectively, with ratios as small as 1.28 +/- 0.15. Plasma level to dose ratios increased with age; peak-to-trough ratios were not age variable. Seizures were not controlled in 23 of 72 patients; low trough plasma levels (approximately 15 microg/ml) were observed. Drowsiness/short attention span in five patients instigated a dosage decrease (peak plasma levels >40 microg/ml). During treatment (6-43 months; mean, 27.2 months), seizure control occurred in 57 of 72 patients (79.2%), including eight refractory patients. In 12 patients with uncontrolled seizures and high ZNS levels, carbamazepine (CBZ) was added (BID; mean total dose, 15.1 +/- 3.0 mg/kg) to ZNS (QD; mean dose, 11.1 +/- 2.5 mg/kg); drug interactions were examined.
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