| Popis: |
The pharmacokinetic data of vamicamide, a new anticholinergic drug, collected from healthy male subjects were analysed to estimate population pharmacokinetic parameters. A total of 48 subjects participated in three single-dose studies and three multiple-dose studies. In the single-dose studies, the subjects were given vamicamide tablets or capsules in doses of 0.7 to 48 mg, and in the multiple-dose studies, doses of 6, 12 or 36 mg two or three times a day for six days. These six studies were conducted independently in two different facilities using the two different dosage forms. Subjects were given the drug after a meal or in a fasting state depending on each study. 931 serum vamicamide concentration data and 143 urinary vamicamide excretion data were analysed using NONMEM, a computer program designed for population pharmacokinetic analysis. The pharmacokinetic model used was a one-compartment model with first-order absorption. A linear or nonlinear regression model was used to evaluate the effects of bodyweight, age, dosage form or food intake on the pharmacokinetic parameters of vamicamide. The mean elimination rate constant (Ke), apparent volume of distribution (Vd/F) and urinary recovery were estimated to be 0.137 hr-1, 2.24 L/kg and 91.6%, respectively. Vd/F varied linearly with bodyweight. Food intake significantly affected absorption rate constant (Ka) and lag time of absorption (to) but not Vd/F. Ka increased from 1.75 hr-1 in a fasting state to 2.63 hr-1 after a meal, and t0 increased from 0.178 hr to 0.347 hr. These increases, however, did not cause any clinically significant difference in maximum serum concentrations, suggesting that the bioavailability of vamicamide appears to be little affected by food intake. Dosage form and subject age, in the range of 22 to 46 years, had no signifficant effect on the pharmacokinetics of vamicamide. The estimates of in terindividual variabilities were 71.3% in Ka, 12.8% in Ke and 11.7% in Vd/F as a coefficient of variation. The residual variabilities in the serum concentrations and in the urinary excretion were 16.5% and 12.0%, respectively. |
