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A population pharmacokinetic analysis of valproic acid in conventional and slow release formulations was carried out. Three hundred and forty-four points in two hundred and fifteen patients were analyzed. The pharmacokinetic model, which took into account the age of the patients and the absorption lag time of the slow release formula tions, and a pharmacostatistical model with individual and residual variability were evaluated. The influence of the age of the patients and the absorption lag time on the valproic acid pharmacokinetics was significant based on the results of the statistical test. The ka of slow release formulations was 0.230 (1/h), the ka of conventional formulations was 8.14 (1/h), the Vd of the conventional and slow release formulations was 0.212 (L/kg) and the ke of the conventional and slow release formulations was 0.0495 (1/h) in adults (≥12 years) and the lag time of the slow release formulations was 1.25 (h). The ka changed with the patient's age. The ka was different for conventional and slow release formulations. Though conventional formulations did not have a lag time, the slow release formulations had a lag time. The patient age and the lag time are thought to be included in the population pharmacokinetic model using a slow release formulation. The findings suggest that the values obtained for these population pharmacokinetic parameters will be useful in optimizing valproic acid therapy for individual patients.

Acetylsalicylic acid (ASA) and salicylic acid (SA) concentrations in plasma were determined by high-pressure liquid chromatography in 14 healthy male Japanese volunteers after single oral administrations of two different aspirin formulations, enteric-coated granules (Minimax®) and a slow-release tablet (Verin®). Seven subjects received 650 mg and the other seven subjects received 1300 mg of each formulation in a randomly assigned cross-over study. Mean peak SA concentrations in the plasma were significantly higher with the enteric-coated granules than with the slow-release tablets (P

The effect of dosing time on salicylic acid (SA) kinetics after single oral administrations of two different aspirin formulations, a slow-release tablet (Veri®) and enteric-coated granules (Minimax®), was investigated in 15 healthy Japanese men. Eight subjects received slow-release tablets and the other seven subjects received enteric-coated granules. Each aspirin formulation was given in the morning (8: 30) or in the evening (20: 30) in a randomly assigned cross-over study. After the single dose study, the SA kinetics following repeated administration of the two different aspirin formulations, 2600 mg daily for five days, was investigated. Eight subjects received the slow-release tablets, and one subject received the enteric-coated granules. No time dependent changes were observed in SA kinetics after single and repeated administra tions of the two different formulations. In both dosing times, the mean peak SA concentrations in plasma were significantly higher in the enteric-coated granules, the mean elimination half-lives of plasma SA were significantly longer in the slow-release tablets, and the mean areas under the curves were significantly larger in the enteric coated granules. In repeated administration of the slow-release tablets, the mean SA concentrations were 47.4 ± 21.9 μ g/ml after administration at 20: 30 and 44.7 ± 24.4μ g/ml after dosing at 8: 30 on the day 5. The plateau SA concentrations in plasma were attained after day 3 to day 4, but after the day 5 SA concentrations in plasma tended to be decreased. This may be due to enzyme induction in the salicylate metabolism.