Prediction of pharmacokinetic parameters and the assessment of their variability in bioequivalence studies by artificial neural networks.

PURPOSE: The methodology of predicting the pharmacokinetic parameters (AUC, cmax, tmax) and the assessment of their variability in bioequivalence studies has been developed with the use of artificial neural networks. METHODS: The data sets included results of 3 distinct bioequivalence studies of oral verapamil products, involving a total of 98 subjects and 312 drug applications. The modeling process involved building feedforward/backpropagation neural networks. Models for pharmacokinetic parameter prediction were also used for the assessment of their variability and for detecting the most influential variables for selected pharmacokinetic parameters. Variables of input neurons based on logistic parameters of the bioequivalence study, clinical-biochemical parameters, and the physical examination of individuals. RESULTS: The average absolute prediction errors of the neural networks for AUC, cmax, and tmax prediction were: 30.54%, 39.56% and 30.74%, respectively. A sensitivity analysis demonstrated that for verapamil the three most influential variables assigned to input neurons were: total protein concentration, aspartate aminotransferase (AST) levels, and heart-rate for AUC, AST levels, total proteins and alanine aminotransferase (ALT) levels, for cmax, and the presence of food, blood pressure, and body-frame for tmax. CONCLUSIONS: The developed methodology could supply inclusion or exclusion criteria for subjects to be included in bioequivalence studies.

Bioavailability of dihydroergosine in healthy volunteers.

Eight healthy volunteers received an oral dose of 10 mg and an intravenous dose of 0.75 mg of dihydroergosine. Plasma concentrations were measured by HPLC method, and some pharmacokinetic parameters were calculated. The biologic half-life in the elimination phase was 8.35 +/- 1.87 h after oral administration and 8.84 +/- 3.64 h after intravenous administration. In both cases of administration a secondary rise in plasma concentration of dihydroergosine was observed, which can be attributed to hepatic recycling. The calculated bioavailability of the drug was 9.80 +/- 2.8%.

Dose-dependent bioavailability of propranolol.

The pharmacokinetics of orally administered propranolol in doses of 10, 40, 80 and 160 mg was studied in eight healthy volunteers in a cross-over trial. The analytical method applied made possible a parallel determination of propranolol and of 4-OH propranolol. The dose-dependent kinetics of orally administered propranolol was demonstrated. In our study linear dependence could be established only within a dosage range of 40 mg to 160 mg. Both substances determined in plasma, propranolol as well as 4-OH propranolol, show a tendency toward non-linearity, particularly at the lower dosage range between 10 and 40 mg.