APPLICATION OF OPTIMAL SAMPLING THEORY TO THE DETERMINATION OF METACYCLINE PHARMACOKINETIC PARAMETERS - EFFECT OF MODEL MISSPECIFICATION

Use of optimal sampling theory (OST) in pharmacokinetic studies allows the number of sampling times to be greatly reduced without loss in pa rameter estimation precision. OST has been applied to the determinatio n of the bioavailability parameters (area under the curve (AUC), maxim al concentration (C-max), time to reach maximal concentration (T-max), elimination half-life (T-1/2), of metacycline in 16 healthy volunteer s. Five different models were used to fit the data and to define the o ptimal sampling times: one-compartment first-order, two-compartment fi rst-order, two-compartment zero-order, two-compartment with Michaelis- Menten absorption kinetics, and a stochastic model. The adequacy of th ese models was first evaluated in a 6-subject pilot study. Only the st ochastic model,oil zero-order absorption kinetics was adequate. Then, bioavailability parameters were estimated in a group of 16 subjects by means of noncompartmental analysis (with 19 samples per subject) usin g each optimal sampling schedule based procedure (with 6 to 9 samples depending on the model). Bias (PE) and precision (RMSE) of each bioava ilability parameter estimation were calculated by reference to noncomp artmental analysis, and were satisfactory for the 3 adequate models. T he most relevant criteria for discrimination of the best model were th e coefficient of determination, tire standard deviation, and the mean residual error vs. time plot. Additional criteria were the number of r equired sampling times and the coefficient of variation of the estimat es. In this context, the stochastic model was superior and yielded ver y good estimates of the bioavailability parameters with only 8 samples per subject.