Bioavailability estimation by semisimultaneous drug administration: a Monte Carlo simulation study.
The performance of a novel method for determination of drug absorption characteristics was evaluated by Monte Carlo simulations. In bioavailability studies with use of this method, the test and the reference doses are administered within a time interval of hours. Estimates of bioavailability are obtained by fitting an appropriate model to the concentration-time profile, which in its terminal portion is thus the summed concentration of the two doses. Drugs with different properties, mimicked by varying the kinetic rate constants (ka, lambda 1 and lambda 2), and experimental designs with different sets of conditions regarding the interval between doses, dose ratio, dose order, and duration of sampling, were simulated to determine what factors govern parameter estimation. The absorption characteristics of the simulated drugs could be adequately determined in experiments lasting for 12 hr or less, provided that a proper design was used. Fitting of a simpler or a more complex disposition model produced estimates with similar accuracy and precision to those noted with the true model. For some conditions the use of an improper absorption model resulted in slightly reduced accuracy, but as these fits were poor there was a clear need to try other models. In another set of simulations the use of the proposed method to assess the relative availability of two extravascular doses was evaluated. The relative rate and extent of absorption could be estimated with good precision for two formulations exhibiting a rapid to moderate rate of absorption.
Karlsson
M O
MO
Department of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Uppsala, Sweden.
Bredberg
U
U
D000042:Absorption; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D008954:Models, Biological; D009010:Monte Carlo Method; D004364:Pharmaceutical Preparations / Q000008:administration & dosage; D010599:Pharmacokinetics; D015203:Reproducibility of Results; D013997:Time Factors
D004364:Pharmaceutical Preparations