Application of optimal sampling theory to the dete

Authors: Michel Tod Christophe Padoin Kamel Louchahi Brigitte MoreauTod Olivier Petitjean Gerard Perret

Publish Date: 1994/04/01

Volume: 22, Issue: 2, Pages: 129-146

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Abstract

Use of optimal sampling theory OST in pharmacokinetic studies allows the number of sampling times to be greatly reduced without loss in parameter estimation precision OST has been applied to the determination of the bioavailability parameters area under the curve AUC maximal concentration Cmax time to reach maximal concentration Tmax elimination halflife T1/2 of metacycline in 16 healthy volunteers Five different models were used to fit the data and to define the optimal sampling times onecompartment firstorder twocompartment firstorder twocompartment zeroorder twocompartment with MichaelisMenten absorption kinetics and a stochastic model The adequacy of these models was first evaluated in a 6subject pilot study Only the stochastic model with zeroorder 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 using each optimal sampling schedule based procedure with 6 to 9 samples depending on the model Bias PE and precision RMSE of each bioavailability parameter estimation were calculated by reference to noncompartmental analysis and were satisfactory for the 3 adequate models The most relevant criteria for discrimination of the best model were the coefficient of determination the standard deviation and the mean residual error vs time plot Additional criteria were the number of required sampling times and the coefficient of variation of the estimates In this context the stochastic model was superior and yielded very good estimates of the bioavailability parameters with only 8 samples per subject

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