Application of optimal sampling theory to the determination of metacycline pharmacokinetic parameters: Effect of model misspecification |
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Authors: | Michel Tod Christophe Padoin Kamel Louchahi Brigitte Moreau-Tod Olivier Petitjean Gerard Perret |
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Institution: | 1. Department de Pharmacotoxicologie, H?pital Avicenne, 125 Route de Stalingrad, 93000, Bobigny, France
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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 half-life (T1/2), of metacycline in 16 healthy volunteers. Five different models were used to fit the data and to define the optimal sampling
times: one-compartment first-order, two-compartment first-order, twocompartment zero-order, two-compartment with Michaelis-Menten
absorption kinetics, and a stochastic model. The adequacy of these models was first evaluated in a 6-subject pilot study.
Only the stochastic model with 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) 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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Keywords: | optimal sampling experimental design parameter estimation model misspecification metacycline pharmacokinetics |
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