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Pharmacodynamic parameter estimation: population size versus number of samples.
Suzette Girgis1, Sudhakar M Pai, Ihab G Girgis
1Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, NJ, USA. suzette.girgis@bms.com
The AAPS Journal
|December 16, 2005
Summary
Accurate pharmacodynamic (PD) parameter estimates require sufficient sampling. Four samples per individual generally suffice, but higher interindividual variability (IIV) may necessitate five samples for reliable results.
Area of Science:
- Pharmacometrics
- Pharmacodynamics
- Population modeling
Background:
- Accurate estimation of pharmacodynamic (PD) parameters is crucial for drug development.
- Understanding the impact of study design on parameter estimation is essential for efficient clinical trials.
Purpose of the Study:
- To assess how population size, sampling frequency, and interindividual variability (IIV) affect the accuracy and precision of PD parameter estimates.
- To identify optimal sampling strategies for reliable PD modeling.
Main Methods:
- Simulated response data using an inhibitory sigmoid Emax model.
- Employed Nonlinear Mixed Effect Modeling (NONMEM) for parameter estimation.
- Investigated seven sampling designs across different concentration windows relative to EC50.
Main Results:
- Four samples per individual provided accurate and precise estimates for most PD and variability parameters at 100 individuals and 30% IIV.
- Reduced sampling led to imprecise variability parameter estimates, while PD estimates remained precise.
- Five samples per individual improved performance over four samples at 45% IIV.
Conclusions:
- Four samples per individual are generally adequate for PD parameter estimation.
- Increased IIV may require a higher number of samples per individual for precise estimation.
- Specific sampling windows (0.1-3 EC50) are sufficient for reliable parameter estimation in moderately variable drugs.