Experimental design and efficient parameter estimation in population pharmacokinetics
- First Online:
- 135 Downloads
A computer simulation technique used to evaluate the influence of several aspects of sampling designs on the efficiency of population pharmacokinetic parameter estimation is described. Although the simulations are restricted to the one-compartment one-exponential model, they provide the basis for a discussion of the structural aspects involved in designing a population study. These aspects include number of subjects required, number of samples per subject, and timing of these samples. Parameter estimates obtained from different sampling schedules based on two- and three-point designs are evaluated in terms of accuracy and precision. These simulated data sets include noise terms for both inter- and intraindividual variability. The results show that the population fixed-effect parameters (mean clearance and mean volume of distribution) for this simple pharmacokinetic model are efficiently estimated for most of the sampling schedules when two or three points are used, but the random-effect parameters (describing inter- and intraindividual variability) are inaccurate and imprecise for most of the sampling schedules when only two points are used. This drawback was remedied by increasing the number of data points per individual to three.
Key wordscomputer simulation parameter estimation population pharmacokinetics experimental design
Unable to display preview. Download preview PDF.
- 1.L. Endrenyi. Design of experiments for estimating enzyme and phamiacokinetic experiments. In L. Endrenyi (ed.),Kinetic Data Analysis, Design and Analysis of Enzyme and Pharmacokinetic Experiments, Plenum Press, New York, 1981, pp. 137–167.Google Scholar
- 2.E. M. Landaw. Optimal design for individual parameter estimation in pharmacokinetics. In M. Rowland, L. M. Sheiner, and J.-L. Steimer (eds.),Variability in Drug Therapy, Description, Estimation and Control, Raven Press, New York, 1985, 187–200.Google Scholar
- 3.E. M. Landaw. Optimal experimental design for biologic compartmental systems with applications to pharmacokinetics. Dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Biomathematics, University of California, Los Angeles, 1981.Google Scholar
- 5.J. J. Di Stefano III. Optimized blood sampling protocols and sequential design of kinetic experiments.Am. J. Physiol. 9:R259–265 (1981).Google Scholar
- 12.C. M. Metzler, G. L. Elfring, and A. J. McEwen.A User's Manual for NONLIN and Associated Programs, Upjohn, Kalamazoo, MI., 1974.Google Scholar
- 14.S. L. Beal and L. B. Sheiner.NONMEM Users Guide, Parts I–VI, Division of Clinical Pharmacology, University of California, San Francisco, 1979–1989.Google Scholar