A Sparse Sampling, Mixed Effects Approach to Toxicokinetic Analyses
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Copyright 0 1997 Drug Information Association Inc
A SPARSE SAMPLING, MIXED EFFECTS APPROACH TO TOXICOKINETIC ANALYSES PETERA. GETHING,BSC Biornetrics Department, RhBne-Poulenc Rorer, West Malling, Kent, United Kingdom
PETERT. DALEY-YATES, PHD Pharmacokinetics Department, Glaxo Wellcome Research and Development, Middlesex, United Kingdom
The use of a satellite group for pharmacokinetic evaluations in preclinical toxicokinetic studies is costly and prohibits direct correlations between toxicological findings and drug concentrations within the same animal. In studies for which some prior information about the kinetics of the drug is available and where the statistical hypotheses to be tested are relatively few, a sparse sampling “population kinetics” approach to the study design has many advantages. This paper describes how the sparse sampling method was used prospectively for a 30-day oral toxicokinetic study involving jive rats of each sex and two sampling days. Population means of the kinetic parameters for a two-compartment model were estimated using the NONMEM mixed-effects modeling package, and the posthoc routine used to produce individual Bayesian estimates for each animal. From the individual kinetic parameters, the noncompartmental parameters: AUC, Cmax, and Tmax, were calculated using SAS. Key Words: Toxicokinetics; Pharmacokinetics; Mixed-effects modeling; Sparse sampling; NONMEM
INTRODUCTION CONVENTIONALLY, MOST toxicokinetic preclinical investigations are performed using two groups of animals, the first group comprising animals for toxicology measurements and the second (usually smaller) satellite group consisting of animals for pharmacokinetic analysis. The major drawbacks of such a design are:
1. The large number of animals required to provide adequate information on both toxicology and pharmacokinetics, and 2. The inability to correlate toxicological effects with drug concentrations observed in the same animal. A sparse sampling “population kinetics” approach to study design not only eliminates the need for a separate group of animals for pharmacokinetic evaluations but also allows both
Reprint address: Peter A. Gething, BSC, Biometrics Department, RhBne-Poulenc Rorer, RPRHouse, 50 Kings Hill Avenue, Kings Hill, West Malling, Kent, ME19 4AH, United Kingdom.
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toxicological and drug concentration measurements on the same animal. Sparse sampling methods are not without their problems, however, due to the infinite number of possible sampling schemes, the complex mixed model analysis, and the difficulty in making prior estimates of the power of the statistical tests to detect dose, day, and sex effects on the kinetics of the drug. Most publications in this field have examined the sparse sampling study design from a theoretical perspective, using simulated data (1,2) or data from an intensively sampled satellite group (3,4,5). Bree et al. (6) report on the use
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