Characterization of Interindividual Variability: Use of Pharmacokinetic and Pharmacodynamic Data for Pharmaceuticals. D. Naumann, Merck & Co., Inc., Whitehouse Station, NJ 08889-0100
The traditional "safety factor" method used to derive health-based limits commonly incorporates a default factor of 10 to account for interindividual variability. Use of this default can lead to overly conservative health-based limits, especially when it is combined with other (up to 10-fold) factors to adjust for interspecies extrapolation and inadequacies in the available data base. In recent years, attempts have been made to quantitate individual sources of uncertainty and variability to improve the scientific basis of health-based limits. Pharmacokinetic and pharmacodynamic data for pharmaceuticals provide scientific support for the consideration of reductions in the traditional 10-fold default uncertainty factor for interindividual variability. Recently proposed alternative methodologies for subdividing uncertainty factors also provide a framework to make maximum use of pharmacokinetic and pharmacodynamic data to reduce uncertainties when setting health-based limits and to replace default UFs with data-derived values. Examples are given to show how readily available information on drugs can be used now to estimate generic probabilistic descriptions of interindividual variability. The systematic evaluation of compound-specific pharmacokinetic and pharmacodynamic data from different chemical classes in the future will enable refinements to these "default" distributions.