Extrapolation of animal toxicity to humans: interspecies comparisons in drug development

Abstract

Different methods for converting the dose-related toxicity of drugs from animals to humans are reviewed. Each method is analyzed with respect to its utility and limitations. Linear extrapolations from animals to humans based on body weight equivalence are shown to be inaccurate unless species-specific conversion factors are used. Extrapolations based on surface area equivalence are more accurate, do not require conversion factors, and may be used when pharmacokinetic data are not available. Ultimately, interspecies conversions are most reliable when pharmacokinetic data are available, assuming that toxic responses are comparable among species for similar blood levels. Two pharmacokinetic-based approaches may be used: direct use of plasma concentration or area under the concentration-time curve (AUC) and physiologically based pharmacokinetic (PBPK) models.