Integration of animal pharmacokinetic and pharmacodynamic data in drug safety assessment.
The role of pharmacokinetics and pharmacodynamics in safety evaluation is the subject of considerable debate. In considering species variation in dose response relationships pharmacokinetic differences are considered by some as the likely major factor. As such measurement of the parent drug concentration in plasma is viewed as a convenient method to correct for these differences. However, even when the variation in dose response is due to species differences in the compound's metabolism or disposition, concentrations at the target organ, active metabolites or protein biding may complicate any relationship with parent drug plasma concentration. Moreover, the variation in dose response may actually reflect differences in the pharmacodynamic response per se, due to the various forms of receptor types expressed in individual species. It is concluded that safety evaluation has to be performed, not just by inter-species plasma concentration comparisons, but by assessment of the ratios between doses and concentrations producing desired effects, and those producing effects not tolerated by animals.
Smith
D A
DA
Department of Drug Metabolism, Pfizer Central Research, Sandwich, Kent, UK.
D000818:Animals; D004285:Dogs; D004361:Drug Tolerance; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D010599:Pharmacokinetics; D010600:Pharmacology; D051381:Rats; D013045:Species Specificity