Interspecies extrapolation in safety evaluation of human medicines in The Netherlands (1990-1992): practical...

Doses used in animal toxicity studies can be extrapolated to therapeutic doses in man on the basis of body weight equivalence, metabolism equivalence, or toxicokinetics. The validity of extrapolation rules is a matter of debate. However, extrapolation on the basis of toxicokinetics is often preferred for human medicines, provided that adequate data are available. In registration dossiers on human medicines, often insufficient data are available to extrapolate on toxicokinetics only. This prompted us to study whether extrapolation on the basis of body weight equivalents or metabolism equivalents resembles the toxicokinetic way of extrapolation best. A survey was made of new chemical entities that have been applied for registration to the Medicines Evaluation Board in The Netherlands (College ter Beoordeling van Geneesmiddelen) between 1990 and 1992. In the majority of cases, larger margins of safety were achieved by extrapolation on the basis of body weight equivalents as compared to toxicokinetic data. Extrapolation on the basis of metabolism equivalents resembled toxicokinetic extrapolation factors better. The method of extrapolation using metabolism equivalents was rarely encountered in the registration dossiers on human medicines submitted to the Board.