INTERSPECIES EXTRAPOLATION IN SAFETY EVALUATION OF HUMAN MEDICINES INTHE NETHERLANDS (1990-1992) - PRACTICAL CONSIDERATIONS

Doses used in animal toxicity studies can be extrapolated to therapeut ic doses in man on the basis of body weight equivalence, metabolism eq uivalence, or toxicokinetics. The validity of extrapolation rules is a matter of debate. However, extrapolation on the basis of toxicokineti cs is often preferred for human medicines, provided that adequate data are available. In registration dossiers on human medicines, often ins ufficient data are available to extrapolate on toxicokinetics only. Th is prompted us to study whether extrapolation on the basis of body wei ght 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 Bo ard in The Netherlands (College ter Beoordeling van Geneesmiddelen) be tween 1990 and 1992. In the majority of cases, larger margins of safet y were achieved by extrapolation on the basis of body weight equivalen ts as compared to toxicokinetic data. Extrapolation on the basis of me tabolism equivalents resembled toxicokinetic extrapolation factors bet ter. The method of extrapolation using metabolism equivalents was rare ly encountered in the registration dossiers on human medicines submitt ed to the Board. (C) 1994 Academic Press, Inc.