Gwm. Petersvolleberg et al., INTERSPECIES EXTRAPOLATION IN SAFETY EVALUATION OF HUMAN MEDICINES INTHE NETHERLANDS (1990-1992) - PRACTICAL CONSIDERATIONS, Regulatory toxicology and pharmacology, 20(3), 1994, pp. 248-258
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.