1 A three-stage protocol is described for a dose-ranging study which defines the maximum repeatable dose (MRD) and provides a preview of the toxicology of new, pharmacologically active, substances before commencing the first formal regulatory toxicity studies, usually of 2 or 4 weeks duration.
2 Additionally, a range of toxicokinetic (TK) data relevant to protocol design for formal studies is generated.
3 Stage A is a dose incrementation process in which the MRD is provisionally determined and basic TK values generated.
4 In stage B the animals are dosed daily for at least 7 d, the MRD is substantiated and a wider range of TK data obtained.
5 In stage C, each of the dose levels identified for a formal study is administered once to investigate the relationship of doses to TK data.
6 This protocol can be completed using as few as 24 rats or six dogs (or primates).
7 Selection of dose levels for the first formal studies can be greatly aided by the results of a well-designed dose-ranging study including TK data.
8 For particularly toxic substances, the findings of studies based on this protocol have frequently been sufficiently clear to warrant early termination of their development.
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