DOSE SELECTION FOR TOXICITY STUDIES - A PROTOCOL FOR DETERMINING THE MAXIMUM REPEATABLE DOSE

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.