Dose selection for toxicity studies: a protocol for determining the maximum repeatable dose.

Abstract

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.