Preclinical toxicology

Before clinical trials can begin, preclinical toxicology studies must be undertaken. This is to investigate the safety of the compound, to define its toxicity profile (side-effects), to investigate the reversibility of the toxic effects, and to determine a safe starting dose for the first Phase I trial. These studies are generally undertaken in two species, often one rodent species (mouse or rat) and one non-rodent (dog). The Cancer Research Campaign in the UK are, however, based on extensive experience, pioneering the use of only rodent species for preclinical toxicology of anti-cancer agents.

The exact design of the studies undertaken should be appropriate for the drug in question. The route and schedule of administration should mimic that proposed for the Phase I clinical trial and the drug should be administered using the clinical formulation.

The initial studies should determine the maximum tolerated dose (MTD) of the drug, or if the compound is not very toxic, the maximum administerable dose (MAD). This is used to calculate the starting dose of the clinical trial which is generally one tenth of the MTD (or MAD) in the most sensitive of the two species, when the dose is related to body surface area (i.e. mg/m2).

The toxicity profile of the drug is established by treating groups of animals at two or three doses (MTD and fractions of the MTD) or vehicle alone. Half of the animals in each group are then subject to haematology, clinical chemistry, and histopathology studies within 1-2 days of dosing. The other half are tested similarly after a 28-day recovery period to assess the reversibility of any toxicities seen. If there is any indication from its properties or its analogues that a particular drug may potentially have a particular toxicity (e.g. nephrotoxicity), specific tests should be undertaken during the toxicology studies to investigate this. Data from the toxicology studies should be used to design the Phase I trial.

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