Preclinical drug development

Following selection of a potential clinical candidate, a number of pre-clinical development activities must be carried out.

Formulation Choice of formulation is influenced by solubility, stability, and dosage requirements (e.g. acute or intermittent oral administration versus chronic oral dosing). Approaches involve the use of various mixed solvent systems as well as more novel delivery methods such as liposomes.

Preclinical pharmacology More detailed pharmacokinetic/ADME studies will be carried out. These will define drug distribution in the body (usually rodents) and the rate and means of drug elimination, including identification of major metabolites.

Preclinical toxicology Usually the final step before Phase I trial in man, the objectives of preclinical toxicology are to define:

♦ Qualitative and quantitative organ toxicities

♦ The reversibility of the effects

♦ The initial safe starting dose

Conditions for the preclinical toxicology should reflect as closely as possible the formulation, schedule, route of administration, and dose/concentration features that will apply in patients. Precise requirements vary between countries and regulatory authorities, but in general there is a two-step approach to define the acute maximum tolerated dose or LD10 (dose giving 10% lethality) in a rodent species usually the mouse and either the rat or dog, followed by a more extensive phase. Organ-specific toxicities are often poorly predicted between species and the main objective is to define a safe starting dose in man.

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