Pre-clinical development

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Pre-clinical development is a stage in the development of a new drug that begins before clinical trials (testing in humans) can begin, and during which important safety and pharmacology data is collected.

The main goals of pre-clinical studies are to determine a drug's pharmacodynamics (PD), pharmacokinetics (PK), ADME, and toxicity through animal testing. This data allows researchers to allometrically estimate a safe starting dose of the drug for clinical trials in humans. Pre-clinical studies must adhere to Good Laboratory Practices (GLP) in ICH Guidelines to be acceptable for submission to regulatory agencies such as the Food & Drug Administration in the United States.

Typically, both in vitro and in vivo tests will be performed. Studies of a drug's toxicity include which organs are targeted by that drug, as well as if there are any long-term carcinogenic effects or toxic effects on mammalian reproduction.

The information collected from these studies is vital so that safe human testing can begin. Typically, animal testing involves two species. The most commonly used models are murine and canine, although primate and porcine are also used. The choice of species is based on which will give the best correlation to human trials. Differences in the gut, enzyme activity, circulatory system, or other considerations make certain models more appropriate based on the dosage form, site of activity, or noxious metabolites. For example, canines may not be good models for solid oral dosage forms because the characteristic carnivore intestine is underdeveloped compared to the omnivore's, and gastric emptying rates are increased. Also, rodents can not act as models for antibiotic drugs because the resulting alteration to their intestinal flora causes significant adverse effects.1 Depending on a drugs functional groups, it may be metabolized in similar or different ways between species, which will effect both efficacy and toxicology.

Based on pre-clinical trials, No Observable Effect Levels (NOEL) on are established, which are used to determine initial phase 1 clinical trial dosage levels on a mass API per mass patient basis. Generally a 1/100 uncertainty factor or "safety margin" is included to account for interspecies (1/10) and inter-individual (1/10) differences).2

Animal testing in the research-based pharmaceutical industry has been reduced in recent years both for ethical and cost reasons.

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[edit] Resources

Martinez, M.N. Interspecies Differences in Physiology and Pharmacology: Extrapolating Preclinical Data to Human Populations. Rogge, M.C. Taft, D.R Preclinical Development Vol 152 2005. ISBN 1-57444-882-X
Amdur, M.O. Doull, J.D. Klaassen, C.D. Toxicology: The Basic Science of Poisons. 1991.