Preclinical Testing

Preclinical testing is conducted to determine safety and efficacy in nonhuman animal studies as well as studies to characterize the chemical properties of the drug, its formulation, and the conditions of storage. Preformulation studies covering the physical and chemical characterization of the new drug substance are also conducted.

Preclinical testing involves the following:

• Safety pharmacology. The purpose of the safety pharmacology is to investigate the effects of the test substance on vital functions. In this regard, the cardiovascular, respiratory, and central nervous systems are usually considered the vital organ systems that should be studied in the core battery.
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    Central nervous system. Effects of the test substance on the central nervous system should be assessed. Motor activity, behavioral changes, coordination, sensory/motor reflex responses, and body temperature should be evaluated.
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    Cardiovascular system. Effects of the test substance on the cardiovascular system should be assessed. Blood pressure, heart rate, and the electrocardiogram should be evaluated. In vivo, in vitro, and ex vivo evaluations, including methods for repolarization and conductance abnormalities, should also be considered.
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    Respiratory system. Effects of the test substance on the respiratory system should be assessed, including respiratory rate, and other measures of respiratory function (such as tidal volume or hemoglobin oxygen saturation) should be evaluated.

Effects of the test substance on organ systems not investigated elsewhere should be assessed when there is a reason for concern. For example, dependency potential or skeletal muscle, immune, and endocrine functions can be investigated.

• Toxicology. Toxicology studies in the preclinical stage are conducted to
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    Select or reject lead candidate
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    General indication of suitability
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    Dose selection and guidance to clinician

The basic studies conducted are

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  Mutagenicity: in vitro Ames test
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  One-week or two-week range finders: mouse or rat, dog or primate
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  Maximum tolerated dose
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  Gross effects, clinical chemistries: What are the toxicities?
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  Gross pathology to indicate target organs

• Pharmacokinetics. The primary objective of pharmacokinetics is to quantify drug absorption, distribution, biotransformation, and excretion of the drug. Based on pharmacokinetics,
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    The performance of dosage forms can be evaluated in terms of rate and amount of drug delivered to the blood
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    The dosage regimen of a drug can be adjusted to produce and maintain therapeutically effective blood concentrations with little or no toxicity