Nonclinical Considerations: Disposition of Drugs

Abstract

In the design and conduct of pharmacokinetic and toxicokinetic studies, several features should be considered to maximize the utility of the resultant data. Recommendations will be offered regarding the conduct of studies relating the advantages of using the same species, route of administration, and frequency of administration, where possible, as that proposed for pharmacologic and toxicologic testing. The period of dosing should be representative of the proposed clinical duration. Possible “endpoints” to be considered include area under the curve, maximum plasma concentration, volume of distribution, time to maximum plasma concentration, clearance, and half-life of elimination. As suitable, the absolute fraction absorbed should be determined following the administration of the drug at various doses. If a drug will be used under steady state or special physiological conditions, additional pharmacokinetic and toxicokinetic studies if conducted under similar conditions offer useful information. It is also important to evaluate the potential to form metabolites and their contribution to the overall activity profile. Pharmacokinetic and toxicokinetic data has “utility” because it provides a rational and scientific basis crucial to understanding the biological effects of a drug, in identifying and designing appropriate nonclinical studies, and in validating extrapolations between animal studies and humans. Pharmacokinetic and toxicokinetic studies play an integral role in assessing safety and effectiveness.