New approaches to the use of pharmacokinetics in toxicology and drug development.
1. The use of pharmacokinetics in toxicology, clinical pharmacology and in the individualization of dosage has been critically examined. 2. In toxicity studies, doses are given to animals with the aim of achieving substantially higher plasma levels than the therapeutic level in man. However, small animals have faster metabolic rates, shorter life spans and drug clearance is many fold faster than in man, and this difference may not be compensated for by simply mg per kg dosing. Since toxicity still occurs at these lower levels, it begs the question whether small animals require such high doses to produce toxic effects. 3. A literature survey revealed that only 5 to 31% of the papers studied attempt to relate activity with plasma levels. Examples are given of how such relationships can be used, as with D-fenfluramine, where by investigating individual responses using drug plasma levels as a probe, a greater understanding of eating disorders may be obtained. Also, with tertatolol its prolonged pharmacological activity (greater than 24 h) can be explained mathematically despite a plasma half-life of only 3 h. 4. The advantages and disadvantages of population kinetics are discussed in relation to its use in individualizing dosage, particularly in disease, its appreciation by pharmaceutical companies and regulatory authorities and the information which has been obtained so far. 5. It is of interest that one of the youngest of drug development disciplines, pharmacokinetics, is now one of the most important.
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Servier Research and Development Ltd., Fulmer, Slough, UK.
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D000818:Animals; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007700:Kinetics; D008657:Metabolic Clearance Rate; D010599:Pharmacokinetics; D014116:Toxicology