Dose-dependent pharmacokinetics: experimental observations and theoretical considerations.
Clinically, absorption and elimination of most drugs follow linear kinetics, and pharmacokinetic parameters describing absorption and elimination of a drug do not change over the therapeutic dose range. However, dose-dependent pharmacokinetics have been reported more frequently in preclinical studies, particularly in toxicity studies, where high doses are often employed. This review highlights the major types of dose-dependent pharmacokinetics with unique examples. Before setting out on a pivotal subchronic and chronic toxicity study of a new drug, a pilot study is often performed to establish a dose range in which a reasonable relationship between plasma AUC and dosage exists to ensure sufficient exposure of animals to the drug. Theoretical bases and possible causes of dose-AUC disproportionality are discussed. Factors affecting the distribution and elimination of drugs and causes of dose-dependent tissue distribution and elimination are also discussed. Often, the non-linear kinetics complicate the design of dosage regimens and prediction of efficacy and toxicity. Thus, an understanding of the influence of dose on the pharmacokinetics is important in the evaluation of the efficacy and toxicity of new drugs.
Lin
J H
JH
Merck Research Laboratories, West Point, PA 19486.
D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008099:Liver / Q000187:drug effects; D010599:Pharmacokinetics; D011485:Protein Binding; D014018:Tissue Distribution
D001798:Blood Proteins