Dose‐dependent pharmacokinetics: Experimental observations and theoretical considerations

Abstract

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.

Elucidation of the Pharmacokinetic/Pharmacodynamic Determinant of Colistin Activity against Pseudomonas aeruginosa in Murine Thigh and Lung Infection Models

“…Both the apparent volume of distribution and the apparent clearance (both of which were referenced to the unbound plasma concentrations) decreased as the dose increased in the single-dose PK study (Table 1). Colistin has been reported to bind extensively to a range of tissues (6), and the trend observed for the unbound apparent volume of distribution (Table 1) is consistent with an increase in the unbound fraction in tissues possibly resulting from the saturation of tissue binding sites at the higher doses (21). The clearance of colistin is almost exclusively by as yet uncharacterized nonrenal elimination pathways (18); the decrease in unbound clearance with increasing dose (Table 1) is consistent with the saturation of intrinsic clearance pathways (32).…”

Preclinical pharmacokinetics of MK-0974, an orally active calcitonin-gene related peptide (CGRP)-receptor antagonist, mechanism of dose dependency and species differences

“…Plasma protein binding restricts drug clearance in the liver but possibly it has little effect on the intestinal metabolism following oral absorption. Another factor for the increased role of intestinal metabolism in determining oral bioavailability is that all of the absorbed dose passes through the enterocytes (assuming low paracellular passage) where metabolism can occur (Lin 1994).…”

Species Difference in the Mechanism of Nonlinear Pharmacokinetics of E2074, a Novel Sodium Channel Inhibitor, in Rats, Dogs, and Monkeys

“…Nonlinearity is caused by several different mechanisms (Ludden, 1991;Lin, 1994). Less than dose-proportional increases in exposure with oral doses could be caused by decreased drug absorption.…”

“…A greater than dose-proportional increase in exposure is most likely due to decreased clearance. Phenytoin, salicylate, and theophylline are the classic examples of drugs that exhibit decreased clearance due to saturated hepatic metabolism (Ludden, 1991;Lin, 1994).…”