General pharmacokinetic model for drugs exhibiting target-mediated drug disposition

• Published in: Journal of pharmacokinetics and pharmacodynamics 2001-12, Vol.28 (6), p.507-532
• Main Authors: MAGER, Donald E, JUSKO, William J
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Dose-Response Relationship, Drug; Drug Delivery Systems - methods; Drug Delivery Systems - statistics & numerical data; Drug Evaluation, Preclinical - methods; Drug Evaluation, Preclinical - statistics & numerical data; Drug therapy; Fluorenes - blood; Fluorenes - pharmacokinetics; General pharmacology; Humans; Hydantoins - blood; Hydantoins - pharmacokinetics; Interferon-beta - blood; Interferon-beta - pharmacokinetics; Male; Medical sciences; Models, Chemical; Nonlinear Dynamics; Pharmacokinetics; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Sulfonamides - blood; Sulfonamides - pharmacokinetics
• ISSN: 1567-567X; 1573-8744
• DOI: 10.1023/a:1014414520282

Drugs that bind with high affinity and to a significant extent (relative to dose) to a pharmacologic target such as an enzyme, receptor, or transporter may exhibit nonlinear pharmacokinetic (PK) behavior. Processes such as receptor-mediated endocytosis may result in drug elimination. A general PK model for characterizing such behavior is described and explored through computer simulations and applications to several therapeutic agents. Simulations show that model predicted plasma concentration vs. time profiles are expected to be polyexponential with steeper distribution phases for lower doses and similar terminal disposition phases. Noncompartmental parameters always show apparent Vss and CL(D) decreasing with dose, but apparent clearance decreases only when the binding process produces drug elimination. The proposed model well captured the time-course of drug concentrations for the aldose reductase inhibitor imirestat, the endothelin receptor antagonist bosentan, and recombinant human interferon-beta 1a. This type of model has a mechanistic basis and considerable utility for fully describing the kinetics for various doses of relevant drugs.