General pharmacokinetic model for drugs exhibiting target-mediated drug disposition

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 mo...

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Bibliographic Details
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
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Summary: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.
ISSN:1567-567X
1573-8744
DOI:10.1023/a:1014414520282