General Pharmacokinetic Model for Drugs Exhibiting Target-Mediated Drug Disposition
Abstract
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.
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Target-mediated drug disposition introduces a saturable, dose- and concentration-dependent component of clearance that no power-law regression can capture.
“More importantly, target-mediated drug disposition (TMDD) introduces a saturable, dose- and concentration-dependent component of clearance that no power-law regression can capture.”
From Beyond Body Weight: A Comprehensive Review of Allometric Scaling in Drug Development for Human Dose Predictions (2026) · cites this paper as [50]
At low concentrations, target-mediated clearance can dominate; at high concentrations, the target is saturated and linear, FcRn-mediated elimination dominates.
“At low concentrations, target-mediated clearance can dominate; at high concentrations, the target is saturated and linear, FcRn-mediated elimination dominates [47,50].”
From Beyond Body Weight: A Comprehensive Review of Allometric Scaling in Drug Development for Human Dose Predictions (2026) · cites this paper as [50]
In biologics first-in-human modelling, not all disposition parameters can be identified simultaneously; FcRn-mediated linear clearance and central volume generally scale reliably from non-human primate data and can be estimated with reasonable confidence, whereas TMDD parameters such as target baseline concentration, target turnover, and binding constants are often poorly identifiable from precl
“A practical constraint in biologics first-in-human modelling is that not all of these disposition parameters can be identified simultaneously. FcRn-mediated linear clearance and central volume of distribution generally scale reliably from non-human primate data and can be estimated with reasonable confidence, whereas TMDD parameters such as target baseline concentration, target turnover, and”
From Beyond Body Weight: A Comprehensive Review of Allometric Scaling in Drug Development for Human Dose Predictions (2026) · cites this paper as [50]
For biologics, not all parameters are simultaneously identifiable: FcRn-mediated linear clearance and central volume can be carried from non-human primate data, whereas poorly identifiable TMDD parameters are fixed to in vitro or literature values rather than estimated.
“For biologics in particular, this also recognizes that not all parameters are simultaneously identifiable: FcRn-mediated linear clearance and central volume can be carried from non-human primate data, whereas poorly identifiable TMDD parameters are fixed to in vitro or literature values rather than estimated [50,51] (Section 4.5).”
From Beyond Body Weight: A Comprehensive Review of Allometric Scaling in Drug Development for Human Dose Predictions (2026) · cites this paper as [50]
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References 40 · Cited by 605
- Authors
- Mager, D. E., & Jusko, W. J.
- Affiliations
- University at Buffalo, State University of New York (US)
- Venue
- Journal of Pharmacokinetics and Pharmacodynamics
- Published
- 2001-12
- Volume
- 28
- Issue
- 6
- Pages
- 507-532
- ISSN
- 1567-567X (ISSN-L)
- 1573-8744
- OpenAlex
- W28215347
- Cited by
- 605
- References
- 40
- Citations by year
- 2026: 40 · 2025: 27 · 2024: 30 · 2023: 32 · 2022: 31 · 2021: 31 · 2020: 40 · 2019: 37 · 2018: 28 · 2017: 31 · 2016: 32 · 2015: 41 · 2014: 31 · 2013: 36 · 2012: 32
- FWCI
- 2.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Journal of Pharmacokinetics and Pharmacodynamics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM 57980, R01GM057980)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Keywords
- target-mediated drug disposition, nonlinear pharmacokinetics, receptor-mediated endocytosis, pharmacokinetic modeling, dose-dependent clearance, drug elimination, bosentan, interferon beta-1a, enzyme inhibitors, receptor antagonists
- MeSH terms
- Bosentan, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Fluorenes, Humans, Hydantoins, Male, Models, Chemical, Pharmacokinetics, Sulfonamides, Drug Delivery Systems, Interferon-beta, Nonlinear Dynamics
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