ArticleJournal of pharmacokinetics and pharmacodynamics2009
Nonlinear pharmacokinetics of therapeutic proteins resulting from receptor mediated endocytosis.
Article in Journal of pharmacokinetics and pharmacodynamics, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers, 2 of them syntheses that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
36 citing papers in PubMed, 2 syntheses or guidelines pooled it, 55 citations in OpenAlex.
- Population Pharmacokinetic/Pharmacodynamic Modeling of Therapeutic Enzymes in Lysosomal Storage Diseases.Clinical pharmacokinetics · 2026Pooled it
- Population pharmacokinetic meta-analysis of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis.Clinical pharmacokinetics · 2011Pooled it
- Exposure-Response Analysis of Necitumumab Efficacy in Squamous Non-Small Cell Lung Cancer Patients.CPT: pharmacometrics & systems pharmacology · 2017Trial
- Relationship between absolute neutrophil count profiles and pharmacokinetics of DA-3031, a pegylated granulocyte colony-stimulating factor (pegylated-G-CSF): a dose block-randomized, double-blind, dose-escalation study in healthy subjects.Clinical drug investigation · 2013Trial
- Phase I First-in-Human Study of TRK-950, an IgG1 Antibody Specific to CAPRIN-1, in Patients with Advanced Solid Tumors.Cancer research communications · 2025Article
- Population pharmacokinetic model of ABL001/CTX-009 (anti-VEGF/DLL4) in adult cancer patients with solid tumor.Cancer science · 2024Article
- Integrated PK/PD Modeling Relates Smoothened Inhibitor Biomarkers to The Heterogeneous Intratumor Disposition of Cetuximab in Pancreatic Cancer Tumor Models.Journal of pharmaceutical sciences · 2024Article
- The quest for balance between capturing data and model complexity: A quantitative clinical pharmacology approach applied to monoclonal antibodies.CPT: pharmacometrics & systems pharmacology · 2023Article
- Preclinical InVivo Data Integrated in a Modeling Network Informs a Refined Clinical Strategy for a CD3 T-Cell Bispecific in Combination with Anti-PD-L1.The AAPS journal · 2022Article
- Estimating drug potency in the competitive target mediated drug disposition (TMDD) system when the endogenous ligand is included.Journal of pharmacokinetics and pharmacodynamics · 2021Article
- Bioaccessibility andInternational journal of molecular sciences · 2021Article
- Understanding Inter-Individual Variability in Monoclonal Antibody Disposition.Antibodies (Basel, Switzerland) · 2019Review
- A systems pharmacokinetic/pharmacodynamic model for concizumab to explore the potential of anti-TFPI recycling antibodies.European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences · 2019Article
- Guiding dose selection of monoclonal antibodies using a new parameter (AFTIR) for characterizing ligand binding systems.Journal of pharmacokinetics and pharmacodynamics · 2019Article
- New Equilibrium Models of Drug-Receptor Interactions Derived from Target-Mediated Drug Disposition.The AAPS journal · 2018Article
- Mathematical description of drug-target interactions: application to biologics that bind to targets with two binding sites.Journal of pharmacokinetics and pharmacodynamics · 2018Article
- Impact of mathematical pharmacology on practice and theory: four case studies.Journal of pharmacokinetics and pharmacodynamics · 2018Article
- Impact of altered endogenous IgG on unspecific mAb clearance.Journal of pharmacokinetics and pharmacodynamics · 2017Article
- Target-mediated drug disposition with drug-drug interaction, Part I: single drug case in alternative formulations.Journal of pharmacokinetics and pharmacodynamics · 2017Article
- Diffusion and Uptake of Tobacco Mosaic Virus as Therapeutic Carrier in Tumor Tissue: Effect of Nanoparticle Aspect Ratio.The journal of physical chemistry. B · 2016Article
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Receptor mediated endocytosis (RME) plays a major role in the disposition of therapeutic protein drugs in the body. It is suspected to be a major source of nonlinear pharmacokinetic behavior observed in clinical pharmacokinetic data. So far, mostly empirical or semi-mechanistic approaches have been used to represent RME. A thorough understanding of the impact of the properties of the drug and of the receptor system on the resulting nonlinear disposition is still missing, as is how to best represent RME in pharmacokinetic models. In this article, we present a detailed mechanistic model of RME that explicitly takes into account receptor binding and trafficking inside the cell and that is used to derive reduced models of RME which retain a mechanistic interpretation. We find that RME can be described by an extended Michaelis-Menten model that accounts for both the distribution and the elimination aspect of RME. If the amount of drug in the receptor system is negligible a standard Michaelis-Menten model is capable of describing the elimination by RME. Notably, a receptor system can efficiently eliminate drug from the extracellular space even if the total number of receptors is small. We find that drug elimination by RME can result in substantial nonlinear pharmacokinetics. The extent of nonlinearity is higher for drug/receptor systems with higher receptor availability at the membrane, or faster internalization and degradation of extracellular drug. Our approach is exemplified for the epidermal growth factor receptor system.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.