ArticleThe AAPS journal2017
Development of a Translational Physiologically Based Pharmacokinetic Model for Antibody-Drug Conjugates: a Case Study with T-DM1.
Article in The AAPS journal, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 34 citations in OpenAlex.
- Applications of Pharmacometrics in Antibody-Drug Conjugate Development.Pharmaceutics · 2026Review
- Review
- Multi-scale computational modeling towards efficacy in radiopharmaceutical therapies while minimizing side effects: Modeling of amino acid infusion.PLoS computational biology · 2025Article
- A translational physiologically-based pharmacokinetic model for MMAE-based antibody-drug conjugates.Journal of pharmacokinetics and pharmacodynamics · 2025Article
- Clinical validation of translational antibody PBPK model using tissue distribution data generated withJournal of pharmacokinetics and pharmacodynamics · 2023Article
- Article
- A physiologically based pharmacokinetic model for V937 oncolytic virus in mice.Frontiers in pharmacology · 2023Article
- Towards a translational physiologically-based pharmacokinetic (PBPK) model for receptor-mediated transcytosis of anti-transferrin receptor monoclonal antibodies in the central nervous system.Journal of pharmacokinetics and pharmacodynamics · 2022Article
- Mathematical Models to Characterize the Absorption, Distribution, Metabolism, and Excretion of Protein Therapeutics.Drug metabolism and disposition: the biological fate of chemicals · 2022Review
- Development of a Physiologically-Based Pharmacokinetic Model for Whole-Body Disposition of MMAE Containing Antibody-Drug Conjugate in Mice.Pharmaceutical research · 2022Article
- Clinical Pharmacology of Antibody-Drug Conjugates.Antibodies (Basel, Switzerland) · 2021Review
- Whole-Body Pharmacokinetics and Physiologically Based Pharmacokinetic Model for Monomethyl Auristatin E (MMAE).Journal of clinical medicine · 2021Article
- Mechanistic Modeling of Intra-Tumor Spatial Distribution of Antibody-Drug Conjugates: Insights into Dosing Strategies in Oncology.Clinical and translational science · 2021Article
- Impact of Physiologically Based Pharmacokinetics, Population Pharmacokinetics and Pharmacokinetics/Pharmacodynamics in the Development of Antibody-Drug Conjugates.Journal of clinical pharmacology · 2020Review
- Bivalent engagement of endothelial surface antigens is critical to prolonged surface targeting and protein delivery in vivo.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
- Capturing the Magic Bullet: Pharmacokinetic Principles and Modeling of Antibody-Drug Conjugates.The AAPS journal · 2020Review
- Drug Exposure to Establish Pharmacokinetic-Response Relationships in Oncology.Clinical pharmacokinetics · 2020Review
- A translational platform PBPK model for antibody disposition in the brain.Journal of pharmacokinetics and pharmacodynamics · 2019Article
- Physiologically-based modeling of monoclonal antibody pharmacokinetics in drug discovery and development.Drug metabolism and pharmacokinetics · 2019Review
- Pharmacokinetic Considerations for Antibody-Drug Conjugates against Cancer.Pharmaceutical research · 2017Review
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
Abstract
Systems pharmacokinetic (PK) models that can characterize and predict whole body disposition of antibody-drug conjugates (ADCs) are needed to support (i) development of reliable exposure-response relationships for ADCs and (ii) selection of ADC targets with optimal tumor and tissue expression profiles. Towards this goal, we have developed a translational physiologically based PK (PBPK) model for ADCs, using T-DM1 as a tool compound. The preclinical PBPK model was developed using rat data. Biodistribution of DM1 in rats was used to develop the small molecule PBPK model, and the PK of conjugated trastuzumab (i.e., T-DM1) in rats was characterized using platform PBPK model for antibody. Both the PBPK models were combined via degradation and deconjugation processes. The degradation of conjugated antibody was assumed to be similar to a normal antibody, and the deconjugation of DM1 from T-DM1 in rats was estimated using plasma PK data. The rat PBPK model was translated to humans to predict clinical PK of T-DM1. The translation involved the use of human antibody PBPK model to characterize the PK of conjugated trastuzumab, use of allometric scaling to predict human clearance of DM1 catabolites, and use of monkey PK data to predict deconjugation of DM1 in the clinic. PBPK model-predicted clinical PK profiles were compared with clinically observed data. The PK of total trastuzumab and T-DM1 were predicted reasonably well, and slight systemic deviations were observed for the PK of DM1-containing catabolites. The ADC PBPK model presented here can serve as a platform to develop models for other ADCs.
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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.