ArticleThe AAPS journal2016
Evolution of Antibody-Drug Conjugate Tumor Disposition Model to Predict Preclinical Tumor Pharmacokinetics of Trastuzumab-Emtansine (T-DM1).
Article in The AAPS journal, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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
31 citing papers in PubMed, 45 citations in OpenAlex.
- Applications of Pharmacometrics in Antibody-Drug Conjugate Development.Pharmaceutics · 2026Review
- Article
- Prediction of a CLDN18.2 Targeted Antibody Drug Conjugate Pharmacokinetics in Cancer Patients Using PBPK Modeling and Simulation.CPT: pharmacometrics & systems pharmacology · 2025Article
- Towards a platform quantitative systems pharmacology (QSP) model for preclinical to clinical translation of antibody drug conjugates (ADCs).Journal of pharmacokinetics and pharmacodynamics · 2024Article
- Quantitative evaluation of trastuzumab deruxtecan pharmacokinetics and pharmacodynamics in mouse models of varying degrees of HER2 expression.CPT: pharmacometrics & systems pharmacology · 2024Article
- Clinical validation of translational antibody PBPK model using tissue distribution data generated withJournal of pharmacokinetics and pharmacodynamics · 2023Article
- Pharmacokinetics and Pharmacodynamics of TAK-164 Antibody Drug Conjugate Coadministered with Unconjugated Antibody.The AAPS journal · 2022Article
- Development of and insights from systems pharmacology models of antibody-drug conjugates.CPT: pharmacometrics & systems pharmacology · 2022Review
- Development of a Physiologically-Based Pharmacokinetic Model for Whole-Body Disposition of MMAE Containing Antibody-Drug Conjugate in Mice.Pharmaceutical research · 2022Article
- Development and Evaluation of Competitive Inhibitors of Trastuzumab-HER2 Binding to Bypass the Binding-Site Barrier.Frontiers in pharmacology · 2022Article
- Simulating the Selection of Resistant Cells with Bystander Killing and Antibody Coadministration in Heterogeneous Human Epidermal Growth Factor Receptor 2-Positive Tumors.Drug metabolism and disposition: the biological fate of chemicals · 2022Article
- Predictive Simulations in Preclinical Oncology to Guide the Translation of Biologics.Frontiers in pharmacology · 2022Article
- Quantitative Evaluation of the Effect of Antigen Expression Level on Antibody-Drug Conjugate Exposure in Solid Tumor.The AAPS journal · 2021Article
- Mechanistic Modeling of Intra-Tumor Spatial Distribution of Antibody-Drug Conjugates: Insights into Dosing Strategies in Oncology.Clinical and translational science · 2021Article
- Evolution of the Systems Pharmacokinetics-Pharmacodynamics Model for Antibody-Drug Conjugates to Characterize Tumor Heterogeneity andThe Journal of pharmacology and experimental therapeutics · 2020Article
- The role of autophagy in the cytotoxicity induced by trastuzumab emtansine (T-DM1) in HER2-positive breast cancer cells.AMB Express · 2020Article
- Evaluation of Quantitative Relationship Between Target Expression and Antibody-Drug Conjugate Exposure Inside Cancer Cells.Drug metabolism and disposition: the biological fate of chemicals · 2020Article
- Antibody Coadministration as a Strategy to Overcome Binding-Site Barrier for ADCs: a Quantitative Investigation.The AAPS journal · 2020Article
- Pharmacokinetic and Pharmacodynamic Properties of Drug Delivery Systems.The Journal of pharmacology and experimental therapeutics · 2019Review
- A "Dual" Cell-Level Systems PK-PD Model to Characterize the Bystander Effect of ADC.Journal of pharmaceutical sciences · 2019Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
A mathematical model capable of accurately characterizing intracellular disposition of ADCs is essential for a priori predicting unconjugated drug concentrations inside the tumor. Towards this goal, the objectives of this manuscript were to: (1) evolve previously published cellular disposition model of ADC with more intracellular details to characterize the disposition of T-DM1 in different HER2 expressing cell lines, (2) integrate the improved cellular model with the ADC tumor disposition model to a priori predict DM1 concentrations in a preclinical tumor model, and (3) identify prominent pathways and sensitive parameters associated with intracellular activation of ADCs. The cellular disposition model was augmented by incorporating intracellular ADC degradation and passive diffusion of unconjugated drug across tumor cells. Different biomeasures and chemomeasures for T-DM1, quantified in the companion manuscript, were incorporated into the modified model of ADC to characterize in vitro pharmacokinetics of T-DM1 in three HER2+ cell lines. When the cellular model was integrated with the tumor disposition model, the model was able to a priori predict tumor DM1 concentrations in xenograft mice. Pathway analysis suggested different contribution of antigen-mediated and passive diffusion pathways for intracellular unconjugated drug exposure between in vitro and in vivo systems. Global and local sensitivity analyses revealed that non-specific deconjugation and passive diffusion of the drug across tumor cell membrane are key parameters for drug exposure inside a cell. Finally, a systems pharmacokinetic model for intracellular processing of ADCs has been proposed to highlight our current understanding about the determinants of ADC activation inside a cell.
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Registered trials
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.