ArticlePharmaceutics2019
A Cell-Level Systems PK-PD Model to Characterize In Vivo Efficacy of ADCs.
Article in Pharmaceutics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 18 citations in OpenAlex.
- Antibody-drug conjugates for infectious and neglected tropical diseases: chemical design principles, target biology, and translational challenges.Frontiers in chemistry · 2026Review
- Review
- Suborgan Level Quantitation of Proteins in Tissues Delivered by Polymeric Nanocarriers.ACS nano · 2024Article
- Development and validation of bioanalytical methods to support clinical study of disitamab vedotin.Bioanalysis · 2024Article
- Translation of the efficacy of antibody-drug conjugates from preclinical to clinical using a semimechanistic PK/PD model: A case study with RC88.Clinical and translational science · 2023Article
- Mathematical modeling of regulatory networks of intracellular processes - Aims and selected methods.Computational and structural biotechnology journal · 2023Review
- Development of and insights from systems pharmacology models of antibody-drug conjugates.CPT: pharmacometrics & systems pharmacology · 2022Review
- Analytical Methods for the Detection and Quantification of ADCs in Biological Matrices.Pharmaceuticals (Basel, Switzerland) · 2020Review
- Evolution of the Systems Pharmacokinetics-Pharmacodynamics Model for Antibody-Drug Conjugates to Characterize Tumor Heterogeneity andThe Journal of pharmacology and experimental therapeutics · 2020Article
- Multi-scale modeling of drug binding kinetics to predict drug efficacy.Cellular and molecular life sciences : CMLS · 2020Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Here, we have presented the development of a systems pharmacokinetics-pharmacodynamics (PK-PD) model for antibody-drug conjugates (ADCs), which uses intracellular target occupancy to drive in-vivo efficacy. The model is built based on PK and efficacy data generated using Trastuzumab-Valine-Citrulline-Monomethyl Auristatin E (T-vc-MMAE) ADC in N87 (high-HER2) and GFP-MCF7 (low-HER2) tumor bearing mice. It was observed that plasma PK of all ADC analytes was similar between the two tumor models; however, total trastuzumab, unconjugated MMAE, and total MMAE exposures were >10-fold, ~1.6-fold, and ~1.8-fold higher in N87 tumors. In addition, a prolonged retention of MMAE was observed within the tumors of both the mouse models, suggesting intracellular binding of MMAE to tubulin. A systems PK model, developed by integrating single-cell PK model with tumor distribution model, was able to capture all in vivo PK data reasonably well. Intracellular occupancy of tubulin predicted by the PK model was used to drive the efficacy of ADC using a novel PK-PD model. It was found that the same set of PD parameters was able to capture MMAE induced killing of GFP-MCF7 and N87 cells in vivo. These observations highlight the benefit of adopting a systems approach for ADC and provide a robust and predictive framework for successful clinical translation of 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.