ArticlePharmaceutical research2015
Mechanism-Based Pharmacokinetic/Pharmacodynamic Model for THIOMAB™ Drug Conjugates.
Article in Pharmaceutical research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 41 citations in OpenAlex.
- A review of conjugation technologies for antibody drug conjugates.Antibody therapeutics · 2025Review
- Pharmacokinetics and Pharmacodynamics of TAK-164 Antibody Drug Conjugate Coadministered with Unconjugated Antibody.The AAPS journal · 2022Article
- Recent Advances in Translational Pharmacokinetics and Pharmacodynamics Prediction of Therapeutic Antibodies Using Modeling and Simulation.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Development of a Physiologically-Based Pharmacokinetic Model for Whole-Body Disposition of MMAE Containing Antibody-Drug Conjugate in Mice.Pharmaceutical research · 2022Article
- Key metrics to expanding the pipeline of successful antibody-drug conjugates.Trends in pharmacological sciences · 2021Review
- Antibody Co-Administration Can Improve Systemic and Local Distribution of Antibody-Drug Conjugates to IncreaseMolecular cancer therapeutics · 2021Article
- Capturing the Magic Bullet: Pharmacokinetic Principles and Modeling of Antibody-Drug Conjugates.The AAPS journal · 2020Review
- Multiple Dose Pharmacokinetic Models Predict Bioavailability of Toxins in Vertebrate Herbivores.Journal of chemical ecology · 2020Article
- An Agent-Based Systems Pharmacology Model of the Antibody-Drug Conjugate Kadcyla to Predict Efficacy of Different Dosing Regimens.The AAPS journal · 2020Article
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- QSP Toolbox: Computational Implementation of Integrated Workflow Components for Deploying Multi-Scale Mechanistic Models.The AAPS journal · 2017Article
- Development and Translational Application of an Integrated, Mechanistic Model of Antibody-Drug Conjugate Pharmacokinetics.The AAPS journal · 2017Article
- Integrated Two-Analyte Population Pharmacokinetic Model for Antibody-Drug Conjugates in Patients: Implications for Reducing Pharmacokinetic Sampling.CPT: pharmacometrics & systems pharmacology · 2016Article
- Multiscale Modeling of Antibody-Drug Conjugates: Connecting Tissue and Cellular Distribution to Whole Animal Pharmacokinetics and Potential Implications for Efficacy.The AAPS journal · 2016Article
- Evolution of Antibody-Drug Conjugate Tumor Disposition Model to Predict Preclinical Tumor Pharmacokinetics of Trastuzumab-Emtansine (T-DM1).The AAPS journal · 2016Article
- Determination of Cellular Processing Rates for a Trastuzumab-Maytansinoid Antibody-Drug Conjugate (ADC) Highlights Key Parameters for ADC Design.The AAPS journal · 2016Article
- Current Status: Site-Specific Antibody Drug Conjugates.Journal of clinical immunology · 2016Review
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Corrections and comments
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Authors and funding
14 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeTHIOMAB™ drug conjugates (TDCs) with engineered cysteine residues allow site-specific drug conjugation and defined Drug-to-Antibody Ratios (DAR). In order to help elucidate the impact of drug-loading, conjugation site, and subsequent deconjugation on pharmacokinetics and efficacy, we have developed an integrated mathematical model to mechanistically characterize pharmacokinetic behavior and preclinical efficacy of MMAE conjugated TDCs with different DARs. General applicability of the model structure was evaluated with two different TDCs.
methodPharmacokinetics studies were conducted for unconjugated antibody and purified TDCs with DAR-1, 2 and 4 for trastuzumab TDC and Anti-STEAP1 TDC in mice. Total antibody concentrations and individual DAR fractions were measured. Efficacy studies were performed in tumor-bearing mice.
resultsAn integrated model consisting of distinct DAR species (DAR0-4), each described by a two-compartment model was able to capture the experimental data well. Time series measurements of each Individual DAR species allowed for the incorporation of site-specific drug loss through deconjugation and the results suggest a higher deconjugation rate from heavy chain site HC-A114C than the light chain site LC-V205C. Total antibody concentrations showed multi-exponential decline, with a higher clearance associated with higher DAR species. The experimentally observed effects of TDC on tumor growth kinetics were successfully described by linking pharmacokinetic profiles to DAR-dependent killing of tumor cells.
conclusionResults from the integrated model evaluated with two different TDCs highlight the impact of DAR and site of conjugation on pharmacokinetics and efficacy. The model can be used to guide future drug optimization and in-vivo studies.
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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.