ArticleJournal of pharmacokinetics and pharmacodynamics2019
Guiding dose selection of monoclonal antibodies using a new parameter (AFTIR) for characterizing ligand binding systems.
Article in Journal of pharmacokinetics and pharmacodynamics, 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, 13 citations in OpenAlex.
- Phase I/II study of the LAG-3 inhibitor ieramilimab (LAG525) ± anti-PD-1 spartalizumab (PDR001) in patients with advanced malignancies.Journal for immunotherapy of cancer · 2022Trial
- Target-Mediated Drug Disposition (TMDD) Revisited: High Versus Low-Affinity Approximations of the TMDD Model.CPT: pharmacometrics & systems pharmacology · 2025Article
- Utility and impact of quantitative pharmacology on dose selection and clinical development of immuno-oncology therapy.Cancer chemotherapy and pharmacology · 2024Review
- Sabatolimab (MBG453) model-informed drug development for dose selection in patients with myelodysplastic syndrome/acute myeloid leukemia and solid tumors.CPT: pharmacometrics & systems pharmacology · 2023Article
- Mechanistically Weighted Metric to Predict In Vivo Antibody-Receptor Occupancy: An Analytical Approach.The Journal of pharmacology and experimental therapeutics · 2023Article
- Which factors matter the most? Revisiting and dissecting antibody therapeutic doses.Drug discovery today · 2021Review
- Estimating drug potency in the competitive target mediated drug disposition (TMDD) system when the endogenous ligand is included.Journal of pharmacokinetics and pharmacodynamics · 2021Article
- Modeling Pharmacokinetics and Pharmacodynamics of Therapeutic Antibodies: Progress, Challenges, and Future Directions.Pharmaceutics · 2021Review
- Beyond Deterministic Models in Drug Discovery and Development.Trends in pharmacological sciences · 2020Review
- 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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Authors and funding
5 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Guiding the dose selection for monoclonal antibody oncology drugs is often done using methods for predicting the receptor occupancy of the drug in the tumor. In this manuscript, previous work on characterizing target inhibition at steady state using the AFIR metric (Stein and Ramakrishna in CPT Pharmacomet Syst Pharmacol 6(4):258-266, 2017) is extended to include a "target-tissue" compartment and the shedding of membrane-bound targets. A new potency metric average free tissue target to initial target ratio (AFTIR) at steady state is derived, and it depends on only four key quantities: the equilibrium binding constant, the fold-change in target expression at steady state after binding to drug, the biodistribution of target from circulation to target tissue, and the average drug concentration in circulation. The AFTIR metric is useful for guiding dose selection, for efficiently performing sensitivity analyses, and for building intuition for more complex target mediated drug disposition models. In particular, reducing the complex, physiological model to four key parameters needed to predict target inhibition helps to highlight specific parameters that are the most important to estimate in future experiments to guide drug development.
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