Translational Pharmacokinetic/Pharmacodynamic Modeling of Tumor Growth Inhibition Supports Dose-Range Selection of the Anti-PD-1 Antibody Pembrolizumab
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Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), has a manageable safety profile and robust clinical activity against advanced malignancies. The lowest effective dose for evaluation in further dose-ranging studies was identified by developing a translational model from preclinical mouse experiments. A compartmental pharmacokinetic model was combined with a published physiologically based tissue compartment, linked to receptor occupancy as the driver of observed tumor growth inhibition. Human simulations were performed using clinical pharmacokinetic data, literature values, and in vitro parameters for drug distribution and binding. Biological and mathematical uncertainties were included in simulations to generate expectations for dose response. The results demonstrated a minimal increase in efficacy for doses higher than 2 mg/kg. The findings of the translational model were successfully applied to select 2 mg/kg as the lowest dose for dose-ranging evaluations.
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Lindauer et al. utilized physiologically based PK and systems pharmacology approaches combining in vitro binding data, mechanistic tumor growth inhibition models, and drug exposure-time-to-event relationships to successfully identify the lowest effective dose for pembrolizumab.
“Lindauer et al. utilized physiologically based PK and systems pharmacology approaches combining in vitro binding data, mechanistic tumor growth inhibition models, and drug exposure‐time‐to‐event relationships to successfully identify the lowest effective dose for evaluation.82”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [82]
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- Authors
- Lindauer, A., Valiathan, C., Mehta, K., Sriram, V, de Greef, R., Elassaiss-Schaap, J., & de Alwis, D.
- Affiliations
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Merck & Co., Inc.; Rahway New Jersey USA
- Venue
- CPT: Pharmacometrics & Systems Pharmacology
- Publisher
- Wiley
- Published
- 2016-11-08
- Volume
- 6
- Issue
- 1
- Pages
- 11-20
- ISSN
- 2163-8306 (ISSN-L)
- PMC
- PMC5270293
- OpenAlex
- W2554268745
- Cited by
- 120
- References
- 26
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 18 · 2023: 5 · 2022: 20 · 2021: 11 · 2020: 14 · 2019: 16 · 2018: 11 · 2017: 7 · 2016: 3 · 2014: 1
- FWCI
- 6.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- CPT Pharmacometrics & Systems Pharmacology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Gilead Sciences
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Keywords
- pembrolizumab, PD-1 inhibitors, tumor growth inhibition, dose-ranging, receptor occupancy, compartmental pharmacokinetic model, monoclonal antibodies, cancer immunotherapy, dose-response relationship
- MeSH terms
- Animals, Antibodies, Monoclonal, Dose-Response Relationship, Drug, Humans, Mice, Inbred C57BL, Models, Biological, Tumor Burden, Mice, Rats, Translational Research, Biomedical, Programmed Cell Death 1 Receptor, Antibodies, Monoclonal, Humanized
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