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Pharmaceutics
Volume 17
Issue 5
10.3390/pharmaceutics17050560
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Article

Physiologically Based Pharmacokinetic Modeling of Biologic Case Studies in Monkeys and Humans Reveals the Necessity of an Additional Clearance Term

by
Felix Stader
1,*,
Pradeep Sharma
2,
Weize Huang
3,
Mary P. Choules
4,
Marie-Emilie Willemin
5,
Xinwen Zhang
6,
Estelle Yau
7,
Abdallah Derbalah
1,
Adriana Zyla
1,
Cong Liu
1 and
Armin Sepp
1
1
Certara Predictive Technologies, Certara UK Ltd., Sheffield S1 2BJ, UK
2
Clinical Pharmacology and Quantitative Pharmacology, Biopharmaceuticals R&D, AstraZeneca, Cambridge CB1 9JS, UK
3
Genentech Inc., South San Francisco, CA 94404, USA
4
Astellas Pharma Global Inc., Northbrook, IL 60062, USA
5
Johnson & Johnson, 2340 Beerse, Belgium
6
Amgen Inc., South San Francisco, CA 94080, USA
7
Sanofi R&D, 94403 Vitry-sur-Seine, France
*
Author to whom correspondence should be addressed.
Pharmaceutics 2025, 17(5), 560; https://doi.org/10.3390/pharmaceutics17050560
Submission received: 9 March 2025 / Revised: 11 April 2025 / Accepted: 22 April 2025 / Published: 24 April 2025
(This article belongs to the Special Issue Advancing Biologic Drug Development Through Physiologically Based Pharmacokinetic Modelling and Simulations)
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Abstract

Background/Objectives: Physiologically based pharmacokinetic (PBPK) modeling is an important tool in biologic drug development. However, a standardized modeling strategy is currently missing. A cross-industry collaboration developed PBPK models for seven case studies, including monoclonal antibodies, antibody–drug conjugates, and bispecific T-cell engagers, to identify key parameters and establish a workflow to simulate biologic drugs in monkeys and in humans. Methods: PBPK models were developed in the monkey with limited data, including the molecular weight, the binding affinity to FcRn, and the additional systemic clearance of IgG, which is 20% of the total clearance. The binding affinity was only available for human FcRn and corrected for the known species-dependent differences in IgG binding. The strategy of monkey simulations was evaluated with an additional 14 studies published in the literature. Three different scenarios were simulated in humans afterwards: without, with allometrically scaled, and with optimized additional systemic clearance. Results: The plasma peak concentration and the area under the curve were predicted within 50% of the observed data for all studied case examples in the monkey, which demonstrates that sparse input parameters are sufficient for successful predictions in the monkey. Simulations in humans demonstrated the need for additional systemic clearance, because drug exposure was highly overpredicted without an additional systemic clearance term. Allometric scaling improved the predictions, but optimization led to the best fit, which is currently a limitation in the translation from animals to humans. Conclusions: This work highlights the importance of understanding the general mechanisms of drug uptake in different tissue types and cells in both target-dependent and -independent processes.
Keywords: physiologically based pharmacokinetic model; monoclonal antibody; antibody–drug conjugate; bispecific antibody; translational study physiologically based pharmacokinetic model; monoclonal antibody; antibody–drug conjugate; bispecific antibody; translational study

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MDPI and ACS Style

Stader, F.; Sharma, P.; Huang, W.; Choules, M.P.; Willemin, M.-E.; Zhang, X.; Yau, E.; Derbalah, A.; Zyla, A.; Liu, C.; et al. Physiologically Based Pharmacokinetic Modeling of Biologic Case Studies in Monkeys and Humans Reveals the Necessity of an Additional Clearance Term. Pharmaceutics 2025, 17, 560. https://doi.org/10.3390/pharmaceutics17050560

AMA Style

Stader F, Sharma P, Huang W, Choules MP, Willemin M-E, Zhang X, Yau E, Derbalah A, Zyla A, Liu C, et al. Physiologically Based Pharmacokinetic Modeling of Biologic Case Studies in Monkeys and Humans Reveals the Necessity of an Additional Clearance Term. Pharmaceutics. 2025; 17(5):560. https://doi.org/10.3390/pharmaceutics17050560

Chicago/Turabian Style

Stader, Felix, Pradeep Sharma, Weize Huang, Mary P. Choules, Marie-Emilie Willemin, Xinwen Zhang, Estelle Yau, Abdallah Derbalah, Adriana Zyla, Cong Liu, and et al. 2025. "Physiologically Based Pharmacokinetic Modeling of Biologic Case Studies in Monkeys and Humans Reveals the Necessity of an Additional Clearance Term" Pharmaceutics 17, no. 5: 560. https://doi.org/10.3390/pharmaceutics17050560

APA Style

Stader, F., Sharma, P., Huang, W., Choules, M. P., Willemin, M.-E., Zhang, X., Yau, E., Derbalah, A., Zyla, A., Liu, C., & Sepp, A. (2025). Physiologically Based Pharmacokinetic Modeling of Biologic Case Studies in Monkeys and Humans Reveals the Necessity of an Additional Clearance Term. Pharmaceutics, 17(5), 560. https://doi.org/10.3390/pharmaceutics17050560

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