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Pharmaceutics
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Advancing Biologic Drug Development Through Physiologically Based Pharmacokinetic Modelling and...
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Advancing Biologic Drug Development Through Physiologically Based Pharmacokinetic Modelling and Simulations

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmacokinetics and Pharmacodynamics".

Deadline for manuscript submissions: 30 September 2025 | Viewed by 5824

Special Issue Editors

Dr. Victor Mangas Sanjuán

E-Mail Website
Guest Editor
Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, 46100 Valencia, Spain
Interests: pharmacokinetics; biopharmaceutics; oral absorption; dissolution methods
Special Issues, Collections and Topics in MDPI journals
Dr. Javier Reig Lopez

E-Mail Website
Guest Editor
1. Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Valencia, Spain
2. Interuniversity Research Institute for Molecular Recognition and Technological Development, University of Valencia, Valencia, Spain
Interests: absorption; DDIs; PBPK; PBBM; drug metabolism and transport; biologics; mechanistic drug modelling

Special Issue Information

Dear Colleagues,

Biologic drugs represent an excellent opportunity to effectively and safely treat many diseases. These advanced therapies bring to the therapeutic options the “magic bullet” concept Paul Ehrlich proposed in the 19th century. However, understanding the pharmacokinetics and pharmacodynamics in the systemic circulation, specific tissues, and the site of action is of great interest to the scientific community in efficiently developing effective and safe drugs for our patients. Because of this, we are pleased to invite you to contribute to the Special Issue entitled “Advancing Biologic Drug Development Through Physiologically Based Pharmacokinetic Modelling and Simulations”.

This Special Issue aims to collect research works where physiologically based pharmacokinetic modeling strategies have been used to advance the knowledge of biological drugs during drug discovery and development.

In this Special Issue, original research articles and reviews are welcome. Research areas may include, but are not limited to, biologics disposition, tissue distribution, receptor occupancy prediction, first-in-human dose selection, dose regimen optimization, and special populations.

We look forward to receiving your contributions. 

Dr. Victor Mangas Sanjuán
Dr. Javier Reig-Lopez
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • monoclonal antibodies
  • antibody-drug conjugates
  • bispecific antibodies
  • PBPK
  • target-mediated drug disposition
  • lysosomal degradation
  • FcRn binding
  • special populations

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Published Papers (5 papers)

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Research

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18 pages, 4976 KiB  
Article
Mechanistic Insights into Cytokine Antagonist-Drug Interactions: A Physiologically Based Pharmacokinetic Modelling Approach with Tocilizumab as a Case Study
by Xian Pan, Cong Liu, Felix Stader, Abdallah Derbalah, Masoud Jamei and Iain Gardner
Pharmaceutics 2025, 17(7), 896; https://doi.org/10.3390/pharmaceutics17070896 - 10 Jul 2025
Viewed by 375
Abstract
Background: Understanding interactions between cytokine antagonists and drugs is essential for effective medication management in inflammatory conditions. Recent regulatory authority guidelines emphasise a systematic, risk-based approach to evaluating these interactions, underscoring the need for mechanistic insight. Proinflammatory cytokines, such as interleukin-6 (IL-6), modulate [...] Read more.
Background: Understanding interactions between cytokine antagonists and drugs is essential for effective medication management in inflammatory conditions. Recent regulatory authority guidelines emphasise a systematic, risk-based approach to evaluating these interactions, underscoring the need for mechanistic insight. Proinflammatory cytokines, such as interleukin-6 (IL-6), modulate cytochrome P450 (CYP) enzymes, reducing the metabolism of CYP substrates. Cytokine antagonists (such as IL-6 receptor antagonists) can counteract this effect, restoring CYP activity and increasing drug clearance. However, quantitative prediction of cytokine-mediated drug interactions remains challenging, as existing models often lack the mechanistic detail needed to capture the dynamic relationship between cytokine signalling, receptor engagement, and downstream modulation of drug metabolism. Methods: A physiologically based pharmacokinetic (PBPK) framework incorporating cytokine–receptor binding, subsequent downregulation of CYP expression, and blockade of the cytokine signalling by a therapeutic protein antagonist was developed to simulate and investigate cytokine antagonist-drug interactions. Tocilizumab, a humanised IL-6 receptor antagonist used to treat several inflammatory conditions associated with elevated IL-6 levels, was selected as a model drug to demonstrate the utility of the framework. Results: The developed PBPK model accurately predicted the pharmacokinetics profiles of tocilizumab and captured clinically observed dynamic changes in simvastatin exposure before and after tocilizumab treatment in rheumatoid arthritis (RA) patients. Simulated IL-6 dynamics aligned with observed clinical profiles, showing transient elevation following receptor blockade and associated restoration of CYP3A4 activity. Prospective simulations with commonly co-administered CYP substrates (celecoxib, chloroquine, cyclosporine, ibuprofen, prednisone, simvastatin, and theophylline) in RA patients revealed dose regimen- and drug-dependent differences in interaction magnitude. Conclusions: This study demonstrated the utility of PBPK models in providing a mechanistic understanding of cytokine antagonist-drug interactions, supporting enhanced therapeutic decision-making and optimising patient care in inflammatory conditions. Full article
(This article belongs to the Special Issue Advancing Biologic Drug Development Through Physiologically Based Pharmacokinetic Modelling and Simulations)
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15 pages, 1142 KiB  
Article
Prediction of Monoclonal Antibody Pharmacokinetics in Pediatric Populations Using PBPK Modeling and Simulation
by Chiara Zunino, Virginie Gualano, Haiying Zhou, Viera Lukacova and Maxime Le Merdy
Pharmaceutics 2025, 17(7), 884; https://doi.org/10.3390/pharmaceutics17070884 - 5 Jul 2025
Viewed by 402
Abstract
Background: Accurately determining pediatric dosing is essential prior to initiating clinical trials or administering medications in routine clinical settings. In children, ethical considerations demand careful evaluation of both safety and effectiveness. Typically, dosing recommendations for therapeutic proteins, such as monoclonal antibodies (mAbs), [...] Read more.
Background: Accurately determining pediatric dosing is essential prior to initiating clinical trials or administering medications in routine clinical settings. In children, ethical considerations demand careful evaluation of both safety and effectiveness. Typically, dosing recommendations for therapeutic proteins, such as monoclonal antibodies (mAbs), are derived from adult dosages using body weight as a scaling factor. However, this method overlooks key physiological and biochemical distinctions between pediatric and adult patients. Therefore, this could lead to the underexposure of mAbs, limiting their efficacy in this population. Additional methods are necessary to predict pediatric doses mechanistically. For small molecules, physiologically based pharmacokinetic (PBPK) models have been extensively used to predict pediatric doses based on physiological age-related changes and enzymes/transporters ontogeny. This study aims to evaluate the ability of PBPK models to predict mAbs’ pediatric exposure. Methods: Three mAbs were used for model development and validation: bevacizumab, infliximab, and atezolizumab. The PBPK models were built using GastroPlus© Biologics module. For each mAb, the PBPK model was developed based on observed data in healthy and/or patient adults. Then, the physiological parameters were scaled to describe the pediatric physiology to predict exposure to the pediatric populations. Predicted plasma concentration–time courses were overlaid with reported observed data to assess the ability of the PBPK model to predict pediatric exposure. Results: Results showed that PBPK models accurately predicted pediatric pharmacokinetics for mAbs. Conclusions: This research marks a significant step in validating mechanistic extrapolation methods for biologics exposure prediction in children using PBPK models. Full article
(This article belongs to the Special Issue Advancing Biologic Drug Development Through Physiologically Based Pharmacokinetic Modelling and Simulations)
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11 pages, 9036 KiB  
Article
Physiologically Based Pharmacokinetic Modeling of Biologic Case Studies in Monkeys and Humans Reveals the Necessity of an Additional Clearance Term
by Felix Stader, Pradeep Sharma, Weize Huang, Mary P. Choules, Marie-Emilie Willemin, Xinwen Zhang, Estelle Yau, Abdallah Derbalah, Adriana Zyla, Cong Liu and Armin Sepp
Pharmaceutics 2025, 17(5), 560; https://doi.org/10.3390/pharmaceutics17050560 - 24 Apr 2025
Viewed by 1197
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Advancing Biologic Drug Development Through Physiologically Based Pharmacokinetic Modelling and Simulations)
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18 pages, 3427 KiB  
Article
Whole-Body Physiologically Based Pharmacokinetic Modeling of GalNAc-Conjugated siRNAs
by Emilie Langeskov Salim, Kim Kristensen and Erik Sjögren
Pharmaceutics 2025, 17(1), 69; https://doi.org/10.3390/pharmaceutics17010069 - 6 Jan 2025
Viewed by 1821
Abstract
Background/Objectives: N-acetyl-galactosamine small interfering RNAs (GalNAc-siRNA) are an emerging class of drugs due to their durable knockdown of disease-related proteins. Direct conjugation of GalNAc onto the siRNA enables targeted uptake into hepatocytes via GalNAc recognition of the Asialoglycoprotein Receptor (ASGPR). With a [...] Read more.
Background/Objectives: N-acetyl-galactosamine small interfering RNAs (GalNAc-siRNA) are an emerging class of drugs due to their durable knockdown of disease-related proteins. Direct conjugation of GalNAc onto the siRNA enables targeted uptake into hepatocytes via GalNAc recognition of the Asialoglycoprotein Receptor (ASGPR). With a transient plasma exposure combined with a prolonged liver half-life, GalNAc-siRNA exhibits distinct disposition characteristics. We aimed to develop a generic GalNAc-siRNAs whole-body physiologically based pharmacokinetic–pharmacodynamic (WB-PBPK-PD) model for describing the pharmacokinetic–pharmacodynamic (PK-PD) relationship and overall tissue distribution in the open-source platform Open Systems Pharmacology Suite. Methods: Model development was performed using published studies in mice leveraging the PK-Sim® standard implementation for large molecules with added implementations of ASGPR-mediated liver disposition and downstream target effects. Adequate model performance was achieved across study measurements and included studies adopting a combination of global and compound-specific parameters. Results: The analysis identified significant compound dependencies, e.g., endosomal stability, with direct consequences for the pharmacological effect. Additionally, knowledge gaps in mechanistic understanding related to extravasation and overall tissue distribution were identified during model development. The presented study provides a generic WB-PBPK-PD model for the investigation of GalNAc-siRNAs implemented in a standardized open-source platform. Full article
(This article belongs to the Special Issue Advancing Biologic Drug Development Through Physiologically Based Pharmacokinetic Modelling and Simulations)
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Review

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28 pages, 7155 KiB  
Review
Accelerating Biologics PBPK Modelling with Automated Model Building: A Tutorial
by Abdallah Derbalah, Tariq Abdulla, Mailys De Sousa Mendes, Qier Wu, Felix Stader, Masoud Jamei, Iain Gardner and Armin Sepp
Pharmaceutics 2025, 17(5), 604; https://doi.org/10.3390/pharmaceutics17050604 - 2 May 2025
Viewed by 1508
Abstract
Physiologically based pharmacokinetic (PBPK) modelling for biologics, such as monoclonal antibodies and therapeutic proteins, involves capturing complex processes, including target-mediated drug disposition (TMDD), FcRn-mediated recycling, and tissue-specific distribution. The Simcyp Designer Biologics PBPK Platform Model offers an intuitive and efficient platform for constructing [...] Read more.
Physiologically based pharmacokinetic (PBPK) modelling for biologics, such as monoclonal antibodies and therapeutic proteins, involves capturing complex processes, including target-mediated drug disposition (TMDD), FcRn-mediated recycling, and tissue-specific distribution. The Simcyp Designer Biologics PBPK Platform Model offers an intuitive and efficient platform for constructing mechanistic PBPK models with pre-defined templates and automated model assembly, reducing manual input and improving reproducibility. This tutorial provides a step-by-step guide to using the platform, highlighting features such as cross-species scaling, population variability simulations, and flexibility for model customization. Practical case studies demonstrate the platform’s capability to streamline workflows, enabling rapid, mechanistic model development to address key questions in biologics drug development. By automating critical processes, this tool enhances decision-making in translational research, optimizing the modelling and simulation of large molecules across discovery and clinical stages. Full article
(This article belongs to the Special Issue Advancing Biologic Drug Development Through Physiologically Based Pharmacokinetic Modelling and Simulations)
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