Stephan Schaller1, Pavel Balazki1, Juri Solodenko2, Jan Schlender3, Michael Sevestre4
1ESQlabs GmbH, 2Bayer AG, 3Novartis Pharma AG , 4Design2Code Inc.
Introduction Model-Informed Drug Development (MIDD) has become an essential pillar in pharmaceutical research and development, providing mechanistic insights into drug behavior across different patient populations and therapeutic areas. The growing complexity of therapeutic modalities, regulatory expectations for model qualification, and the increasing adoption of open-source tools necessitate a structured, automated, and scalable MIDD ecosystem. The advent of Open Systems Pharmacology (OSP) Suite [1] Version 12 introduces groundbreaking modularization capabilities that enable a fully integrated, continuously evolving Quantitative Model-Informed Drug Development (MIDD) ecosystem. This ecosystem supports the seamless development, validation, and deployment of Physiologically Based Pharmacokinetic (PBPK) and Quantitative Systems Pharmacology/Toxicology (QSP/T) models, ensuring robust, reproducible, and transparent decision-making across the entire drug development pipeline. It was initially conceived to improve efficiency of PBPK-QSP platform management of the Diabetes Disease Platform [2, 3]. Methods & Results The development of an end-to-end MIDD ecosystem requires a structured approach to model storage, validation, modularization, and continuous integration. The OSP Suite V12 provides the necessary foundation to achieve this by implementing modular PBPK-QSP workflows, enabling automated qualification, and facilitating model reuse. The following are key components of this ecosystem: 1. Utilization of a Continuously Built PK-Sim Model Library of Qualified PBPK Models and Use Cases A cornerstone of the MIDD ecosystem is the establishment of a continuously expanding PK-Sim model library, comprising qualified PBPK models across various drugs, populations, and mechanistic scenarios. This library provides a centralized repository of verified PBPK models that can be reused, extended, and adapted for different research applications, including: Drug-specific PBPK models: Systematically developed and validated models for small and large molecules, ensuring high regulatory confidence. Population-based PBPK models: Age-specific models (e.g., pediatric, geriatric), disease-state models, and ethnicity-based variations. Use-case driven model selection: Application of predefined PBPK model templates to support specific pharmacokinetic inquiries, including drug-drug interaction (DDI) assessments, formulation optimization, and extrapolation to special populations. Automated Model Qualification: Systematic, reproducible verification of PBPK model accuracy, ensuring consistency and reliability for regulatory submissions. This continuously evolving PK-Sim library serves as the backbone of the MIDD ecosystem, reducing model duplication, standardizing methodologies, and enhancing cross-project reproducibility. 2. Utilization of a Continuously Built MoBi Module Library for Community-Driven QSP/T Models and Use Cases In parallel with PBPK model libraries, the MIDD ecosystem integrates a MoBi module library, a systematically curated repository of community-driven QSP/T models that encapsulate disease biology, drug mechanisms of action, and multiscale pharmacodynamics. Key aspects include: Modular disease progression models: Prebuilt, validated models representing disease-specific mechanistic pathways, allowing for easy incorporation into new QSP/T workflows. Reusable pharmacodynamic effect models: Standardized modules capturing biomarker dynamics, receptor occupancy, and drug response. Pathway-based integration of PBPK-QSP models: Seamless connectivity between PBPK models from PK-Sim and QSP/T models in MoBi, ensuring physiologically and mechanistically consistent predictions. Community-driven contributions: A framework for open-source model sharing, validation, and improvement, encouraging global collaboration and standardization. Automated Model Updates & Version Control: Ensuring consistency and traceability of model refinements over time. The MoBi module library supports a plug-and-play approach, empowering researchers to build customized PBPK-QSP/T models without redundant model redevelopment, significantly enhancing efficiency and knowledge integration. 3. Modular Interchangeability of PBPK Models within QSP Platforms Enabling CI/CD for PBPK in PBPK-QSP Platforms and Fully Automated Platform Qualification A key innovation introduced in OSP Suite V12 is the modular interchangeability of PBPK models within QSP platforms, enabling Continuous Integration/Continuous Deployment (CI/CD) of PBPK models in PBPK-QSP platforms. This feature streamlines model development, validation, and deployment, ensuring models remain up-to-date and continuously qualified. Dynamic PBPK Model Replacement in QSP Frameworks: Researchers can seamlessly swap or update PBPK models within established QSP platforms without disrupting downstream analyses. Automated PBPK-QSP Platform Qualification: The MIDD ecosystem implements rigorous, automated qualification pipelines that validate model changes against predefined acceptance criteria, ensuring regulatory compliance. Standardized Interface for Model Interchangeability: Facilitating rapid model testing, extension, and adaptation across different drugs and therapeutic areas. Enhanced Model Reusability: Enabling efficient application of PBPK models across multiple projects while maintaining accuracy and scientific integrity. CI/CD Framework for Model Qualification: By integrating automated model qualification processes, the ecosystem ensures that PBPK models remain robust, up-to-date, and ready for regulatory engagement. This approach bridges the gap between PBPK and QSP/T modeling, offering a seamless framework where PBPK models act as dynamic components of larger disease models, optimizing predictive accuracy and mechanistic insights. The ecosystem has been successfully implemented across model pipelines integrating in-vitro systems models, a High-Throughput PBPK framework, PBPK intended use scenarios including custom modules for ocular absorption, pregnancy, lactation, and the female reproductive tract and integrated with disease progression and drug effect modules across safety endpoints and therapeutic areas. Conclusion: The development of an end-to-end MIDD ecosystem represents a paradigm shift in PBPK-QSP modeling, bridging the gap between model development, qualification, and regulatory acceptance. The key advantages of this ecosystem, powered by OSP Suite V12, include: A continuously evolving PK-Sim PBPK model library, ensuring reusable, validated, and standardized models for regulatory decision-making. A MoBi module library supporting community-driven QSP/T models, enabling modular, scalable, and collaborative disease modeling approaches. Modular interchangeability and CI/CD for PBPK models within QSP platforms, fostering an agile, automated, and regulatory-aligned modeling framework. By implementing automated model qualification, standardized model repositories, and modular modeling workflows, integrated with the OSP-R and ESQlabs-R packages environment, the MIDD ecosystem significantly enhances transparency, reproducibility, and regulatory credibility. This approach ultimately empowers regulatory engagement by providing robust, continuously validated models that seamlessly integrate into decision-making frameworks, accelerating drug development timelines, reducing uncertainty in model predictions, and supporting evidence-based regulatory approvals. As the field of model-informed drug development (MIDD) evolves, the combination of open-source software, modular workflows, and automated qualification pipelines will be pivotal in ensuring that PBPK-QSP models continue to drive innovative, efficient, transparent and impactful pharmaceutical research and development.
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Reference: PAGE 33 (2025) Abstr 11671 [www.page-meeting.org/?abstract=11671]
Poster: Methodology - Other topics