Pavel Balazki1, Felix Mil1, Brian Cicali2, Stephan Schaller1, Stephan Schmidt2
1ESQlabs GmbH, 2Center for Pharmacometrics and Systems Pharmacology, University of Florida College of Pharmacy
Objective Combined oral contraceptives (COCs) are commonly used worldwide to prevent unintended pregnancies. However, other medications can affect COCs’ metabolism, leading to reduced effectiveness or adverse events. Thus, drug developers must evaluate potential drug-drug interactions (DDIs) with COCs to ensure safety and efficacy. Physiologically-Based Pharmacokinetic (PBPK) models are a powerful alternative to conducting DDI clinical studies accepted by regulatory agencies. The Open Systems Pharmacology (OSP) platform (1) provides a comprehensive database of free and open-source PBPK models of inhibitors and inducers of various enzymes and transporters qualified for predictions of DDI. Our aim is to develop an easy-to-use yet powerful Clinical Trial Simulator (CTS) that allows automated prediction of the effects of DDI on COC exposure leveraging the available and continuously growing model database. Methods All models have been developed with the OSP software (PK-Sim and MoBi) and are hosted on GitHub (2). The CTS is developed in R utilizing R packages from the OSP ecosystem: esqlabsR (3), ospsuite-r, TLF. The graphical user interface (GUI) is implemented using the Shiny framework. Results The CTS allows automated model assembly from given single-compound models, definition of study design, running specified DDI simulations, and processing the results, estimating the impact of DDI on the efficacy and safety of the selected victim drug. Using either an Application Programming Interface (API) or a GUI, the user can: -Browse the database of available models -Retrieve information about the models -Select compounds that should be evaluated in an in silico DDI study -Specify study protocol (re-utilizing protocols available in the model database) -Run the DDI study -Analyze the results The CTS has been applied to predict the effects of DDI on the exposure and response for efficacy (Pearl Index) and safety (breakthrough bleeding) for the COCs levonorgestrel and drospirenone . Conclusion The developed CTS enables the application of freely available PBPK models from the OSP model database in a user-friendly, GUI supported framework and makes the models available and accessible not only to expert PBPK modelers, but also to experts from other areas like clinicians. The framework has the potential to widen the application areas and support the re-usability of PBPK models, strengthening the open-source open-science approach for model-informed drug development. In the future, the CTS can be extended to support the new modularization features of the OSP software implemented in version 12. The modularization concept allows not only the combination of PBPK models, but easy integration of quantitative systems pharmacology (QSP) modules to couple PK with the predictions of treatment effects. Backed by a database of QSP modules, the CTS could emerge to a platform giving access to available models to support drug development throughout the whole development cycle.
1. Community OSP. Open Systems Pharmacology [Internet]. [cited 2024 Mar 11]. Available from: https://www.open-systems-pharmacology.org/ 2. OSP S. GitHub. 2022 [cited 2022 Aug 13]. Open-Systems-Pharmacology/OSP-Qualification-Reports: Qualification Reports recreated with every new OSP Release. Available from: https://github.com/Open-Systems-Pharmacology/OSP-Qualification-Reports 3. esqLABS GmbH. esqlabsR utilities package [Internet]. [cited 2024 Mar 11]. Available from: https://esqlabs.github.io/esqlabsR/index.html
Reference: PAGE 33 (2025) Abstr 11333 [www.page-meeting.org/?abstract=11333]
Poster: Drug/Disease Modelling - Absorption & PBPK