Enhanced Drug Safety During Pregnancy: An Innovative Three-Organ Microphysiological System

Challenges in Drug Safety During Pregnancy

Ensuring medication safety during pregnancy remains a well-known issue in pharmacology. Due to ethical and regulatory restrictions, pregnant women are often excluded from clinical trials. However, almost 90% of pregnant women take medications, for conditions such as infections, hypertension, or autoimmune diseases. Only around 10% of approved drugs have been specifically tested for safety in pregnant women. The placental transfer potential of many substances remains unclear, increasing the risk of unexpected side effects. The lack of comprehensive data complicates both the safe prescription of drugs and the management of chronic conditions during pregnancy.

Limitations of Traditional Testing Methods

Pharmacological predictions have traditionally relied on animal models, ex vivo placental perfusion systems, and physiologically based pharmacokinetic (PBPK) models. However, these methods face significant limitations, including restricted transferability, variability, and the need for experimental validation. Animal models do not accurately reflect human pregnancy, as placental barriers differ between species. Ex vivo models, while offering realistic conditions for studying drug transfer, are limited by the availability of human tissue and high inter-individual variability. PBPK models require robust experimental data to generate reliable simulations.

First-of-its-kind collaboration in the consumer health industry

In March 2023 a collaboration between Bayer’s Consumer Health Division, ESQlabs, Dynamic42 GmbH and Placenta Lab of Jena University Hospital set of to develop an organ-on-chip platform and interactive computational software to understand whether small molecules can cross the blood-placenta-barrier in pregnant women. The collaboration brought together ESQlabs’ unique expertise in computational modelling of biomedical systems, Dynamic42’s expertise in in-depth tissue and hardware engineering, Bayer’s leading expertise in human pharmacokinetic predictions and the Placenta Labs unique experience in developing and building placenta-on-chip models. (Find the original press release here)

Dynamic42: Advancing Microphysiological Systems (MPS)

As a result of this collaboration, Dynamic42, has developed an innovative three-organ MPS that replicates the gut, liver, and placenta on biochips. This organ-on-chip technology utilizes human cells in microfluidic systems to create realistic conditions for studying drug absorption, metabolism, and placental transfer. The organ models are interconnected via microfluidic channels, allowing complex physiological interactions to be simulated. This enables a deeper understanding of pharmacokinetic processes and reduces the reliance on animal testing.

ESQlabs: Simulation with Digital Twin Technology

When combined with digital twin technology—computational models that accurately replicate real biological processes – both acute drug effects and long-term impacts can be simulated. ESQlabs integrates experimental data from the Dynamic42 MPS into mathematical models to realistically predict drug distribution and metabolism in pregnant women. The digital twin accurately captured the pharmacokinetics of the individual on-chip models, closely aligned with the experimental data generated with the three-organ model and clinical data from pregnant woman. This approach enhances the prediction of dose-response relationships and improves drug safety assessments, helping to ensure safety for vulnerable populations without animal testing.

Case Study with Prednisone: Key Insights

Prednisone, a commonly prescribed corticosteroid, was used as a model substance in the study. The findings demonstrated:

/ Efficient Metabolism: Prednisone was successfully converted into prednisolone, accurately reflecting hepatic metabolism.

/ Limited Placental Transfer: The placental barrier significantly reduced fetal exposure, consistent with clinical observations.

/ Stable Cellular Integrity: The system maintained functionality throughout the tests, highlighting its robustness.

/ Optimized population PBPK model: The MPS-digital twin could predict clinically relevant levels of maternal prednisone and likely safe, but underpredicted exposure levels of fetal prednisolone.

These results underscore the potential of Dynamic42’s system and ESQlabs model to simulate complex pharmacological processes in vitro, enabling more precise predictions for drug safety.

Future Perspectives

Dynamic42’s and ESQlabs technology offers promising opportunities for:

/ Reducing Animal Testing: By using realistic human cell models that better reflect human physiology.

/ Early Detection of Risky Medications: For pregnant women and other underrepresented groups, facilitating faster identification of potentially harmful substances.

/ Expanding the System: To include additional organs such as the kidney, lung, or fetal tissues for more comprehensive pharmacokinetic analyses.

/ Optimizing Personalized Medicine: By integrating patient data, individualized treatment strategies could be developed

Conclusion

The combination of organ-on-chip models with digital twin technology represents a significant advancement in prenatal pharmacology. MPS can help improve drug safety for pregnant women and enable the early identification of risks, paving the way for safer medications tailored to the unique needs of this vulnerable group.

Read the full publication here.

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