(T-027) Integrated Microphysiological System and PBPK Modeling for Prediction of Human Diclofenac Pharmacokinetics

Dong-seok Yim, MD., PhD – Professor, Catholic university of Korea; Sungpil Han, MD., PhD – Assistant professor, Catholic university of Korea; Jeonghyun Lee, M.S – Student, Catholic university of Korea

Objective: The primary objective of this study was to combine an integrated microphysiological system (MPS) with a computational multicompartmental physiologically-based pharmacokinetic (PBPK) model to improve methods for predicting human pharmacokinetics using diclofenac. We also tried to identify transcriptomic biomarkers that respond significantly to diclofenac exposure in MPS chip to determine the similarity of human drug responses to those of the MPS and the potential for using the MPS to improve our understanding of the pharmacodynamics of drugs.

Methods: The MPS used advanced microfluidic technology and co-cultures of physiologically relevant human cell types to form a comprehensive model of human organ systems. The system was integrated with a PBPK model to simulate drug absorption, distribution, metabolism, and excretion (ADME) processes and compared to real-world human pharmacokinetic results. The study also performed transcriptomic profiling to validate the predictive accuracy of the MPS against clinical pharmacokinetic data for diclofenac and to correlate drug exposure with gene expression changes.

Results: The results from the blank and MPS chips yielded adequate key parameters (CLint,h = 3,342 L/h, Papp, h = 0.000427 cm/s, Papp, g = 0.000968 cm/s) and simulations combining these results with a PBPK model built using only the in vitro results showed relatively good agreement with clinical data for the pharmacokinetics of diclofenac without additional optimization (AUCR(predicted/observed) = 0.89). In addition, transcriptomic analyses showed a high correlation in gene expression associated with diclofenac exposure, particularly those involved in gastrointestinal toxicity and other systemic effects.

Conclusion: The findings support the potential of MPS as a reliable alternative to traditional animal testing for predicting drug response in humans. It has shown the potential to improve the drug development process by more accurately predicting pharmacokinetics and pharmacodynamics in humans at an early stage, and identifying novel transcriptomic markers which might help us understand drug mechanisms and safety profiles.

Citations: [1] Prantil-Baun, R., et al., Physiologically Based Pharmacokinetic and Pharmacodynamic Analysis Enabled by Microfluidically Linked Organs-on-Chips. Annu Rev Pharmacol Toxicol, 2018. 58: p. 37-64
[2] Herland, A., et al., Quantitative prediction of human pharmacokinetic responses to drugs via fluidically coupled vascularized organ chips. Nature biomedical engineering, 2020. 4(4): p. 421-436.