Miao-Chan Huang (1), Kristof De Vos (1), Pieter Annaert (1,2)
(1) Drug delivery and disposition, Department of Pharmaceutical and Pharmacological sciences, KU Leuven, Leuven, Belgium; (2) BioNotus, Niel, Belgium
Objectives: In Western countries, drug-induced liver injury (DILI) has been the major source of acute liver failure [1,2]. When DILI is reported as adverse events, based on the stage during the drug life cycle, it can lead to termination of the drug development program, disapproval of the drug license, or black-boxed warnings [3,4]. Approximately half of the DILI events were reported to have cholestatic clinical presentations, known as drug-induced cholestasis (DiCho). DiCho is associated with disturbed homeostasis of bile acids (BAs) where the synthesis, metabolism, and/or disposition of BAs are interfered with. Among the cholestatic drugs, bosentan, an endothelin receptor agonist, is known to inhibit the bile-salt efflux pump (BSEP)[5,6] and is hypothesized to cause subsequent intrahepatic accumulation of BAs. In the in vitro and in vivo settings, disentangling the effect of a single mechanism can be challenging when multiple mechanisms are involved, not to mention translating it to a whole-body level. Physiologically-based kinetic (PBK) modeling features the physiologic system in its model structure and can be designated to study mechanistic interactions, which allows for revealing the contribution from a single mechanism at a whole-body level. This work tested the BSEP inhibition hypothesis with the PBK modeling of both bosentan and BAs.
Methods: The PBK models were modified from a published BA model [7] and built in PK-Sim® and MoBi® (version 11.1; Open Systems Pharmacology Suite; open-systems-pharmacology.org). The BA model assumed glycochenodeoxycholic acid (GCDCA) to be the only BA species, and the structure included an endogenous synthetic rate to cover the upstream BA synthesis in a simplified manner. Activities of the hepatic transporters NTCP, BSEP, ASBT, and OSTα-OSTβ were included to describe the enterohepatic recirculation of GCDCA. OATP1B1/1B3, CYP2C9 and CYP3A4 were implemented in the bosentan model for its hepatic uptake and biotransformation. Bosentan’s inhibition on BSEP was modeled as a non-competitive process. Enzymatic and transport kinetic data from in vitro studies were extrapolated considering the intersystem difference in protein abundance and calibrated with clinical data. The average fold errors and absolute average fold errors of the area-under-the-curve were estimated to evaluate the bosentan model’s prediction performance. The evaluation of the BA model was based on the comparison of the trough-to-peak level between the simulation and clinically reported values. Four scenarios were simulated: (1) control (normal BSEP expression); (2) 10% BSEP expression; (3) 50% BSEP expression; (4) BSEP inhibition following oral administration of bosentan (125mg and 500mg).
Results: The simulated GCDCA levels in the systemic plasma, liver tissue, and hepatocyte in populations with 10% and 50% BSEP expression were 16-to-24-fold and 2-fold higher than the control group. This evidenced the functionality of the BA model to reflect the inhibition of BSEP. On the other hand, limited effect on the peak BA level was observed in the simulation of bosentan administration due to low hepatocellular exposure to bosentan.
Conclusions: The lack of GCDCA accumulation in hepatocytes is consistent with the findings reported in the sandwich-cultured human hepatocytes [8]. As the current modeling system simplified the handling of BAs and the modulation by bosentan, the simulated results should be interpreted with caution. In future efforts, more mechanisms will be included and explored in the model to gain a clearer insight into the various pathways underlying bosentan-induced cholestasis.
References:
[1] Reuben A., Koch DG., Lee WM. et al. Hepatol Baltim Md. 2010;52(6):2065-2076.
[2] Wei G., Bergquist A., Broomé U. et al. J Intern Med. 2007;262(3):393-401.
[3] Ballet. J Hepatol. 1997;26(2):26-36.
[4] Watkins PB. Clin Pharmacol Ther. 2011;89(6):788-790.
[5] Fattinger K., Funk C., Pantze M. et al. Clin Pharmacol Ther. 2001; 69(4):223-231.
[6] Mano Y., Usui T, and Kamimuar H. J Pharmacol Exp Ther. 2007; 321(3):1170-1178.
[7] Baier V., Cordes H., Thiel C. et al. Front Physiol. 2019; 10:1192.
[8] Oorts M., Van Brantegem P., Deferm B. et al. J Pharmacol Exp Ther. 2021; 379(1): 20-32.
Reference: PAGE 32 (2024) Abstr 11115 [www.page-meeting.org/?abstract=11115]
Poster: Drug/Disease Modelling - Absorption & PBPK