Vanessa Baier (1), Christoph Thiel (1), Henrik Cordes (1), Lars M. Blank (1), Lars Kuepfer (1)
(1) Institute of Applied Microbiology - iAMB, Aachen Biology and Biotechnology – ABBt, RWTH Aachen University, 52074 Aachen, Germany
Objectives: Drug-induced liver injuries (DILI) are a frequent reason for safety-related project closure of pharmaceutical development programs as their mechanisms are unclear and they are often unidentifiable in standard preclinical tests [1]. Cholestasis, the state of impaired bile secretion, is a common clinical manifestation of DILI. Dedicated computational models would be useful for prior identification of potential aberrant states of bile acid metabolism and a subsequent early identification of compounds with cholestatic risk. As bile acids undergo extensive enterohepatic cycling and are distributed on a whole-body scale, a systemic model at organism level is needed to truly understand the occurrence of cholestasis. Our objectives are 1) to develop a PB model of bile acid metabolism in healthy men, 2) to quantify the effects of different phenotypes on bile acid metabolism, and 3) to predict drug-induced cholestasis.
Methods: The developed bile acid model (BAM) was structurally derived from the physiology-based pharmacokinetic (PBPK) model implemented in PKSim® (Open Systems Pharmacology Suite, version 7.2) [2, 3]. Processes essential for bile acid metabolism such as biosynthesis, excretion, and active transports were identified by comprehensive literature research and were included in the model [3–5]. Additionally, gallbladder emptying following meal intake was considered. So far, one exemplary bile acid – glycochenodeoxycholic acid – was used as a surrogate bile acid for the total pool. Parameter estimation was performed by fitting the model to bile acid concentration-time profiles in blood reported in literature [6–8].
Results: The developed whole-body physiology-based BAM describes the bile acid metabolism in a healthy reference individual. The model was validated with literature values for bile acid plasma levels at steady state as well as dynamic changes following ingestion of three meals per day and consequent gallbladder emptying. The model allows simulation of bile acid concentrations in tissue compartments such as the intracellular space of the liver which is of particular relevance to mechanistically assess occurrence of cholestasis. Based on the healthy reference model, two different impairments of the bile salt export pump (BSEP) were simulated. First, the simulation of genetic defects in BSEP like Benign Recurrent Intrahepatic Cholestasis (BRIC) type 2 [9] points to slightly increased bile acid concentrations (3% and 15% in venous blood and liver cells, respectively) in these individuals. Our model therefore suggests a special susceptibility of this phenotype towards occurrence of DILI. In a second in silico study, effects of Cyclosporine A (CsA) on bile acid metabolism were predicted by combining the BAM with a PBPK model of CsA [10] and in vitro inhibitory data [11]. Simulations of a twice daily CsA administration revealed more pronounced effects in BRIC patients than in healthy individuals with increased bile acid concentrations of 6% vs. 3.5% and 41% vs. 23% in venous blood and liver cells, respectively. Taken together, the simulated scenarios are a first step towards an in silico risk assessment for drug-induced cholestasis.
Conclusion: The physiology-based model of bile acid metabolism describes the circulation of bile acids within the human body at organism level. It was initially validated for a healthy reference state and subsequently used to investigate aberrant states of bile acid metabolism such as drug-induced cholestasis. Straightforward integration of in vitro data, for example describing changes in ADME gene expression (ADME: absorption, distribution, metabolism and excretion), allows predictions about drug-induced effects on bile acid metabolism. Next, we will integrate high-quality time-resolved omics data gathered within the HeCaToS project to enhance the models significance [12]. The model can support the early identification of drug-induced cholestasis to avoid project closure at late phases of clinical development as well as to increase patient safety in general.
References:
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[8] Schalm SW, Larusso NF, Hofmann AF, Hoffman NE, van Berge-Henegouwen GP, Korman MG. Diurnal serum levels of primary conjugated bile acids Assessment by specific radioimmunoassays for conjugates of cholic and chenodeoxycholic acid. Gut 1978; 19(11):1006–14.
[9] Noe J, Kullak-Ublick GA, Jochum W, Stieger B, Kerb R, Haberl M et al. Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis. J Hepatol 2005; 43(3):536–43.
[10] Thiel C, Cordes H, Fabbri L, Aschmann HE, Baier V, Smit I et al. A Comparative Analysis of Drug-Induced Hepatotoxicity in Clinically Relevant Situations. PLoS Comput Biol 2017; 13(2):e1005280.
[11] Böhme M, Jedlitschky G, Leier I, Büchler M, Keppler D. ATP-dependent export pumps and their inhibition by cyclosporins. Advances in Enzyme Regulation 1994; 34:371–80.
[12] Kuepfer L, Clayton O, Thiel C, Cordes H, Nudischer R, Blank LM et al. A model-based assay design to reproduce in vivo patterns of acute drug-induced toxicity. Archives of Toxicology 2017.
Reference: PAGE 27 (2018) Abstr 8685 [www.page-meeting.org/?abstract=8685]
Poster: Drug/Disease Modelling - Absorption & PBPK