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1142A AASLD ABSTRACTS HEPATOLOGY, October, 2015 *Median [Min, Max]; ** P-values from Fisher’s Exact for categorical variables, Wilcoxon-Mann-Whitney for continuous variables Disclosures: Dean W. Roberts - Management Position: Acetaminophen Toxicity Diagnostics, LLC William M. Lee - Consulting: Eli Lilly, Sanofi; Grant/Research Support: Gilead, BMS, Vertex, Merck Laura James - Grant/Research Support: NIDDK; Management Position: Acetaminophen Toxicity Diagnostics, LLC The following authors have nothing to disclose: Jack A. Hinson, Shasha Bai, R. Todd Stravitz, Adrian Reuben, Christopher J. Swearingen, Pippa Simpson 1915 Understanding the Relationship between Systemic and Hepatic Exposure of Obeticholic Acid for the Treatment of Liver Disease in Patients with Cirrhosis Jeffrey Edwards 1 , Carl LaCerte 1 , Nathalie H. Gosselin 2 , Thomas Peyret 2 , J.F. Marier 2 , Alan F. Hofmann 3 , David Shapiro 1 ; 1 Intercept Pharmaceuticals, San Diego, CA; 2 Pharsight, a Certara Company, Princeton, NJ; 3 Department of Medicine, University of California San Diego, San Diego, CA Obeticholic acid (OCA) is a selective and potent farnesoid X receptor (FXR) agonist in development for the treatment of primary biliary cirrhosis (PBC) and other liver diseases. OCA is structurally similar to chenodeoxycholic acid (CDCA) and has similar pharmacokinetics (PK), including conjugation and enterohepatic circulation. The amidates of OCA activate FXR in the intestine and liver, leading to a reduced hepatic bile acid pool. Patients with cirrhosis have higher systemic exposure of bile acids (x18) while hepatic exposure of bile acids is only ~2-fold higher (Fischer et al. Clinica Chimica Acta 1996 251:173). In OCA-treated patients, systemic OCA exposure was significantly higher in those with moderate (x4) and severe (x17) hepatic impairment, similar to increases in systemic exposure of endogenous bile acids. FXR activation (measured by fibroblast growth factor-19) was similar in patients with hepatic impairment versus healthy volunteers, consistent with similar liver and intestinal OCA exposure. Thus systemic exposure of OCA is not reflective of hepatic concentrations of OCA, the primary site of action for safety and efficacy. To understand the relationship between systemic and hepatic exposure of OCA and its pharmacologically active conjugates in patients with and without hepatic (cirrhosis) impairment, a physiologic PK model of OCA was developed. The PK model for OCA was based on a multi-compartment PK model for CDCA (Molino et al. Eur J Clin Invest 1986 16:397) and consisted of systemic, hepatobiliary, and intestinal systems. The model accounted for the pathophysiology associated with cirrhosis including decreased hepatic uptake of OCA, portal-systemic shunting, decreased physiologic/functional liver volume, and differences in amino acid conjugation. The PK model was used to simulate the overall mean concentration-time profile of total OCA in plasma and liver. There was good agreement between predicted and observed increases in systemic exposure of total OCA (the sum of OCA and its conjugates) after a single 10 mg dose in subjects with mild (x1.4), moderate (x8), and severe (x13) hepatic impairment relative to healthy subjects. The predicted increases in liver exposure for subjects with mild, moderate, and severe hepatic impairment were only 1.1-, 1.5-, and 1.7-fold, respectively, relative to healthy participants and are similar to the hepatic exposure of bile acids observed in patients with cirrhosis. Model-predicted hepatic exposure of OCA, consistent with clinical study results, support the safety and efficacy of OCA in PBC patients with cirrhosis at the therapeutic doses used in non-cirrhotic patients. Disclosures: Jeffrey Edwards - Employment: Intercept Pharmaceuticals; Stock Shareholder: Intercept Pharmaceuticals Carl LaCerte - Employment: Amylin Pharmaceuticals; Stock Shareholder: Amylin Pharmaceuticals Nathalie H. Gosselin - Employment: Pharsight Thomas Peyret - Employment: Pharsight Alan F. Hofmann - Board Membership: Vital Therapies, Vital Therapies; Consulting: Albireo Pharma, Shire, Intercept Pharma, Relypsa; Stock Shareholder: Intercept Pharma David Shapiro - Employment: Inttercept Pharmaceuticals; Management Position: Intercept Pharmaceuticals; Stock Shareholder: Intercept Pharmaceuticals The following authors have nothing to disclose: J.F. Marier 1916 Transcriptional Profiling Of Primary Human Hepatocytes Under Hemodynamics And Transport Differentiates Distinct Mechanisms Of Drug-Induced Liver Injury. Robert Figler 1 , Brett R. Blackman 1 , Charles Qualls 2 , Svetlana Marukian 1 , Sol Collado 1 , Mark Lawson 1 , Aaron J. Mackey 1 , David Manka 1 , Brian R. Wamhoff 1 , Ajit Dash 1 ; 1 HemoShear Therapeutics, Charlottesville, VA; 2 Qualls Preclinical Solutions LLC, Thousand Oaks, CA Drug induced liver injury (DILI) is a major cause of liver failure, drug withdrawal and non-approval. Predicting DILI is challenging since drug concentrations used in in vitro hepatocyte cultures are often significantly higher than therapeutic plasma concentrations, making mechanistic pathway changes difficult to interpret. We have described a system using liver-derived blood flow parameters to restore primary human hepatocyte biology, allowing for culture at close to physiological insulin/ glucose conditions and eliciting drug responses at clinically-relevant concentrations. We used this system to assess three DILI causing drugs, Acetaminophen (APAP), Trovafloxacin (TVX) and Chlorpromazine (CPZ), to differentiate their potential for toxicity and transcriptomic signatures, at concentrations approximating both therapeutic and toxic levels. For instance, the toxic concentration of APAP used (1323 μM) was based on serum levels that would initiate treatment for acute toxicity using the Rumack-Matthew nomogram, and is significantly lower than concentrations typically reported in conventional in vitro culture systems. Primary hepatocytes from 5 human donors plated in the system were exposed to the drugs for 48 hours. Whole genome transcriptomics was performed using RNAseq, along with functional assays for CYP activity and function. Distinctive responses distinguishing the toxicity potential of the drugs at a signaling and phenotypic level underscored the differences in underlying mechanisms. Cholestasis-related pathways and genes were perturbed by CPZ and TVX but not APAP, consistent with lack of cholestatic phenotype in clinical reports of APAP toxicity. Fibrotic potential, reflected by increased TGF-β signaling, and inflammatory changes evidenced by NFκB activation were only seen with TVX. Coagulation and complement activation was noted only with APAP while CPZ exhibited activation of unfolded protein response. Novel findings including suppression of TGF-β with APAP, are currently being explored. The correlation of the cellular responses to clinical effects reported with the drugs, demonstrates the system’s ability to
HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 1143A predict toxicity mechanisms at clinically relevant concentrations and differentiate distinct mechanisms of DILI. Disclosures: Robert Figler - Employment: HemoShear Therapeutics, LLC Brett R. Blackman - Board Membership: HemoShear LLC; Management Position: HemoShear LLC; Patent Held/Filed: HemoShear LLC; Stock Shareholder: HemoShear LLC Svetlana Marukian - Employment: HemoShear LLC Mark Lawson - Employment: Hemoshear Aaron J. Mackey - Employment: HemoShear, LLC David Manka - Employment: HemoShear Therapeutics; Stock Shareholder: HemoShear Therapeutics Brian R. Wamhoff - Stock Shareholder: HemoShear, LLC Ajit Dash - Employment: HemoShear LLC The following authors have nothing to disclose: Charles Qualls, Sol Collado 1917 Caffeine Confers Hepatoprotection by Preconditioning Hepatocytes with Superior Ability to Withstand DNA Damage through Regulation of ATM Signaling Pathways Priya Gupta 1 , Yogeshwar Sharma 1 , Sanjeev Gupta 2 , Preeti Viswanathan 2 ; 1 Medicine and Pathology, Marion Bessin Liver Centre, Albert Einstein College of Medicine, Bronx, NY; 2 Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children’s Hospital at Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY Background: Epidemiological <strong>studies</strong> indicate that regular consumption of caffeine decreases severity of chronic hepatitis, cirrhosis, etc. However, the molecular basis for this organ protective effect of caffeine is unknown. To develop needed paradigms for defining hepatoprotective basis of caffeine we hypothesized that ATM signaling pathways, which protect cells from DNA damage, will be involved since caffeine inhibits ATM kinase activity. Methods: We used HuH-7 human hepatocellular carcinoma cells for model development, including IC50 cytotoxicity with acetaminophen (APAP) using MTT cell viability assays, DNA damage by γH2AX staining and Comet formation, and a cell subline expressing hATM promoter-driven tdTomato reporter for evaluating global pathway-specific changes. Cells were studied with or without caffeine preconditioning over 5 d. Flow cytometry was performed to analyze cell cycling with PI staining and Side Population (SP) was analyzed by Hoechst dyes with or without verapamil pretreatment to inhibit dye efflux through MDR activity. Results: APAP toxicity in HuH-7 cells led to dose-dependent increases in γH2AX expression, Comet formation and greater ATM promoter activity. When cells were exposed to APAP plus 10 mM caffeine overnight, cytotoxicity was worsened, along with further significant increases in γH2AX expression, Comet formation and ATM promoter activity, along with depletion of cells in S and G2/M, p
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1000A AASLD ABSTRACTS HEPATOLOGY, O
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1312A AUTHOR INDEX HEPATOLOGY, Octo
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1366A CATEGORY INDEX HEPATOLOGY, Oc
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