Understanding and predicting dose dependent and idiosyncratic events

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Drug PBPK model BA Transport Inhibition Model Bile Acids <strong>and</strong> DILI Drug inhibits BA transporters Bile Acid Homeostasis Model Cellular ATP Model Bile acid accumulation disrupts cellular energy balance BA H+ Gradient Uncoupling Hepatocyte Life-Cycle Disrupted cellular energy balance can cause hepatocyte necrosis 14
AMG 009 No evidence of liver injury in multiple species • Rats, mice, non-human primates, hamsters or rabbits – During Phase I clinical trials in healthy volunteers, 5/8 patients showed significant <strong>and</strong> reversible transaminase elevations – Development of AMG 009 was halted – Bile acid transporter inhibition was the only mechanism identified as likely contributors to AMG 009 hepatotoxicity • No reactive metabolites, covalent binding, or mitochondrial toxicities were detected 15
Page 1 and 2: ® Modeling Hepatoxicity: Understan
Page 3 and 4: Outline of Talk 1). Problem of live
Page 5 and 6: Posted: 5:17 p.m. Friday, Nov. 4, 2
Page 7 and 8: UNC Institute for Drug Safety Scien
Page 9 and 10: Approach 1). Build mechanistic “m
Page 11 and 12: Outline of Talk 1). Problem of drug
Page 13: Drugs Can Inhibit Bile Acid Transpo
Page 17 and 18: Modeling in vitro transporter inhib
Page 19 and 20: DILIsym ® Predicts Dose-Dependent
Page 21 and 22: AMG 853 • AMG 853 was the backup
Page 23 and 24: Why mechanism of transport inhibiti
Page 25: Posted: 5:17 p.m. Friday, Nov. 4, 2
Page 28 and 29: Two issues with solithromycin: - Im
Page 30 and 31: DILIsym ® Mechanism-Based Modeling
Page 32 and 33: Contribution to Predicted ALT eleva
Page 34 and 35: Contribution to Predicted ALT eleva
Page 36 and 37: FDA panel narrowly backs Cempra ant
Page 38 and 39: Multiple Steps Involved in Idiosync
Page 40 and 41: Multiple Steps Involved in Idiosync
Page 42 and 43: Summary New mechanistic biomarkers
Page 44 and 45: DILIsym ® Mechanism-Based Modeling
Page 46 and 47: Confidence in Predictions Depends o
Page 48 and 49: Conclusion Quantitative Systems Pha
Page 50 and 51: Special thanks to the DILIsim Partn
Page 52 and 53: Back up

Understanding and predicting dose dependent and idiosyncratic events

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