Dose‐dependent acute liver injury with hypersensitivity features in humans due to a novel microsomal prostaglandin E synthase 1 inhibitor

• Published in: British journal of clinical pharmacology Vol. 84; no. 1; pp. 179 - 188
• Main Authors: Jin, Yan, Regev, Arie, Kam, Jeanelle, Phipps, Krista, Smith, Claire, Henck, Judith, Campanale, Kristina, Hu, Leijun, Hall, D. Greg, Yang, Xiao Yan, Nakano, Masako, McNearney, Terry Ann, Uetrecht, Jack, Landschulz, William
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.01.2018
• Subjects: Administration, Oral; Adult; Area Under Curve; Celecoxib - adverse effects; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - pathology; Cyclooxygenase 2 Inhibitors - adverse effects; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Hypersensitivity - etiology; Drug Hypersensitivity - pathology; Drug Safety; drug‐induced liver injury; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; eosinophilia; Female; Half-Life; Healthy Volunteers; hepatocellular injury; Humans; Imidazoles - administration & dosage; Imidazoles - adverse effects; Imidazoles - pharmacokinetics; Imidazoles - pharmacology; Liver - drug effects; Liver - immunology; Liver - pathology; Male; Middle Aged; nonsteroidal anti‐inflammatory drugs; Pain - drug therapy; Prostaglandin-E Synthases - antagonists & inhibitors; rashes; Withholding Treatment; drug-induced liver injury; nonsteroidal anti-inflammatory drugs; eosinophilia; hepatocellular injury; rashes

Aims LY3031207, a novel microsomal prostaglandin E synthase 1 inhibitor, was evaluated in a multiple ascending dose study after nonclinical toxicology studies and a single ascending dose study demonstrated an acceptable toxicity, safety and tolerability profile. Methods Healthy subjects were randomi...