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
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.13423

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 randomized to receive LY3031207 (25, 75 and 275 mg), placebo or celecoxib (400 mg) once daily for 28 days. The safety, tolerability and pharmacokinetic and pharmacodynamic profiles of LY3031207 were evaluated. Results The study was terminated when two subjects experienced drug‐induced liver injury (DILI) after they had received 225 mg LY3031207 for 19 days. Liver biopsy from these subjects revealed acute liver injury with eosinophilic infiltration. Four additional DILI cases were identified after LY3031207 dosing had been stopped. All six DILI cases shared unique presentations of hepatocellular injury with hypersensitivity features and demonstrated a steep dose‐dependent trend. Prompt discontinuation of the study drug and supportive medical care resulted in full recovery. Metabolites from metabolic activation of the imidazole ring were observed in plasma and urine samples from all subjects randomized to LY3031207 dosing. Conclusions This study emphasized the importance of careful safety monitoring and serious adverse events management in phase I trials. Metabolic activation of the imidazole ring may be involved in the development of hepatotoxicity of LY3031207.