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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 randomised 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 emphasised 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.
|Authors:||Yan Jin, Arie Regev, Jeanelle Kam, Krista Phipps, Claire Smith, Judith Henck, Kristina Campanale, Leijun Hu, D. Greg Hall, Xiao Yan Yang, Masako Nakano, Terry Ann McNearney, Jack Uetrecht, William Landschulz|
|Journal:||British Journal of Clinical Pharmacology|
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