Safety, Pharmacokinetics, and Pharmacodynamics of CC‐90001 (BMS‐986360), a c‐Jun N‐terminal Kinase Inhibitor, in Phase 1 Studies in Healthy Participants

Autor: Ying, Ye, Allison, Gaudy, Michael, Thomas, Josephine, Reyes, Barbara, Burkhardt, Gerald, Horan, Liangang, Liu, Jian, Chen, Atalanta, Ghosh, Leonidas N, Carayannopoulos, Daniel A, Tatosian, Maria, Palmisano
Rok vydání: 2022
Předmět:
Zdroj: Clinical Pharmacology in Drug Development. 11:1394-1404
ISSN: 2160-7648
2160-763X
DOI: 10.1002/cpdd.1178
Popis: CC-90001 selectively inhibits c-Jun N-terminal kinase (JNK), a stress-activated protein implicated in fibrosis. In 3 phase 1 trials evaluating CC-90001 pharmacokinetics, pharmacodynamics, and safety, healthy adults (N = 184) received oral CC-90001 in a single dose (10-720 mg) or multiple doses (30-480 mg once daily for 7-18 days) or placebo. CC-90001 was rapidly absorbed (median time to maximum concentration, 1-4 hours) and eliminated with a mean terminal elimination half-life of 12-28 hours. Steady state was reached on day 5, with a mean accumulation ratio of 1.5- to 2-fold following daily dosing. Exposure was similar in fed versus fasted participants and in Japanese versus non-Japanese participants. CC-90001 demonstrated dose- and exposure-dependent inhibition of JNK as determined by histopathological analysis of c-Jun phosphorylation in ultraviolet-irradiated skin. The most common treatment-emergent adverse events were nausea and headache; all were mild or moderate in intensity. Based on exposure-response analysis using high-quality electrocardiogram data, no clinically relevant QT prolongation liability for CC-90001 was observed. Overall, single- and multiple-dose CC-90001 were generally safe and well tolerated at the tested doses and demonstrated JNK pathway engagement. These results support further clinical evaluation of CC-90001.
Databáze: OpenAIRE
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