No QTc prolongation with CDK 4/6 inhibitor FCN-437c: results of a concentration-QTc analysis from a dedicated study in adult healthy subjects

• Published in: Frontiers in pharmacology Vol. 15; p. 1433663
• Main Authors: Zhao, Lin, Sun, Yi, Yang, Xiaoran, Tian, Ling, Li, Lize, Wang, Fangfang, Niu, Xiaoye, Diao, Lei, Li, Haiyan
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 12.08.2024
• Subjects: C-QT; CDK4/6 cell cycle inhibitors; concentration-QTC modeling; FCN-437c; Pharmacology; QT interval; QT interval; C-QT; concentration-QTC modeling; CDK4/6 cell cycle inhibitors; FCN-437c
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2024.1433663

Cardiotoxicity and QT interval prolongation have been a common cause of withdrawal of drugs from the market. FCN-437c is an oral, second-generation, potent, and selective CDK4/6 inhibitor for the treatment of patients with HR+/HER2- metastatic breast cancer. A single-center, double-blind, randomized, and placebo-controlled clinical study in healthy subjects was conducted to investigate the QTc prolongation potential of FCN-437c utilizing Concentration-QTc (C-QTc) modeling approach. FCN-437c was administered at doses of 300, and 400 mg with single oral administration, along with placebo, in 18 healthy subjects. Electrocardiograms (ECGs) through 24 h holter monitor and blood samples were collected. The C max of 400 mg single dose in healthy subjects is similar to that from therapeutic dose 200 mg QD at steady state in patients with cancer. The 90% CI upper limit of ΔΔQTcF at the C max geometric mean in both dose groups were <10 ms. It is concluded that FCN-437c has low risk of prolonging the QT interval at therapeutic dose.