Ribociclib (Mechanism of Action)

In this article, we will discuss Ribociclib (Mechanism of Action). So, let’s get started.

Mechanism of Action

Ribociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. These kinases are activated upon binding to D￾cyclins and play a crucial role in signaling pathways which lead to cell cycle progression and cellular proliferation. The cyclin D-CDK4/6 complex regulates cell cycle progression through phosphorylation of the retinoblastoma protein (pRb). In vitro, ribociclib decreased pRb phosphorylation leading to arrest in the G1 phase of the cell cycle and reduced cell proliferation in breast cancer cell lines. In vivo, treatment with single agent ribociclib in a rat xenograft model with human tumor cells led to decreased tumor volumes, which correlated with inhibition of pRb phosphorylation. In studies using patient-derived estrogen receptor positive breast cancer xenograft models, combination of ribociclib and antiestrogen (e.g. letrozole) resulted in increased tumor growth inhibition compared to each drug alone.

Pharmacodynamics

Cardiac Electrophysiology

Serial, triplicate ECGs were collected following a single dose and at steady-state to evaluate the effect of ribociclib on the QTc interval in patients with advanced cancer. A pharmacokinetic-pharmacodynamic analysis included a total of 267 patients treated with ribociclib at doses ranging from 50 to 1200 mg, including 193 patients treated with ribociclib 600 mg. The analysis suggested that ribociclib causes concentration-dependent increases in the QTc interval. The estimated mean change from baseline in QTcF was 22.9 ms (90% CI: 21.6, 24.1) at the mean observed Cmax at steady-state following administration at the recommended 600 mg dose.

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