Ribociclib

Breast Feeding; Lactation; Milk, Human; Antineoplastic Agents; Enzyme Inhibitors; Protein Kinase Inhibitors; Signal Transduction Inhibitors

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

This chemical does not meet GHS hazard criteria for 14.3% (1 of 7) of reports.

Danger

H360 (14.3%): May damage fertility or the unborn child [Danger Reproductive toxicity]

P203, P260, P273, P280, P318, P319, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 7 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

In the large clinical trials, adverse events were common and led to dose reductions in 45% of patients and discontinuation in 7%. In preregistration clinical trials, ALT elevations occurred in 46% of ribociclib vs 36% of control subjects and elevations above 5 times the ULN in 10% vs 1%. In one study, 1% of recipients developed clinically apparent liver injury with jaundice, but all recovered. The liver injury arose after 3 to 5 cycles and presented with asymptomatic elevations in serum ALT followed by symptoms and jaundice. Immunoallergic and autoimmune features were not present, although liver histology sometimes showed autoimmune hepatitis-like features. Recovery was slow (3 to 5 months), but ultimately complete. Restarting ribociclib resulted in more rapid and severe recurrence. Thus, experience with ribociclib is limited, but it appears to be capable of causing significant liver injury.

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

Ribociclib causes concentration-dependent changes in QTcF interval. It should be used with caution in patients undergoing treatment with other QTc-prolonging agents, or in patients pre-disposed to the development of Torsades de Pointes (TdP) (e.g. those with long QT syndrome, LQTS).

Ribociclib is a selective inhibitor of cyclin-dependent kinases (CDK) 4 and 6. These kinases are activated upon binding to D-cyclins and are downstream of 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). Ribociclib has been shown _in vitro_ to decrease pRb phosphorylation, resulting in arrest in the G1 phase of the cell cycle and reduced proliferation in breast cancer-derived models. The inhibition of pRb phosphorylation is correlated with a decrease in the volume of tumor cells.

At steady-state in patients with advanced cancer, the mean plasma effective half-life of ribociclib was 32 hours. In healthy adults receiving the 600 mg dose, the mean apparent plasma terminal half-life of ribociclib ranged from 29.7 to 54.7 hours and mean apparent oral clearance of ribociclib ranged from 39.9 to 77.5 L/h.

Ribociclib undergoes extensive hepatic metabolism, primarily via oxidative reactions mediated by CYP3A4. Major circulating metabolites following oral administration include metabolite M13 (CCI284, N-hydroxylation), M4 (LEQ803, N-demethylation), and M1 (secondary glucuronide), each representing an estimated 9%, 9%, and 8% of total radioactivity, and 22%, 20%, and 18% of ribociclib exposure. Parent drug is the major circulating entity in plasma, accounting for 44% of total exposure.

TK8ERE8P56

RIBOCICLIB

Established Pharmacologic Class [EPC] - Kinase Inhibitor

Mechanisms of Action [MoA] - Kinase Inhibitors

Mechanisms of Action [MoA] - Cytochrome P450 3A Inhibitors

Ribociclib is a Kinase Inhibitor. The mechanism of action of ribociclib is as a Kinase Inhibitor and Cytochrome P450 3A Inhibitor.

The mean absolute bioavailability of ribociclib after a single oral dose of 600 mg was 65.8%. Following repeated 600 mg once daily administration, steady-state was generally achieved after 8 days and the mean steady-state Cmax and AUC were 1820 ng/mL and 23800 ng*h/mL, respectively. The Tmax of ribociclib at steady-state generally occurs between 1 and 4 hours following administration.

Unchanged parent drug accounts for only 17% and 12% of the administered dose excreted in feces and urine, respectively. Metabolite M4 (LEQ803) represented approximately 14% and 4% of the administered dose in feces and urine, respectively.

At steady-state, the apparent volume of distribution of ribociclib was 1090 L.

At steady-state in patients with advanced cancer administered receiving the 600 mg dose, the mean apparent oral clearance of ribociclib was 25.5 L/h. At steady-state in patients with early breast cancer administered receiving the 400 mg dose, the mean apparent oral clearance of ribociclib was 38.4 L/h.