아베마시클립

Pharmaceuticals -> Antineoplastic and immunomodulating agents -> Antineoplastic agents

Pharmaceuticals -> Listed in ZINC15

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

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

This chemical does not meet GHS hazard criteria for 20% (1 of 5) of reports.

Danger

H360 (60%): 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 5 reports by companies from 4 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 up to one-half of patients and discontinuation in 9%. In preregistration clinical trials, ALT elevations occurred in 31% to 41% of abemaciclib treated subjects which were above 5 times the ULN in 3% to 5%. In one study, several recipients developed clinically apparent liver injury with jaundice and one recipient died of hepatic failure, but these outcomes were considered to be unrelated to abemaciclib therapy. Thus, there were no cases of clinically apparent liver injury that could be attributed to abemaciclib therapy during prelicensure studies. Since the approval and more widescale use of abemaciclib, there have been several published reports of its hepatotoxicity. Most reports of liver injury from abemaciclib are marked by prominent serum aminotransferase elevations (5 to 20 times ULN) with minimal bilirubin elevations and few symptoms arising 1 to 3 months after initiation of therapy, and with rapid resolution upon stopping abemaciclib. In several cases there was rapid recurrence on restarting, but subsequent tolerance without serum enzyme elevations upon switching to other cyclin-dependent kinase inhibitors such as palbociclib or ribociclib. Isolated cases of liver injury with jaundice and severe outcomes including fatalities attributed to abemaciclib have been reported but are rare.

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

According to in vitro models using animal brain tissues, the protein binding of abemaciclib is approximately 95-98%. While abemaciclib demonstrated *in vitro* binding to serum albumin, alpha-1-acid glycoprotein and other human plasma proteins in a concentration-depedent manner, its major metabolites are also shown to bind to plasms proteins as well. The approximate bound fractions of M2, M18 and M20 are 93.4%, 96.8% and 97.8%, respectively.

In combination with fulvestrant, the progression-free survival for patients with HR-positive, HER2-negative breast cancer was 16.4 months compared to 9.3 months for patients taking a placebo with fulvestrant. As a monotherapy, 19.7% of patients taking abemaciclib achieved complete or partial shrinkage of their tumors for a median 8.6 months after treatment. Abemaciclib induces cell cycle arrest and exerts an antitumor activity in human tumor xenograft models. In patient investigations and a healthy volunteer study, abemaciclib is not shown to induce any clinically significant changes in the QTc interval.

Regulation of cell cycle is crucial in maintaining proper cell growth; dysregulated cell cycle signalling pathway is a key component in inducing hyperproliferation of cells and tumor formation in various cancers. G1 to S phase cell cycle progression, or transition through the G1 restriction point (R), is promoted by the retinoblastoma tumor suppressor protein (Rb)-mediated pathway. Activation of Rb-mediated pathway requires the interaction of Cyclin-dependent kinases (CDK) 4 and 6 with D-type cyclins, which drives the formation of active CDK4/CDK6 and subsequent phosphorylation of Rb. Rb is a tumor suppressant protein that inhibits proliferation through binding to and suppressing the activity of the E2F family of transcription factors. However, phosphorylation of Rb relieves suppression of E2F to allow expression of genes required for passage through the restriction point. This leads to increased expression of downstream signalling molecules and activity of protein kinases that promote the cell cycle progression and initiation of DNA replication. Phosphorylation of Rb and other proteins by CDK4/6 additionally leads to transcription of genes involved in cell cycle-independent activities including signal transduction, DNA repair transcriptional control, and mRNA processing. Abemaciclib selectively inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells. Unlike other CDK inhibitors such as [DB09073] and [DB11730], abemaciclib exhibits greater selectivity for CDK4 compared to CDK6.