Singapore Drugs Database

Indication

* Indicated in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. * Inidicated as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.

Mechanism of Action

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 [A27281, A27282]. Rb is a tumor suppressant protein that inhibits proliferation through binding to and suppressing the activity of the E2F family of transcription factors [A27281]. However, phosphorylation of Rb relieves suppression of E2F to allow expression of genes required for passage through the restriction point [A27281]. 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 [A27281]. 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 [A27281]. Unlike other CDK inhibitors such as [DB09073] and [DB11730], abemaciclib exhibits greater selectivity for CDK4 compared to CDK6 [A27282].

Pharmacokinetics

Absorption

The plasma concentration of the drug increases in a dose-proportional manner. Following a single oral dose administration of 200 mg abemaciclib, the mean peak plasma concentration (Cmax) of 158 ng/mL is reached after 6 hours. The median time to reach maximum plasma concentration (Tmax) ranges from 4-6 hours following an oral administration of abemaciclib over a range of 50–275 mg [A27282], but may range up to 24 hours [FDA Label]. The absolute bioavailability of the drug is reported to be 45% [FDA Label].

Distribution

The geometric mean systemic volume of distribution is approximately 690.3 L (49% CV) [FDA Label].

Metabolism

Abemaciclib mainly undergoes hepatic metabolism mediated by CYP3A4. The major metabolite formed is N-desethylabemaciclib (M2), while other metabolites hydroxyabemaciclib (M20), hydroxy-N-desethylabemaciclib (M18), and an oxidative metabolite (M1) are also formed. M2, M18, and M20 are equipotent to abemaciclib and their AUCs accounted for 25%, 13%, and 26% of the total circulating analytes in plasma, respectively [FDA Label].

Elimination

Clearance

The geometric mean hepatic clearance (CL) of abemaciclib in patients was 26.0 L/h (51% CV) [FDA Label].

Toxicity

According to the bacterial reverse mutation (Ames) assay, abemaciclib and its active metbolites M2 and M20 did not display mutagenic properties. Abemaciclib was not clastogenic *in vitro* rat bone marrow micronucleus assay. Repeat-dose toxicity studies were performed to assess the effects of abemaciclib in testis, epididymis, prostate, and seminal vesicle at doses ≥10 mg/kg/day in rats and ≥0.3 mg/kg/day in dogs which exceed the recommeded therapeutic doses in humans. The findings included decreased organ weights, intratubular cellular debris, hypospermia, tubular distillation, atrophy and degeneration or necrosis [FDA Label].

Active Ingredient/Synonyms

LY2835219 | Abemaciclib |