Mechanism of action

Abemaciclib is a potent and selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), and most active against Cyclin D1/CDK4 in enzymatic assays. Abemaciclib prevents retinoblastoma protein (Rb) phosphorylation, blocking cell cycle progression from the G1 to the S-phase of cell division, leading to suppression of tumour growth. In oestrogen receptor-positive breast cancer cell lines, sustained target inhibition with abemaciclib prevented rebound of Rb phosphorylation resulting in cell senescence and apoptosis. In vitro, Rb-negative and Rb-depleted cancer cell lines are generally less sensitive to abemaciclib. In breast cancer xenograft models, abemaciclib dosed daily without interruption at clinically relevant concentrations alone or in combination with anti-oestrogens resulted in reduction of tumour size.

Pharmacodynamic properties

Pharmacodynamic effects

In cancer patients, abemaciclib inhibits CDK4 and CDK6 as indicated by inhibition of phosphorylation of Rb and topoisomerase II alpha, which results in cell cycle inhibition upstream of the G1 restriction point.

Cardiac electrophysiology

The effect of abemaciclib on the QTcF interval was evaluated in 144 patients with advanced cancer. No large change (that is, >20 ms) in the QTcF interval was detected at the mean observed maximal steady state abemaciclib concentration following a therapeutic dosing schedule.

In an exposure-response analysis in healthy subjects at exposures comparable to a 200 mg twice-daily dose, abemaciclib did not prolong the QTcF interval to any clinically relevant extent.

Pharmacokinetic properties


Abemaciclib absorption is slow, with a Tmax of 8 hours and a mean absolute bioavailability of approximately 45%. In the therapeutic dose range of 50-200 mg, the increase in plasma exposure (AUC) and Cmax is approximately dose proportional. Steady state was achieved within 5 days following repeated twice daily dosing, and abemaciclib accumulated with a geometric mean accumulation ratio of 3.7 (58% CV) and 5.8 (65% CV) based on Cmax and AUC, respectively. A high-fat meal increased combined AUC of abemaciclib and its active metabolites by 9% and increased Cmax by 26%. These changes were not considered to be clinically relevant. Therefore, abemaciclib can be taken with or without food.


Abemaciclib is highly bound to plasma proteins in humans (mean bound fraction approximately 96% to 98%). The geometric mean systemic volume of distribution is approximately 750 L (69% CV), indicating distribution of abemaciclib into tissues.

Concentrations of abemaciclib and its active metabolites in cerebrospinal fluid are comparable to unbound plasma concentrations.


Hepatic metabolism is the main route of clearance for abemaciclib. Abemaciclib is metabolised to several metabolites primarily by cytochrome P450 (CYP) 3A4. The primary biotransformation is hydroxylation to a metabolite that circulates with an AUC that is 77% of parent drug. In addition, N-desethyl and N-desethylhydroxy metabolites circulate at AUCs that are 39% and 15% of parent drug. These circulating metabolites are active with similar potency to abemaciclib.


The geometric mean hepatic clearance (CL) of abemaciclib was 21.8 L/h (39.8% CV), and the mean plasma elimination half-life for abemaciclib in patients was 24.8 hours (52.1% CV). After a single oral dose of [14C]-abemaciclib, approximately 81% of the dose was excreted in faeces and 3.4% excreted in urine. The majority of the dose eliminated in faeces was metabolites.

Special populations

Age, gender, and body weight

Age, gender, and body weight had no effect on the exposure of abemaciclib in a population pharmacokinetic analysis in patients with cancer (135 males and 859 females; age range 24-91 years; and body weight range 36-175 kg).

Hepatic impairment

Abemaciclib is metabolised in the liver. Mild (Child Pugh A) and moderate (Child Pugh B) hepatic impairment had no effect on the exposure of abemaciclib. In subjects with severe hepatic impairment (Child Pugh C), the AUC0-∞ of abemaciclib and potency adjusted unbound abemaciclib plus its active metabolites increased 2.1-fold and 2.4-fold, respectively. The half-life of abemaciclib increased from 24 to 55 hours.

Renal impairment

Renal clearance of abemaciclib and its metabolites is minor. Mild and moderate renal impairment had no effect on the exposure of abemaciclib. There are no data in patients with severe renal impairment, end stage renal disease or in patients on dialysis.

Preclinical safety data

The primary target organ findings of potential relevance to humans included gastrointestinal and haematolymphopoietic organ effects in rats and dogs in studies up to 13 weeks duration. Effects in lung and skeletal muscle occurred only in rats at exposure levels approximately 2-fold higher than human exposure levels and effects in kidney occurred only in rats at exposure levels approximately 6-fold higher than human exposure levels. Complete or partial recovery was observed for all target organs at the end of the 28-day recovery period.


Abemaciclib was not mutagenic in a bacterial reverse mutation (Ames) assay, was not clastogenic in an in vitro chromosomal aberration assay in human peripheral blood lymphocytes, and was not clastogenic in an in vivo rat bone marrow micronucleus assay.


Specific animal studies to test abemaciclib for carcinogenic potential have not been performed.

Developmental toxicity

Abemaciclib was teratogenic and caused decreased foetal weight at maternal exposures similar to the recommended human dose.

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