Abemaciclib

Abemaciclib is a selective, ATP-competitive inhibitor of cyclin-dependent kinases 4 and 6, with its greatest activity against the cyclin D1–CDK4 complex. In hormone receptor-positive breast cancer, oestrogen signalling drives cyclin D expression, so these tumours depend heavily on CDK4/6 to pass the G1 restriction point. Blocking the kinases stops the cell cycle before DNA synthesis begins.

Mechanism of Action

• Cell-cycle control: CDK4 and CDK6 bind D-type cyclins and phosphorylate the retinoblastoma protein (Rb). Phosphorylated Rb releases E2F transcription factors, which switch on the genes needed for the transition from G1 to S phase.
• Inhibition: abemaciclib prevents Rb phosphorylation, so E2F stays bound and the cell is held in G1. In patients, reduced phosphorylation of Rb and of topoisomerase II alpha has been shown at therapeutic exposure.
• Sustained effect: in oestrogen receptor-positive breast cancer cell lines, continuous target inhibition prevented the rebound of Rb phosphorylation and led to cellular senescence and apoptosis. This is why abemaciclib is dosed continuously rather than in cycles.
• Dependence on Rb: Rb-negative or Rb-depleted cancer cells are generally less sensitive in vitro.
• Active metabolites: the main circulating metabolites (N-desethylabemaciclib, hydroxyabemaciclib and hydroxy-N-desethylabemaciclib) are about as potent as the parent drug and contribute to its activity.
• Cardiac electrophysiology: no clinically relevant QTc prolongation was found at steady-state exposures.

Pharmacokinetics

• Absorption: slow; peak plasma levels about 8 hours after a dose, with an absolute bioavailability of about 45%. Exposure rises roughly in proportion to dose between 50 and 200 mg. Steady state is reached within 5 days of twice-daily dosing. A high-fat meal has no clinically relevant effect.
• Distribution: about 96–98% bound to plasma proteins; volume of distribution around 750 L, indicating extensive tissue distribution. Concentrations in cerebrospinal fluid are comparable to unbound plasma concentrations.
• Metabolism: mainly hepatic, through CYP3A4, to several active metabolites.
• Elimination: mean elimination half-life about 25 hours; hepatic clearance about 22 L/h. After a radiolabelled dose, about 81% was recovered in faeces (mostly as metabolites) and about 3% in urine.
• Special populations: age, sex and body weight do not affect exposure. Mild and moderate hepatic impairment do not change exposure; severe hepatic impairment increases it.

Abemaciclib is always used in combination with endocrine therapy.

• Early breast cancer (adjuvant treatment): adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive early breast cancer at high risk of recurrence. In pre- or perimenopausal women, an aromatase inhibitor should be combined with a luteinising hormone-releasing hormone (LHRH) agonist.
• Advanced or metastatic breast cancer: women with HR-positive, HER2-negative locally advanced or metastatic breast cancer, in combination with an aromatase inhibitor or fulvestrant as initial endocrine-based therapy, or in women who have received prior endocrine therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with an LHRH agonist.

• Hypersensitivity to abemaciclib or to any of the excipients.

The most common side effects are diarrhoea, infections, neutropenia, leukopenia, anaemia, fatigue, nausea, vomiting, alopecia and decreased appetite. Apart from neutropenia, leukopenia and diarrhoea, severe (grade 3 or higher) events occurred in fewer than 5% of patients.

Very common (≥1/10): infections, neutropenia, leukopenia, anaemia, thrombocytopenia, lymphopenia, decreased appetite, headache, dysgeusia, dizziness, diarrhoea, vomiting, nausea, stomatitis, alopecia, pruritus, rash, pyrexia, fatigue, increased alanine and aspartate aminotransferase.

Common (≥1/100 to <1/10): increased lacrimation, venous thromboembolism (including deep vein thrombosis and pulmonary embolism), interstitial lung disease or pneumonitis, dyspepsia, nail disorder, dry skin, muscular weakness.

Uncommon (≥1/1,000 to <1/100): febrile neutropenia, photopsia, keratitis.

Rare (≥1/10,000 to <1/1,000): erythema multiforme.

Some reactions are more frequent in the metastatic than in the early setting, and the reverse. Diarrhoea usually starts within the first week or so of treatment and is most frequent in the first month.

Abemaciclib is metabolised mainly by CYP3A4, so strong modulators of this enzyme change its exposure substantially.

• Strong CYP3A4 inhibitors (clarithromycin, itraconazole, ketoconazole, lopinavir/ritonavir, posaconazole, voriconazole): clarithromycin raised abemaciclib exposure 3.4-fold. Avoid the combination; if it cannot be avoided, reduce the abemaciclib dose (see Administration and Dosage).
• Moderate or weak CYP3A4 inhibitors: no dose change, but monitor closely for toxicity.
• Strong CYP3A4 inducers (carbamazepine, phenytoin, rifampicin, St John’s wort): rifampicin cut abemaciclib exposure by 95%. Avoid the combination because of the risk of lost efficacy.
• Transporter substrates: abemaciclib and its active metabolites inhibit the renal transporters OCT2, MATE1 and MATE2-K, so interactions with substrates such as dofetilide may occur. The 37% rise in metformin exposure seen in a study was not clinically relevant. Tubular secretion of creatinine is also blocked: serum creatinine rises in almost all patients without any fall in glomerular filtration, and returns to baseline after treatment stops.
• Grapefruit: grapefruit and grapefruit juice inhibit CYP3A4 and must be avoided.

Treatment should be started and supervised by a physician experienced in anti-cancer therapy. The tablets are swallowed whole, with or without food, at about the same times each day; they must not be chewed, crushed or split.

Recommended Dose

• 150 mg twice daily, together with endocrine therapy (dosed according to its own SmPC).
• Early breast cancer: continuously for 2 years, or until disease recurrence or unacceptable toxicity.
• Advanced or metastatic breast cancer: continuously for as long as the patient benefits, or until unacceptable toxicity.

Dose Adjustments for Side Effects

• First reduction to 100 mg twice daily; second reduction to 50 mg twice daily.
• Blood counts and liver aminotransferases are checked before starting, every 2 weeks for the first 2 months, monthly for the next 2 months, and then as clinically indicated. Recommended thresholds before starting are an absolute neutrophil count of at least 1,500/mm³, platelets of at least 100,000/mm³ and haemoglobin of at least 8 g/dL.
• Grade 3 or 4 neutropenia, persistent grade 2 or higher diarrhoea, raised aminotransferases and interstitial lung disease are managed by interrupting the dose and resuming at a lower dose. Grade 3 or 4 pneumonitis, or aminotransferases above 3 times the upper limit with bilirubin above 2 times the upper limit, requires permanent discontinuation.

With Strong CYP3A4 Inhibitors

If a strong inhibitor cannot be avoided, reduce the dose to 100 mg twice daily (from 100 mg to 50 mg twice daily if already reduced). When the inhibitor is stopped, return to the previous dose after 3 to 5 of its half-lives.

Special Populations

• Elderly: no dose adjustment.
• Renal impairment: no adjustment in mild or moderate impairment; no data in severe impairment, end-stage renal disease or dialysis, so use with caution and close monitoring.
• Hepatic impairment: no adjustment in mild or moderate (Child-Pugh A or B) impairment; in severe (Child-Pugh C) impairment, reduce the dosing frequency to once daily.
• Children and adolescents: safety and efficacy below 18 years have not been established.

Missed or Vomited Dose

Do not take an extra dose. Take the next dose at its usual time.

Diarrhoea

Diarrhoea is the most common side effect. Patients should start an antidiarrhoeal medicine such as loperamide at the first loose stool, drink more fluids and tell their doctor. Diarrhoea of grade 2 or higher may need a dose interruption or reduction.

Neutropenia and Infections

Neutropenia is common and infections occur more often than with endocrine therapy alone; fatal neutropenic sepsis has been reported in fewer than 1% of patients with metastatic disease. Patients should report any fever promptly.

Thromboembolism

Venous thromboembolic events have been reported, and an increased risk of serious arterial events (ischaemic stroke, myocardial infarction) has been seen in metastatic breast cancer studies. Watch for signs of deep vein thrombosis and pulmonary embolism.

Liver Function and Lung Disease

Monitor aminotransferases as described above. Interstitial lung disease or pneumonitis can occur; investigate new respiratory symptoms and stop permanently for grade 3 or 4 events.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential must use highly effective contraception during treatment and for at least 3 weeks after the last dose.
• Pregnancy: not recommended; animal studies showed reproductive toxicity.
• Breastfeeding: patients should not breastfeed during treatment.
• Fertility: findings in animals suggest that male fertility may be impaired.

Lactose

The tablets contain lactose. Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them.

Effect on Driving

Abemaciclib has a minor influence on the ability to drive. Patients who feel tired or dizzy should take care.

Verzenios tablets need no special storage conditions. Keep them in the original blister pack, out of the sight and reach of children.

3 years from manufacture. Do not use after the expiry date on the pack.

Prescription only (Rx), on the prescription of a specialist experienced in cancer treatment. Abemaciclib is taken at home, so it is supplied to the patient or to the treating clinic on prescription.