Abemaciclib is a unique cyclin-dependent kinase inhibitor that is used in combination with an antiestrogen in the treatment of postmenopausal women with metastatic breast cancer. Abemaciclib is associated with a moderate rate of serum aminotransferase elevations during therapy and is suspected to be a rare cause of clinically apparent liver injury.
Abemaciclib (a bem" a sye' klib) is an orally available, small molecule inhibitor of cyclin-dependent kinases (CDK) 4 and 6 that is used in combination with fulvestrant in the therapy of postmenopausal women with metastatic breast cancer that is positive for the estrogen receptor (ER) but negative for human epidermal growth factor receptor 2 (HER2). The cyclin kinases 4 and 6 regulate the cellular transition from the G1 to the S phase of the cell cycle acting through the retinoblastoma protein (Rb) pathway. Inhibition of this transition blocks the progression of the cell cycle and results in growth arrest in rapidly dividing cells. Components of this pathway are often mutated or overexpressed in cancer cells. In several clinical trials, the addition of abemaciclib to fulvestrant (a steroidal antiestrogen) therapy of metastatic breast cancer (ER+, HER2-) in postmenopausal women was associated with a prolongation of disease-free survival. As monotherapy, abemaciclib was also found effective in adult patients with refractory, metastatic HR+, HER2- breast cancer. Abemaciclib received accelerated approval for these indications in the United States in 2017, the third CDK 4/6 inhibitor approved as therapy of breast cancer, following palbociclib (Ibrance: 2015) and ribociclib (Kisqali: 2017). Abemaciclib is also under investigation as therapy of several solid tumors and lymphomas, but the initial indications were limited to metastatic ER+, HER2- breast cancer in postmenopausal women. Abemaciclib is available in tablets of 50, 100, 150 and 200 mg under the brand name Verzenio, and the initial recommended dose is 150 mg twice daily in combination with fulvestrant or 200 mg twice daily if used alone, continued indefinitely or until there is disease progression or unacceptable toxicity. Common side effects include diarrhea, neutropenia, fatigue, nausea, anorexia, thrombocytopenia, headache and back pain. Less common but potentially severe adverse reactions include venous thromboembolism, severe neutropenia, fever, neutropenic sepsis, infections and embryo-fetal toxicity.
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 no published reports of its hepatotoxicity. Nevertheless, the high rate of serum enzyme elevations during therapy and the similarity of abemaciclib to ribociclib and palbociclib makes it an agent that should be suspected of causing rare instances of clinically significant liver injury.
Mechanism of Injury
The causes of serum enzyme elevations and liver injury from abemaciclib therapy are not known. Abemaciclib is extensively metabolized in the liver largely through the CYP 3A4 pathway and liver injury might be caused by production of a toxic or immunogenic intermediate. On the other hand, inhibition of cyclin-dependent kinases 4 and 6 may also affect hepatocytes and have direct toxicity. Because it is a substrate for CYP 3A4, abemaciclib is susceptible to drug-drug interactions with agents that inhibit or induce this specific hepatic microsomal activity.
Outcome and Management
The product label for abemaciclib recommends prospective monitoring of liver tests during therapy, with values obtained before starting, at 2-week intervals during the first two cycles and at the beginning of the ensuing 4 cycles, and "as clinically indicated" thereafter. The product label also provides careful recommendations for dose interruption, reduction or discontinuation based upon toxicities (neutropenia, liver injury, QTc prolongation), with dose interruption until recovery for aminotransferase elevations above 3 times ULN, interruption until normal and subsequent dose reduction if above 5 times ULN, and permanent discontinuation if above 20 times ULN or in the presence of ALT elevations and jaundice. There is no information regarding cross reactivity in risk for adverse events, hypersensitivity or hepatic injury between abemaciclib and ribociclib or palbociclib or other cyclin-dependent kinase inhibitors.
Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors
Other Cyclin-Dependent Kinase Inhibitor Drugs: Palbociclib, Ribociclib
Abemaciclib – Verzenio®
|DRUG||CAS REGISTRY NO.||MOLECULAR FORMULA||STRUCTURE|
Top of page