Abemaciclib

Last updated

Abemaciclib
Abemaciclib.svg
Clinical data
Pronunciation /əˌbɛməˈsaɪklɪb/
ə-BEM-ə-SY-klib
Trade names Verzenio, Verzenios, Ramiven, others
Other namesLY2835219
AHFS/Drugs.com Monograph
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 45%
Protein binding 96.3%
Elimination half-life 18.3 hrs
Excretion 81% via feces, 3% via urine
Identifiers
  • N-[5-[(4-Ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl]-2-pyrimidinamine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.233.787 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C27H32F2N8
Molar mass 506.606 g·mol−1
3D model (JSmol)
  • CCN1CCN(CC1)Cc2ccc(nc2)Nc3ncc(c(n3)c4cc5c(c(c4)F)nc(n5C(C)C)C)F
  • InChI=1S/C27H32F2N8/c1-5-35-8-10-36(11-9-35)16-19-6-7-24(30-14-19)33-27-31-15-22(29)25(34-27)20-12-21(28)26-23(13-20)37(17(2)3)18(4)32-26/h6-7,12-15,17H,5,8-11,16H2,1-4H3,(H,30,31,33,34)
  • Key:UZWDCWONPYILKI-UHFFFAOYSA-N

Abemaciclib, sold under the brand name Verzenio among others, is a medication for the treatment of advanced or metastatic breast cancers. It was developed by Eli Lilly and it acts as a CDK inhibitor selective for CDK4 and CDK6. [4]

Contents

It was designated as a breakthrough therapy for breast cancer by the US Food and Drug Administration (FDA) in October 2015. [5]

In September 2017, it was approved for use in the United States by the FDA for the treatment of certain breast cancers. [6]

Medical uses

Since September 2017, abemaciclib has been approved in the US for "adults who have hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer that has progressed after taking therapy that alters a patient's hormones". [6]

In studies that compared fulvestrant plus abemaciclib to fulvestrant plus placebo in breast cancer patients, progression-free survival under abemaciclib therapy was 16.4 months on average, as compared to 9.3 months under the placebo arm.

Side effects

Side effects that occurred in 20% or more of patients in studies were diarrhea, nausea and vomiting, leukopenia (low white blood cell count) including neutropenia, anemia (low red blood cell count), thrombocytopenia (low platelet count), stomach pain, infections, fatigue, decreased appetite, and headache. [7] [8]

Interactions

As abemaciclib is mainly metabolized by the liver enzyme CYP3A4, inhibitors of this enzyme (such as ketoconazole) are expected to increase its blood plasma concentrations. Conversely, CYP3A4 inducers lower plasma concentrations of abemaciclib, as has been shown in a study with rifampicin. [8]

Pharmacology

Mechanism of action

Like the related drugs palbociclib and ribociclib, abemaciclib inhibits the enzymes cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6). [8] These enzymes are responsible for phosphorylating and thus deactivating the retinoblastoma protein, which plays a role in cell cycle progression from the G1 (first gap) to the S (synthesis) phase. [9] Blocking this pathway prevents cells from progressing to the S phase, thereby inducing apoptosis (cell death). [8] In vitro analysis using cancer cell lines, it is reported that abemaciclib induces non-apoptotic cell death characterized by formation of cytoplasmic vacuoles derived from lysosomes. This result suggests that there may be a mechanism of action other than inhibition of a cyclin-dependent kinase. [10]

Pharmacokinetics

N-desethylabemaciclib (M2), the main metabolite Abemaciclib metabolite.svg
N-desethylabemaciclib (M2), the main metabolite

After oral intake, absolute bioavailability is 45%. Highest blood plasma concentrations are reached after 8 hours on average (range: 4.1–24.0 hours). When in the circulation, 96.3% of abemaciclib is bound to plasma proteins. The substance is mainly metabolized by the liver enzyme CYP3A4 to N-desethylabemaciclib (M2), and to a lesser extent to hydroxy derivatives (M18, M20) and another oxidative metabolite (M1). These metabolites have high plasma protein binding rates similar to the parent substance. [8]

Abemaciclib is excreted mainly via the feces (81%) and to a small extent via the urine (3%). Its elimination half-life is 18.3 hours on average. [8]

Clinical trials

Successful trials against pre-treated metastatic breast cancer were announced for Phase I in May 2014, [11] Phase II in December 2014, [12] and Phase III in February 2017. [13] Abemaciclib was approved by the FDA in September 2017 either in combination with fulvestrant or as a monotherapy for women with HR+, HER2- advanced or metastatic breast cancer that had progressed while receiving endocrine therapy. [14] Abemaciclib was approved for the adjuvant treatment of HR+, HER2-, node-positive adjuvant breast cancer at high risk of recurrence in March 2023. [15] [16]

As of 2023, abemaciclib was involved in two Phase III clinical trials:

Abemaciclib is in Phase I and II clinical trials for head and neck squamous cell carcinoma, [19] biliary tract carcinoma, [20] brain tumors, [21] [22] [23] neurofibromatosis, [24] Kaposi sarcoma, [25] metastatic renal cell carcinoma, [26] and Mantle Cell lymphoma. [27]

Chemistry

Abemaciclib may be synthesized in a four step manner using a Suzuki coupling, followed by a Buchwald–Hartwig amination with the final step being a reductive amination using the Leuckart reaction. [28]

Related Research Articles

<span class="mw-page-title-main">Cyclin-dependent kinase</span> Class of enzymes

Cyclin-dependent kinases (CDKs) are a predominant group of serine/threonine protein kinases involved in the regulation of the cell cycle and its progression, ensuring the integrity and functionality of cellular machinery. These regulatory enzymes play a crucial role in the regulation of eukaryotic cell cycle and transcription, as well as DNA repair, metabolism, and epigenetic regulation, in response to several extracellular and intracellular signals. They are present in all known eukaryotes, and their regulatory function in the cell cycle has been evolutionarily conserved. The catalytic activities of CDKs are regulated by interactions with CDK inhibitors (CKIs) and regulatory subunits known as cyclins. Cyclins have no enzymatic activity themselves, but they become active once they bind to CDKs. Without cyclin, CDK is less active than in the cyclin-CDK heterodimer complex. CDKs phosphorylate proteins on serine (S) or threonine (T) residues. The specificity of CDKs for their substrates is defined by the S/T-P-X-K/R sequence, where S/T is the phosphorylation site, P is proline, X is any amino acid, and the sequence ends with lysine (K) or arginine (R). This motif ensures CDKs accurately target and modify proteins, crucial for regulating cell cycle and other functions. Deregulation of the CDK activity is linked to various pathologies, including cancer, neurodegenerative diseases, and stroke.

<span class="mw-page-title-main">Sunitinib</span> Cancer medication

Sunitinib, sold under the brand name Sutent, is an anti-cancer medication. It is a small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST) in January 2006. Sunitinib was the first cancer drug simultaneously approved for two different indications.

<span class="mw-page-title-main">Lapatinib</span> Cancer medication

Lapatinib (INN), used in the form of lapatinib ditosylate (USAN) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways. It is used in combination therapy for HER2-positive breast cancer. It is used for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (ErbB2).

The Cyclin D/Cdk4 complex is a multi-protein structure consisting of the proteins Cyclin D and cyclin-dependent kinase 4, or Cdk4, a serine-threonine kinase. This complex is one of many cyclin/cyclin-dependent kinase complexes that are the "hearts of the cell-cycle control system" and govern the cell cycle and its progression. As its name would suggest, the cyclin-dependent kinase is only active and able to phosphorylate its substrates when it is bound by the corresponding cyclin. The Cyclin D/Cdk4 complex is integral for the progression of the cell from the Growth 1 phase to the Synthesis phase of the cell cycle, for the Start or G1/S checkpoint.

Triple-negative breast cancer (TNBC) is any breast cancer that either lacks or shows low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification. Triple-negative is sometimes used as a surrogate term for basal-like.

<span class="mw-page-title-main">Olaparib</span> Chemical compound (cancer therapy drug)

Olaparib, sold under the brand name Lynparza, is a medication for the maintenance treatment of BRCA-mutated advanced ovarian cancer in adults. It is a PARP inhibitor, inhibiting poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which include some ovarian, breast, and prostate cancers.

<span class="mw-page-title-main">Phosphoinositide 3-kinase inhibitor</span>

Phosphoinositide 3-kinase inhibitors are a class of medical drugs that are mainly used to treat advanced cancers. They function by inhibiting one or more of the phosphoinositide 3-kinase (PI3K) enzymes, which are part of the PI3K/AKT/mTOR pathway. This signal pathway regulates cellular functions such as growth and survival. It is strictly regulated in healthy cells, but is always active in many cancer cells, allowing the cancer cells to better survive and multiply. PI3K inhibitors block the PI3K/AKT/mTOR pathway and thus slow down cancer growth. They are examples of a targeted therapy. While PI3K inhibitors are an effective treatment, they can have very severe side effects and are therefore only used if other treatments have failed or are not suitable.

A CDK inhibitor is any chemical that inhibits the function of CDKs. They are used to treat cancers by preventing overproliferation of cancer cells. The US FDA approved the first drug of this type, palbociclib (Ibrance), a CDK4/6 inhibitor, in February 2015, for use in postmenopausal women with breast cancer that is estrogen receptor positive and HER2 negative. While there are multiple cyclin/CDK complexes regulating the cell cycle, CDK inhibitors targeting CDK4/6 have been the most successful; four CDK4/6 inhibitors have been FDA approved. No inhibitors targeting other CDKs have been FDA approved, but several compounds are in clinical trials.

<span class="mw-page-title-main">Palbociclib</span> Medication for HR+ HER2− breast cancer

Palbociclib, sold under the brand name Ibrance among others, is a medication developed by Pfizer for the treatment of HR-positive and HER2-negative breast cancer. It is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6. Palbociclib was the first CDK4/6 inhibitor to be approved as a cancer therapy.

<span class="mw-page-title-main">Buparlisib</span> Chemical compound

Buparlisib is an experimental anti-cancer medication. It is a small molecule orally-available pan-class I phosphoinositide 3-kinase (PI3K) inhibitor. Buparlisib was under investigation as a treatment for advanced breast cancer but was abandoned due to negative results. It is still under investigation as a potential treatment for head and neck squamous cell carcinoma (HNSCC).

<span class="mw-page-title-main">Ribociclib</span> Chemical compound

Ribociclib, sold under the brand name Kisqali, is a medication used for the treatment of certain kinds of breast cancer. Ribociclib is a kinase inhibitor. It was developed by Novartis and Astex Pharmaceuticals.

<span class="mw-page-title-main">Alpelisib</span> Chemical compound

Alpelisib, sold under the brand name Piqray among others, is a medication used to treat certain types of breast cancer. It is used together with fulvestrant. It is taken by mouth. It is marketed by Novartis.

<span class="mw-page-title-main">Elacestrant</span> Chemical compound

Elacestrant, sold under the brand name Orserdu, is an anticancer medication which is used in the treatment of breast cancer. It is taken by mouth.

<span class="mw-page-title-main">Tucatinib</span> Chemical compound

Tucatinib, sold under the brand name Tukysa, is an anticancer medication used for the treatment of HER2-positive breast cancer. It is a small molecule inhibitor of HER2. It was developed by Array BioPharma and licensed to Cascadian Therapeutics.

<span class="mw-page-title-main">Gedatolisib</span> Chemical compound

Gedatolisib (PF-05212384) is an experimental drug for treatment of cancer in development by Celcuity, Inc. The mechanism of action is accomplished by binding the different p110 catalytic subunit isoforms of PI3K and the kinase site of mTOR.

<span class="mw-page-title-main">G1 Therapeutics</span> Pharmaceutical company

G1 Therapeutics, Inc. is an American biopharmaceutical company headquartered in Research Triangle Park, North Carolina. The company specializes in developing and commercializing small molecule therapeutics for the treatment of patients with cancer.

Endocrine therapy is a common treatment for estrogen receptor positive breast cancer. However, resistance to this therapy can develop, leading to relapse and progression of disease. This highlights the need for new strategies to combat this resistance.

<span class="mw-page-title-main">Inavolisib</span> Chemical compound

Inavolisib, or GDC-0077, is an investigational, highly selective inhibitor and degrader of mutant phosphatidylinositol 3-kinase (PI3K) alpha. The PI3K-mediated signalling pathway has shown to play an important role in the development of tumours as dysregulation is commonly associated with tumour growth and resistance to antineoplastic agents and radiotherapy.

<span class="mw-page-title-main">Capivasertib</span> Medication

Capivasertib, sold under the brand name Truqap, is an anti-cancer medication used for the treatment of breast cancer. It is taken by mouth.

<span class="mw-page-title-main">Dalpiciclib</span> Chemical compound

Dalpiciclib is a drug for the treatment of various forms of cancer.

References

  1. ↑ "Verzenio (Eli Lilly Australia Pty Ltd)". Therapeutic Goods Administration (TGA). 28 September 2022. Archived from the original on 18 March 2023. Retrieved 9 April 2023.
  2. ↑ "Summary Basis of Decision (SBD) for Verzenio". Health Canada . 23 October 2014. Archived from the original on 31 May 2022. Retrieved 29 May 2022.
  3. ↑ "Verzenios EPAR". European Medicines Agency. 27 September 2018. Retrieved 17 June 2024.
  4. ↑ Lu J (August 2015). "Palbociclib: a first-in-class CDK4/CDK6 inhibitor for the treatment of hormone-receptor positive advanced breast cancer". Journal of Hematology & Oncology. 8 (1): 98. doi: 10.1186/s13045-015-0194-5 . PMC   4534142 . PMID   26264704.
  5. ↑ Digiulio S (8 October 2015). "FDA's Breakthrough Therapy Designation to Abemaciclib for Breast Cancer". Oncology Times. LWW Journals. Archived from the original on 4 June 2021. Retrieved 30 March 2016.
  6. 1 2 "FDA approves new treatment for certain advanced or metastatic breast cancers" (Press release). Food and Drug Administration. 28 September 2017. Archived from the original on 23 April 2019. Retrieved 29 September 2017.
  7. ↑ Drugs.com: Abemaciclib Monograph . Accessed 22 November 2017.
  8. 1 2 3 4 5 6 "Highlights of Prescribing Information for Verzenio" (PDF). September 2017. Archived (PDF) from the original on 5 September 2021. Retrieved 22 November 2017.
  9. ↑ Goodrich DW, Wang NP, Qian YW, Lee EY, Lee WH (October 1991). "The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle". Cell. 67 (2): 293–302. doi:10.1016/0092-8674(91)90181-w. PMID   1655277. S2CID   12990398.
  10. ↑ Hino H, Iriyama N, Kokuba H, et al. (June 2020). "Abemaciclib induces atypical cell death in cancer cells characterized by formation of cytoplasmic vacuoles derived from lysosomes". Cancer Sci. 111 (6): 2132–2145. doi:10.1111/cas.14419. PMC   7293084 . PMID   32304130.
  11. ↑ "LY2835219 Shows Strong Single-Agent Activity in Preliminary Study in Metastatic Breast Cancer". Archived from the original on 18 September 2015. Retrieved 8 January 2016.
  12. ↑ Dickler MN, Tolaney SM, Rugo HS, Cortés J, Diéras V, Patt D, et al. (September 2017). "MONARCH 1, A Phase II Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with Refractory HR+/HER2- Metastatic Breast Cancer". Clinical Cancer Research. 23 (17): 5218–5224. doi:10.1158/1078-0432.CCR-17-0754. PMC   5581697 . PMID   28533223.{{cite journal}}: CS1 maint: overridden setting (link)
  13. ↑ Sledge GW, Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. (September 2017). "MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy". Journal of Clinical Oncology. 35 (25): 2875–2884. doi:10.1200/JCO.2017.73.7585. PMID   28580882.{{cite journal}}: CS1 maint: overridden setting (link)
  14. ↑ Center for Drug Evaluation and Research (9 February 2019). "FDA approves abemaciclib for HR-positive, HER2-negative breast cancer". FDA.
  15. ↑ Royce M, Osgood C, Mulkey F, Bloomquist E, Pierce WF, Roy A, et al. (April 2022). "FDA Approval Summary: Abemaciclib With Endocrine Therapy for High-Risk Early Breast Cancer". Journal of Clinical Oncology. 40 (11): 1155–1162. doi:10.1200/JCO.21.02742. PMC   8987222 . PMID   35084948.{{cite journal}}: CS1 maint: overridden setting (link)
  16. ↑ Center for Drug Evaluation and Research (24 March 2023). "FDA D.I.S.C.O. Burst Edition: FDA approval of Verzenio (abemaciclib) with endocrine therapy for patients with HR-positive, HER2-negative, node-positive, early breast cancer". FDA.
  17. ↑ "SARC041: Study of Abemaciclib Versus Placebo in Patients With Advanced Dedifferentiated Liposarcoma". www.clinicaltrials.gov. Retrieved 20 July 2023.
  18. ↑ "A Study of Abemaciclib (LY2835219) With Abiraterone in Men With Prostate Cancer That Has Spread to Other Parts of the Body and is Expected to Respond to Hormonal Treatment (Metastatic Hormone-Sensitive Prostate Cancer) (CYCLONE 3)". www.clinicaltrials.gov. Retrieved 20 July 2023.
  19. ↑ "Immune Modulation by Abemaciclib in HNSCC. (AIM Trial)". www.clinicaltrials.gov. Retrieved 20 July 2023.
  20. ↑ "A Study to Evaluate Abemaciclib in Advanced Biliary Tract Carcinoma". www.clinicaltrials.gov. Retrieved 20 July 2023.
  21. ↑ "Abemaciclib (LY2835219) in Patients With Recurrent Primary Brain Tumors". www.clinicaltrials.gov. Retrieved 20 July 2023.
  22. ↑ "Abemaciclib in Children With DIPG or Recurrent/Refractory Solid Tumors (AflacST1501)". www.clinicaltrials.gov. Retrieved 20 July 2023.
  23. ↑ "Abemaciclib w/Bevacizumab in Recurrent GBM Pts w/Loss of CDKN2A/B or Gain or Amplification of CDK4/6". www.clinicaltrials.gov. Retrieved 20 July 2023.
  24. ↑ "Cyclin-Dependent Kinase (CDK)4/6 Inhibitor Abemaciclib for Neurofibromatosis Type I (NF1) Related Atypical Neurofibromas". www.clinicaltrials.gov. Retrieved 20 July 2023.
  25. ↑ "Abemaciclib in Patients With HIV-associated and HIV-negative Kaposi Sarcoma". www.clinicaltrials.gov. Retrieved 20 July 2023.
  26. ↑ "A Study of Abemaciclib in Combination With Sunitinib in Metastatic Renal Cell Carcinoma". www.clinicaltrials.gov. Retrieved 20 July 2023.
  27. ↑ "Study of LY2835219 for Mantle Cell Lymphoma". www.clinicaltrials.gov. Retrieved 20 July 2023.
  28. ↑ Frederick MO, Kjell DP (February 2015). "A synthesis of abemaciclib utilizing a Leuckart–Wallach reaction". Tetrahedron Letters. 56 (7): 949–951. doi:10.1016/j.tetlet.2014.12.082.
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