Abemaciclib Explained

Pronounce:
Tradename:Verzenio, Verzenios, Ramiven, others
Dailymedid:Abemaciclib
Routes Of Administration:By mouth
Atc Prefix:L01
Atc Suffix:EF03
Legal Au:S4
Legal Au Comment:[1]
Legal Ca:Rx-only
Legal Ca Comment:/ Schedule D[2]
Legal Us:Rx-only
Legal Eu:Rx-only
Legal Eu Comment:[3]
Bioavailability:45%
Protein Bound:96.3%
Elimination Half-Life:18.3 hrs
Excretion:81% via feces, 3% via urine
Cas Number:1231929-97-7
Pubchem:46220502
Drugbank:DB12001
Chemspiderid:29340700
Chembl:3301610
Pdb Ligand:6ZV
Kegg:D10688
Unii:60UAB198HK
Synonyms:LY2835219
Iupac Name:N-[5-[(4-Ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-(1-methylethyl)-1''H''-benzimidazol-6-yl]-2-pyrimidinamine
C:27
H:32
F:2
N:8
Smiles:CCN1CCN(CC1)Cc2ccc(nc2)Nc3ncc(c(n3)c4cc5c(c(c4)F)nc(n5C(C)C)C)F
Stdinchi: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)
Stdinchikey: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]

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".

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.

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). 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).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

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.

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.

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]

Notes and References

  1. Web site: Verzenio (Eli Lilly Australia Pty Ltd) . Therapeutic Goods Administration (TGA) . 28 September 2022 . 9 April 2023 . 18 March 2023 . https://web.archive.org/web/20230318074344/https://www.tga.gov.au/resources/prescription-medicines-registrations/verzenio-eli-lilly-australia-pty-ltd-0 . live .
  2. Web site: Summary Basis of Decision (SBD) for Verzenio . . 23 October 2014 . 29 May 2022 . 31 May 2022 . https://web.archive.org/web/20220531055840/https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00445&lang=en . live .
  3. Web site: Verzenios EPAR . European Medicines Agency . 27 September 2018 . 17 June 2024.
  4. Lu J . 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 . August 2015 . 26264704 . 4534142 . 10.1186/s13045-015-0194-5 . free .
  5. FDA's Breakthrough Therapy Designation to Abemaciclib for Breast Cancer. Oncology Times. 8 October 2015. LWW Journals. 30 March 2016. Digiulio S . 4 June 2021. https://web.archive.org/web/20210604174348/https://journals.lww.com/oncology-times/blog/fdaactionsandupdates/pages/post.aspx?PostID=119. live.
  6. FDA approves new treatment for certain advanced or metastatic breast cancers . . 28 September 2017 . 29 September 2017 . 23 April 2019 . https://web.archive.org/web/20190423191918/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm578071.htm . live .
  7. [Drugs.com]
  8. Web site: Highlights of Prescribing Information for Verzenio. September 2017. 22 November 2017. 5 September 2021. https://web.archive.org/web/20210905021959/https://s3-us-west-2.amazonaws.com/drugbank/fda_labels/DB12001.pdf?1507131925. live.
  9. Goodrich DW, Wang NP, Qian YW, Lee EY, Lee WH . Eva Y.-H. P. Lee . The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle . Cell . 67 . 2 . 293–302 . October 1991 . 1655277 . 10.1016/0092-8674(91)90181-w . 12990398 .
  10. Hino H, Iriyama N, Kokuba H, et al. . Abemaciclib induces atypical cell death in cancer cells characterized by formation of cytoplasmic vacuoles derived from lysosomes. . Cancer Sci. . 111 . 6 . 2132–2145 . Jun 2020 . 32304130 . 10.1111/cas.14419 . 7293084 .
  11. Web site: LY2835219 Shows Strong Single-Agent Activity in Preliminary Study in Metastatic Breast Cancer . 8 January 2016 . 18 September 2015 . https://web.archive.org/web/20150918174440/http://www.ascopost.com/issues/may-1,-2014/ly2835219-shows-strong-single-agent-activity-in-preliminary-study-in-metastatic-breast-cancer.aspx . live .
  12. Dickler MN, Tolaney SM, Rugo HS, Cortés J, Diéras V, Patt D, Wildiers H, Hudis CA, O'Shaughnessy J, Zamora E, Yardley DA, Frenzel M, Koustenis A, Baselga J . 6 . 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 . September 2017 . 28533223 . 5581697 . 10.1158/1078-0432.CCR-17-0754 .
  13. Sledge GW, Toi M, Neven P, Sohn J, Inoue K, Pivot X, Burdaeva O, Okera M, Masuda N, Kaufman PA, Koh H, Grischke EM, Frenzel M, Lin Y, Barriga S, Smith IC, Bourayou N, Llombart-Cussac A . 6 . 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 . September 2017 . 28580882 . 10.1200/JCO.2017.73.7585 .
  14. Center for Drug Evaluation and Research . 9 February 2019 . FDA approves abemaciclib for HR-positive, HER2-negative breast cancer . FDA . en.
  15. Royce M, Osgood C, Mulkey F, Bloomquist E, Pierce WF, Roy A, Kalavar S, Ghosh S, Philip R, Rizvi F, Mixter BD, Tang S, Pazdur R, Beaver JA, Amiri-Kordestani L . 6 . FDA Approval Summary: Abemaciclib With Endocrine Therapy for High-Risk Early Breast Cancer . Journal of Clinical Oncology . 40 . 11 . 1155–1162 . April 2022 . 35084948 . 8987222 . 10.1200/JCO.21.02742 .
  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 . en.
  17. Web site: SARC041: Study of Abemaciclib Versus Placebo in Patients With Advanced Dedifferentiated Liposarcoma . 20 July 2023 . www.clinicaltrials.gov.
  18. Web site: 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) . 20 July 2023 . www.clinicaltrials.gov.
  19. Web site: Immune Modulation by Abemaciclib in HNSCC. (AIM Trial) . 20 July 2023 . www.clinicaltrials.gov.
  20. Web site: A Study to Evaluate Abemaciclib in Advanced Biliary Tract Carcinoma . 20 July 2023 . www.clinicaltrials.gov.
  21. Web site: Abemaciclib (LY2835219) in Patients With Recurrent Primary Brain Tumors . 20 July 2023 . www.clinicaltrials.gov.
  22. Web site: Abemaciclib in Children With DIPG or Recurrent/Refractory Solid Tumors (AflacST1501) . 20 July 2023 . www.clinicaltrials.gov.
  23. Web site: Abemaciclib w/Bevacizumab in Recurrent GBM Pts w/Loss of CDKN2A/B or Gain or Amplification of CDK4/6 . 20 July 2023 . www.clinicaltrials.gov.
  24. Web site: Cyclin-Dependent Kinase (CDK)4/6 Inhibitor Abemaciclib for Neurofibromatosis Type I (NF1) Related Atypical Neurofibromas . 20 July 2023 . www.clinicaltrials.gov.
  25. Web site: Abemaciclib in Patients With HIV-associated and HIV-negative Kaposi Sarcoma . 20 July 2023 . www.clinicaltrials.gov.
  26. Web site: A Study of Abemaciclib in Combination With Sunitinib in Metastatic Renal Cell Carcinoma . 20 July 2023 . www.clinicaltrials.gov.
  27. Web site: Study of LY2835219 for Mantle Cell Lymphoma . 20 July 2023 . www.clinicaltrials.gov.
  28. Frederick MO, Kjell DP . A synthesis of abemaciclib utilizing a Leuckart–Wallach reaction. Tetrahedron Letters. February 2015. 56. 7. 949–951. 10.1016/j.tetlet.2014.12.082.

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Abemaciclib".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.