Abemaciclib

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Abemaciclib
Abemaciclib.svg
Clinical data
Trade names Verzenio
Synonyms LY2835219
AHFS/Drugs.com Consumer Drug Information
Routes of
administration
Oral (tablets)
ATC code
  • None
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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
Chemical and physical data
Formula C27H32F2N8
Molar mass 506.61 g·mol−1
3D model (JSmol)

Abemaciclib (trade name Verzenio) is a drug 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.[1]

It was designated as a breakthrough therapy for breast cancer by the U.S. Food and Drug Administration (FDA) in October 2015.[2]

On 28 September 2017, it was approved for use in the United States by the FDA for the treatment of certain breast cancers.[3]

Medical uses[edit]

Since September 2017 Abemaciclib is approved in the US for "adult patients 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".[3]

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 regimen.[4]

Side effects[edit]

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.[5][4]

Interactions[edit]

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.[4]

Pharmacology[edit]

Mechanism of action[edit]

Like the related drugs palbociclib and ribociclib, abemaciclib inhibits the enzymes cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6).[4] 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.[6] Blocking this pathway prevents cells from progressing to the S phase, thereby inducing apoptosis (cell death).[4]

Pharmacokinetics[edit]

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 are 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.[4]

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.[4]

Clinical trials[edit]

Successful Phase I[7] and Phase II[8] trials against breast cancer were announced in May and December 2014 respectively.

As of early 2016, abemaciclib was involved in 3 Phase III clinical trials:

  • The MONARCH 3 study[15] is investigating the effectiveness of abemaciclib, plus either anastrozole or letrozole, as a first-line treatment for women with breast cancer.[16] The trial is expected to end in June 2017.[15]

Chemistry[edit]

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.[17]

References[edit]

  1. ^ Lu, Janice (13 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). doi:10.1186/s13045-015-0194-5.
  2. ^ "FDA's Breakthrough Therapy Designation to Abemaciclib for Breast Cancer". Oncology Times. LWW Journals. Retrieved 30 March 2016.
  3. ^ a b "FDA approves new treatment for certain advanced or metastatic breast cancers" (Press release). Food and Drug Administration. September 28, 2017.
  4. ^ a b c d e f g "Highlights of Prescribing Information for Verzenio" (PDF). September 2017.
  5. ^ Drugs.com: Abemaciclib Monograph. Accessed 2017-11-22.
  6. ^ Goodrich DW, Wang NP, Qian YW, Lee EY, Lee WH (November 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.
  7. ^ LY2835219 Shows Strong Single-Agent Activity in Preliminary Study in Metastatic Breast Cancer
  8. ^ Clinical Activity of Abemaciclib (LY2835219), a Cell Cycle Inhibitor Selective for CDK4 and CDK6, in Patients with Relapsed or Refractory Mantle Cell Lymphoma
  9. ^ a b A Study of Abemaciclib (LY2835219) in Participants With Previously Treated KRAS Mutated Lung Cancer (JUNIPER)
  10. ^ Goldman, Jonathan W.; Shi, Peipei; Reck, Martin; Paz-Ares, Luis; Koustenis, Andrew; Hurt, Karla C. (January 2016). "Treatment Rationale and Study Design for the JUNIPER Study: A Randomized Phase III Study of Abemaciclib With Best Supportive Care Versus Erlotinib With Best Supportive Care in Patients With Stage IV Non–Small-Cell Lung Cancer With a Detectable KRAS Mutation Whose Disease Has Progressed After Platinum-Based Chemotherapy". Clinical Lung Cancer. 17 (1): 80–84. doi:10.1016/j.cllc.2015.08.003.
  11. ^ Llombart, Antonio; Toi, Masakazu; Klise, Suzanne R; Frenzel, Martin; Chan, Edward M; Sledge, George W (30 April 2015). "Abstract OT1-1-07: A phase III study of abemaciclib (LY2835219) combined with fulvestrant in women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer (MONARCH 2)". Cancer Research. 75 (9 Supplement): OT1–1–07–OT1–1–07. doi:10.1158/1538-7445.SABCS14-OT1-1-07.
  12. ^ A Study of Abemaciclib (LY2835219) Combined With Fulvestrant in Women With Hormone Receptor Positive HER2 Negative Breast Cancer (MONARCH 2)
  13. ^ Lilly Announces Phase 3 MONARCH 2 Breast Cancer Study of Abemaciclib Met Primary Endpoint of Progression-Free Survival, Eli Lilly, 20 March 2017
  14. ^ Abemaciclib Receives FDA Approval for Certain Metastatic Breast Cancers. Sept 2017
  15. ^ a b A Study of Nonsteroidal Aromatase Inhibitors Plus Abemaciclib (LY2835219) in Postmenopausal Women With Breast Cancer (MONARCH 3)
  16. ^ Goetz, Matthew P; Toi, Masakazu (2015). "MONARCH 3: A randomized phase III study of anastrozole or letrozole plus abemaciclib, a CDK4/6 inhibitor, or placebo in first-line treatment of women with HR+, HER2-locoregionally recurrent or metastatic breast cancer (MBC)". Journal of Clinical Oncology. 33 (No 15_suppl). doi:10.1200/jco.2015.33.15_suppl.tps624.
  17. ^ Frederick, Michael O.; Kjell, Douglas P. (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.