Palbociclib: Difference between revisions
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It is a selective [[enzyme inhibitor|inhibitor]] of the [[cyclin-dependent kinase]]s [[CDK4]] and [[CDK6]].<ref name=Finn2009>{{Cite journal | pmid = 19874578 | year = 2009 | last1 = Finn | first1 = RS | last2 = Dering | first2 = J | last3 = Conklin | first3 = D | last4 = Kalous | first4 = O | last5 = Cohen | first5 = DJ | last6 = Desai | first6 = AJ | last7 = Ginther | first7 = C | last8 = Atefi | first8 = M | last9 = Chen | first9 = I | last10 = Fowst | first10 = Camilla | last11 = Los | first11 = Gerret | last12 = Slamon | first12 = Dennis J | title = PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro | volume = 11 | issue = 5 | pages = R77 | doi = 10.1186/bcr2419 | pmc = 2790859 | journal = Breast cancer research : BCR| display-authors = 8 }}</ref><ref name="pmid24369047">{{cite journal |vauthors=Rocca A, Farolfi A, Bravaccini S, Schirone A, Amadori D | title = Palbociclib (PD 0332991): targeting the cell cycle machinery in breast cancer | journal = Expert Opin Pharmacother | volume = 15 | issue = 3 | pages = 407–20 | year = 2014 | pmid = 24369047 | doi = 10.1517/14656566.2014.870555 }}</ref> |
It is a selective [[enzyme inhibitor|inhibitor]] of the [[cyclin-dependent kinase]]s [[CDK4]] and [[CDK6]].<ref name=Finn2009>{{Cite journal | pmid = 19874578 | year = 2009 | last1 = Finn | first1 = RS | last2 = Dering | first2 = J | last3 = Conklin | first3 = D | last4 = Kalous | first4 = O | last5 = Cohen | first5 = DJ | last6 = Desai | first6 = AJ | last7 = Ginther | first7 = C | last8 = Atefi | first8 = M | last9 = Chen | first9 = I | last10 = Fowst | first10 = Camilla | last11 = Los | first11 = Gerret | last12 = Slamon | first12 = Dennis J | title = PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro | volume = 11 | issue = 5 | pages = R77 | doi = 10.1186/bcr2419 | pmc = 2790859 | journal = Breast cancer research : BCR| display-authors = 8 }}</ref><ref name="pmid24369047">{{cite journal |vauthors=Rocca A, Farolfi A, Bravaccini S, Schirone A, Amadori D | title = Palbociclib (PD 0332991): targeting the cell cycle machinery in breast cancer | journal = Expert Opin Pharmacother | volume = 15 | issue = 3 | pages = 407–20 | year = 2014 | pmid = 24369047 | doi = 10.1517/14656566.2014.870555 }}</ref> |
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In the G1 phase of the [[cell cycle]], [[mammal]]ian cells must pass a checkpoint known as the [[restriction point]], R, in order to complete the cell cycle and divide. [[Cyclin-dependent kinase 4|CDK4]] and [[Cyclin-dependent kinase 6|CDK6]] complex with [[Cyclin D|cyclin]] D drive the [[phosphorylation]] of the [[retinoblastoma protein]], Rb, which allows the cell to pass R and commit to [[Cell division|division]].<ref name=":1">{{Cite journal|last=Xu|first=Hanxiao|last2=Yu|first2=Shengnan|last3=Liu|first3=Qian|last4=Yuan|first4=Xun|last5=Mani|first5=Sridhar|last6=Pestell|first6=Richard G.|last7=Wu|first7=Kongming|date=2017-04-24|title=Recent advances of highly selective CDK4/6 inhibitors in breast cancer|url=https://doi.org/10.1186/s13045-017-0467-2|journal=Journal of Hematology & Oncology|volume=10|pages=97|doi=10.1186/s13045-017-0467-2|issn=1756-8722}}</ref> Regulation of one or more proteins involved in this checkpoint is lost in many cancers. However |
In the G1 phase of the [[cell cycle]], [[mammal]]ian cells must pass a checkpoint known as the [[restriction point]], R, in order to complete the cell cycle and divide. [[Cyclin-dependent kinase 4|CDK4]] and [[Cyclin-dependent kinase 6|CDK6]] complex with [[Cyclin D|cyclin]] D drive the [[phosphorylation]] of the [[retinoblastoma protein]], Rb, which allows the cell to pass R and commit to [[Cell division|division]].<ref name=":1">{{Cite journal|last=Xu|first=Hanxiao|last2=Yu|first2=Shengnan|last3=Liu|first3=Qian|last4=Yuan|first4=Xun|last5=Mani|first5=Sridhar|last6=Pestell|first6=Richard G.|last7=Wu|first7=Kongming|date=2017-04-24|title=Recent advances of highly selective CDK4/6 inhibitors in breast cancer|url=https://doi.org/10.1186/s13045-017-0467-2|journal=Journal of Hematology & Oncology|volume=10|pages=97|doi=10.1186/s13045-017-0467-2|issn=1756-8722}}</ref> Regulation of one or more proteins involved in this checkpoint is lost in many cancers. However by inhibiting CDK4/6, palbociclib ensures that the cyclin D-CDK4/6 complex cannot aid in phosphorylating Rb. This prevents the cell from passing R and exiting G1, and in turn from proceeding through the cell cycle.<ref name=":1" /> |
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== Administration == |
== Administration == |
Revision as of 00:38, 6 February 2018
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Clinical data | |
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Trade names | Ibrance |
Other names | PD-0332991 |
AHFS/Drugs.com | ibrance |
MedlinePlus | a615013 |
License data | |
Routes of administration | By mouth (capsules) |
ATC code | |
Legal status | |
Legal status |
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Pharmacokinetic data | |
Bioavailability | 46% |
Protein binding | 85% |
Metabolism | Liver (CYP3A, SULT2A1, glucuronidation) |
Elimination half-life | 29 (±5) hours |
Excretion | 74% feces, 18% urine |
Identifiers | |
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CAS Number | |
PubChem CID | |
DrugBank | |
ChemSpider | |
UNII | |
KEGG | |
ChEBI | |
ChEMBL | |
PDB ligand | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.238.221 |
Chemical and physical data | |
Formula | C24H29N7O2 |
Molar mass | 447.533 g/mol g·mol−1 |
3D model (JSmol) | |
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Palbociclib (codenamed PD-0332991, trade name Ibrance) is a drug for the treatment of ER-positive and HER2-negative breast cancer developed by Pfizer. It is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6.[1][2] Palbociclib was the first CDK4/6 inhibitor to be approved as a cancer therapy by any organization, and as of December 2017 has been prescribed more than 90,000 times.[3]
Mechanism of action
It is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6.[1][2]
In the G1 phase of the cell cycle, mammalian cells must pass a checkpoint known as the restriction point, R, in order to complete the cell cycle and divide. CDK4 and CDK6 complex with cyclin D drive the phosphorylation of the retinoblastoma protein, Rb, which allows the cell to pass R and commit to division.[4] Regulation of one or more proteins involved in this checkpoint is lost in many cancers. However by inhibiting CDK4/6, palbociclib ensures that the cyclin D-CDK4/6 complex cannot aid in phosphorylating Rb. This prevents the cell from passing R and exiting G1, and in turn from proceeding through the cell cycle.[4]
Administration
Palbociclib is taken daily orally with food in a cycle of 21 days of active medication followed by 7 without. Currently palbociclib is prescribed as a combination therapy with either letrozole or fulvestrant.[5] Patients should also not consume CYP3A inhibitors or inducers while taking palbociclib. FDA information also cautions against consuming grapefruit products while taking palbociclib.[5]
Approvals and indications
ER+ breast cancer
The drug was reviewed and approved under the Food and Drug Administration’s (FDA) accelerated Priority Review and Breakthrough Therapy designation programs on February 3, 2015 as a treatment (in combination with letrozole) for patients with estrogen receptor positive advanced breast cancer.[6] This was an accelerated approval.[7]
In March 2017, the FDA granted regular approval to palbociclib for HER2 negative breast cancer, in combination with an aromatase inhibitor.[8]
A phase 3 trial, PALOMA-2, was fully enrolled by February 2015 and reported positive results in April 2016.[9] The results of PALOMA-2 trial (published November 2016) showed significantly longer progression-free survival in patients on palbociclib in combination with letrozole, compared to patients on letrozole and placebo. Progression-free survival was assessed by radiologically confirmed disease progression by RECIST criteria or death during the study. At the time of publication, there was insufficient data on overall survival, and a final analysis is planned after a total of 390 deaths occur per protocol and in agreement with regulatory agencies. Of note, it was noted that the addition of palbociclib caused higher rates of myelotoxic events in the study.[10]
The drug was approved for use in the European Union in November 2016 as a treatment for hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative locally advanced or metastatic breast cancer either in combination with an aromatase inhibitor or, for women who have received prior endocrine therapy, in combination with fulvestrant. In pre- or perimenopausal women, a luteinizing hormone releasing hormone agonist should also be given.[11]
In December 2017, palbociclib, was accepted for use by the NHS after going through the Scottish Medicines Consortium's process for medicines used to treat very rare and end-of-life breast cancer.[12]
Adverse effects
A majority of patients taking palbociclib experiencing neutropenia, a condition where a patient has an abnormally low number of neutrophils. This side effect impacts the immune system, and is thus likely responsible for the second most common side effect, infection.[13] Leukopenia and anemia are also frequent among patients taking palbociclib.[13] More than 10% of patients also experience side effects such as fatigue, nausea, diarrhea, respiratory infection, headache, thrombocytopenia, vomiting, and decreased appetite.[14][13] The FDA also indicates that patients should be vigilant to monitor themselves for any sign of pulmonary embolism. The FDA further cautions that women should be aware that the medication can have a harmful effect on a fetus, and thus should not be taken while pregnant.[5]
Clinical trials
HR+ breast cancer
The PALOMA-3 trial announced in April 2015 that the addition of palbociclib was superior to fulvestrant alone for progression-free survival.[15]
In the phase 2 PALOMA-1 trial reported at the April 2014 annual meeting of the American Association for Cancer Research, the addition of palbociclib to letrozole was shown to significantly slow the progression of advanced cancer (median progression-free survival increased from 10.2 months to 20.2 months), but was not shown to have a statistically significant effect on increasing patients' overall survival times.[16][17][18]
Active clinical trials
According to the NIH National Cancer Institute there are currently 39 active clinical trials testing palbociclib on its own or in combination with other medications. While a majority of these are exploring the further uses of palbociclib to treat breast cancer, other trials are investigating the potential applications of palbociclib to head and neck cancers, non-small cell lung cancer, recurring brain metastasis, squamous cell carcinoma, central nervous system tumors, and other solid tumor types.[19]
In December 2017, Pfizer announced that the PALOMA-2 trial, an ongoing phase 3 trial combining palbociclib with letrozole, showed a 44% reduction in risk of disease progression among trial subjects. The trial has also demonstrated greater than a year’s improved median progression free survival for patients on the combined therapy (as compared to letrozole on its own). PALOMA-2 median patient follow-up time now exceeds three years, making it the longest traceable data for phase 3 study of a CDK4/6 inhibitor.[3]
Pricing
Ibrance "can be ordered through select" specialty pharmacies and "sells for $9,850 for 30 days or $118,200 for a year's supply before discounts."[20] According to a statement by the New York–based Pfizer the price "is not the cost that most patients or payors pay" since most prescriptions are dispensed through health plans, which negotiate discounts for medicines or get government-mandated price concessions.[20] In the United States specialty pharmacies fill prescriptions for drugs that are usually high cost.[21][22]
Resistance to cost
In February 2017, the National Institute for Health and Care Excellence (NICE) in the United Kingdom published a statement stating that the cost of Ibrance (approximately $3700 USD/28 days) did not make the added health benefits worth the cost.[23] Though the committee acknowledged Ibrance's ability to extend patient life by approximately 10 months, it was stated that with the side effects caused by Ibrance, it was not a cost effective medication for NICE to endorse.[24] At the time, a year's treatment with palbociclib and a drug such as fulvestrant was priced at $106,105 USD (£79,650).[24] In November 2017 NICE announced that, after negotiation with Pfizer, the price would be discounted, and the drug would be recommended for use.[25]
Drugs with a similar mechanism of action
Palbociclib has several direct competitors currently on the market or in clinical trials. In September 2017, abemaciclib, another selective CDK4/6 inhibitor owned and manufactured by Eli Lily, was approved for HR-positive, HER2-negative advanced metastatic breast cancer both in combination with fulvestrant and as a monotherapy. In March 2017, the FDA also approved ribociclib, owned by Novartis, as a combination therapy with aromatase inhibitors for indications similar to those of palbociclib and ribociclib. Notably, ribociclib seems to also have an inhibitory effect on Cyclin D3/CDK6 activity.[26] G1 therapeutics also has a Cdk4/6 inhibitor, trilaciclib, which is currently in phase 2 trials, but as of December 2017 has not gained FDA approval.[27]
References
- ^ a b Finn, RS; Dering, J; Conklin, D; Kalous, O; Cohen, DJ; Desai, AJ; Ginther, C; Atefi, M; et al. (2009). "PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro". Breast cancer research : BCR. 11 (5): R77. doi:10.1186/bcr2419. PMC 2790859. PMID 19874578.
{{cite journal}}
: CS1 maint: unflagged free DOI (link) - ^ a b Rocca A, Farolfi A, Bravaccini S, Schirone A, Amadori D (2014). "Palbociclib (PD 0332991): targeting the cell cycle machinery in breast cancer". Expert Opin Pharmacother. 15 (3): 407–20. doi:10.1517/14656566.2014.870555. PMID 24369047.
- ^ a b "Updated Data from Phase 3 Trial of IBRANCE® (palbociclib) Plus Letrozole in ER+, HER2- Metastatic Breast Cancer Confirm Improvement in Progression-Free Survival | Pfizer: One of the world's premier biopharmaceutical companies". www.pfizer.com. Retrieved 2017-12-16.
- ^ a b Xu, Hanxiao; Yu, Shengnan; Liu, Qian; Yuan, Xun; Mani, Sridhar; Pestell, Richard G.; Wu, Kongming (2017-04-24). "Recent advances of highly selective CDK4/6 inhibitors in breast cancer". Journal of Hematology & Oncology. 10: 97. doi:10.1186/s13045-017-0467-2. ISSN 1756-8722.
{{cite journal}}
: CS1 maint: unflagged free DOI (link) - ^ a b c "IBRANCE FDA Drug Label" (PDF). Retrieved 2017-12-15.
{{cite web}}
: Cite has empty unknown parameter:|dead-url=
(help) - ^ "FDA Approves Palbociclib for Metastatic Breast Cancer". OncLive. 3 Feb 2015.
- ^ "Pfizer Receives U.S. FDA Accelerated Approval of IBRANCE (palbociclib)". Pfizer. 3 Feb 2015.
- ^ cite web | url=https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm549978.htm
- ^ Late-stage study of expanded use of Pfizer's Ibrance successful; global regulatory applications to follow. April 2016
- ^ Finn; et al. (November 17, 2016). "Palbociclib and Letrozole in Advanced Breast Cancer". NEJM. pp. 1925–1936. doi:10.1056/NEJMoa1607303.
{{cite web}}
: Explicit use of et al. in:|author=
(help) - ^ Ibrance (palbociclib) European public assessment report
- ^ "Breast cancer drug approved for NHS use". BBC News. 2017-12-11. Retrieved 2017-12-11.
- ^ a b c Research, Center for Drug Evaluation and. "Approved Drugs - Palbociclib (IBRANCE)". www.fda.gov. Retrieved 2017-12-16.
- ^ Turner, Nicholas C.; Ro, Jungsil; André, Fabrice; Loi, Sherene; Verma, Sunil; Iwata, Hiroji; Harbeck, Nadia; Loibl, Sibylle; Huang Bartlett, Cynthia (2015-07-16). "Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer". New England Journal of Medicine. 373 (3): 209–219. doi:10.1056/NEJMoa1505270. ISSN 0028-4793. PMID 26030518.
- ^ "Pfizer Announces PALOMA-3 Trial For IBRANCE (Palbociclib) Stopped Early Due To Efficacy Seen In Patients With HR+, HER2- Metastatic Breast Cancer Whose Disease Has Progressed Following Endocrine Therapy". April 15, 2015.
- ^ Breast Cancer Drug Shows ‘Groundbreaking’ Results By ANDREW POLLACK, APRIL 6, 2014
- ^ Beasley, Deena (6 April 2014). "Pfizer drug doubles time to breast cancer tumor growth in trial". Yahoo! News. Reuters. Retrieved 7 April 2014.
- ^ Palbociclib Shows Promising Results in Patients With Hormone Receptor-positive Metastatic Breast Cancer, AACR in the News, April 6, 2014
- ^ "Intervention Dynamic Trial Listing Page". National Cancer Institute. Retrieved 2017-12-16.
- ^ a b "Pfizer breast cancer drug gets early FDA approval". Daily Mail. London. Associated Press. 3 February 2015. Retrieved 2 November 2015.
- ^ Herper, Matthew (19 February 2010), "The World's Most Expensive Drugs", Forbes, retrieved 25 June 2015
- ^ Thomas, Kate; Pollack, Andrew (15 July 2015). "Specialty Pharmacies Proliferate, Along With Questions". Sinking Spring, Pa.: New York Times. Retrieved 5 October 2015.
- ^ "UK agency says Pfizer breast cancer drug too expensive". Reuters. 3 February 2017. Retrieved 2017-12-16.
- ^ a b "Breast cancer drug costs too high in relation to benefits for routine NHS funding". NICE. Retrieved 2017-12-16.
- ^ "Breast cancer patients to have routine access to two life extending drugs after new deal, say NICE in draft guidance". NICE. Retrieved 2017-12-16.
- ^ "NCI Drug Dictionary". National Cancer Institute. Retrieved 2017-12-16.
- ^ "G1T28 - G1 Therapeutics". www.g1therapeutics.com. Retrieved 2017-12-16.