Pomalidomide

Pomalidomide (INN; marketed as Pomalyst in the US[3] and Imnovid in the European Union and Russia) is a derivative of thalidomide marketed by Celgene. It is anti-angiogenic and also acts as an immunomodulator.

Pomalidomide
Clinical data
Trade namesPomalyst, Imnovid
AHFS/Drugs.comMonograph
MedlinePlusa613030
License data
Pregnancy
category
  • AU: X (High risk)[1]
Routes of
administration		By mouth (capsules)
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only) [2]
  • US: ℞-only [3]
  • EU: Rx-only [4]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability73% (at least)[5]
Protein binding12–44%
MetabolismLiver (mostly CYP1A2- and CYP3A4-mediated; some minor contributions by CYP2C19 and CYP2D6)
Elimination half-life7.5 hours
ExcretionUrine (73%), faeces (15%)
Identifiers
IUPAC name
  • 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.232.884
Chemical and physical data
FormulaC13H11N3O4
Molar mass273.248 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
SMILES
  • C1CC(=O)NC(=O)C1N2C(=O)C3=C(C2=O)C(=CC=C3)N
InChI
  • InChI=1S/C13H11N3O4/c14-7-3-1-2-6-10(7)13(20)16(12(6)19)8-4-5-9(17)15-11(8)18/h1-3,8H,4-5,14H2,(H,15,17,18) N
  • Key:UVSMNLNDYGZFPF-UHFFFAOYSA-N N
 NY (what is this?)  (verify)

Pomalidomide was approved in February 2013, by the US Food and Drug Administration (FDA) as a treatment for relapsed and refractory multiple myeloma.[6] It has been approved for use in people who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy.[7] It received a similar approval from the European Commission in August 2013.[8][4]

Origin and development

The parent compound of pomalidomide, thalidomide, was originally discovered to inhibit angiogenesis in 1994.[9] Based upon this discovery, thalidomide was taken into clinical trials for cancer, leading to its ultimate FDA approval for multiple myeloma.[10] Structure-activity studies revealed that amino substituted thalidomide had improved antitumor activity, which was due to its ability to directly inhibit both the tumor cell and vascular compartments of myeloma cancers.[11] This dual activity of pomalidomide makes it more efficacious than thalidomide in vitro and in vivo.[12]

Mechanism of action

Pomalidomide directly inhibits angiogenesis and myeloma cell growth. This dual effect is central to its activity in myeloma, rather than other pathways such as TNF alpha inhibition, since potent TNF inhibitors including rolipram and pentoxifylline do not inhibit myeloma cell growth or angiogenesis.[11] Upregulation of interferon gamma, IL-2 and IL-10 as well as downregulation of IL-6 have been reported for pomalidomide. These changes may contribute to pomalidomide's anti-angiogenic and anti-myeloma activities.

Pregnancy and sexual contact warnings

Because pomalidomide can cause harm to unborn babies when administered during pregnancy, women taking pomalidomide must not become pregnant.[4]

To avoid embryo-fetal exposure, a "Risk Evaluation and Mitigation Strategy" (REMS) program was developed to ensure pregnancy prevention or distribution of the drug to those who are or might become pregnant.[13] Women must produce two negative pregnancy tests and use contraception methods before beginning pomalidomide. Women must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning four weeks prior to initiating treatment with pomalidomide, during therapy, during dose interruptions and continuing for four weeks following discontinuation of pomalidomide therapy.

Pomalidomide is present in the semen of people receiving the drug.[4][3] Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking pomalidomide and for up to 28 days after discontinuing pomalidomide, even if they have undergone a successful vasectomy.[3] Males taking pomalidomide must not donate sperm.[3]

Clinical trials

Phase I trial results showed tolerable side effects.[14]

Phase II clinical trials for multiple myeloma and myelofibrosis reported 'promising results'.[15][16]

Phase III results showed significant extension of progression-free survival, and overall survival (median 11.9 months vs. 7.8 months; p = 0.0002) in patients taking pomalidomide and dexamethasone vs. dexamethasone alone.[17]

See also

References
  1. "Pomalidomide (Pomalyst) Use During Pregnancy". Drugs.com. 14 May 2020. Retrieved 21 September 2020.
  2. "Imnovid 1 mg hard capsules - Summary of Product Characteristics (SmPC)". (emc). 16 June 2020. Retrieved 21 September 2020.
  3. "Pomalyst- pomalidomide capsule". DailyMed. 7 December 2017. Retrieved 21 September 2020.
  4. "Imnovid EPAR". European Medicines Agency (EMA). Retrieved 21 September 2020.
  5. "Imnovid 1 mg Hard Capsules. Summary of Product Characteristics. 5.2 Pharmacokinetic properties" (PDF). Celgene Europe Ltd. p. 22. Retrieved 21 August 2016.
  6. "Drug Approval Package: Pomalyst (pomalidomide) Capsules NDA #204026". U.S. Food and Drug Administration (FDA). 8 February 2013. Retrieved 21 September 2020. Lay summary (PDF). {{cite web}}: Cite uses deprecated parameter |lay-url= (help)
  7. "Pomalyst (Pomalidomide) Approved By FDA For Relapsed And Refractory Multiple Myeloma". The Myeloma Beacon. Retrieved 10 August 2013.
  8. "Pomalidomide Approved In Europe For Relapsed And Refractory Multiple Myeloma". The Myeloma Beacon. Retrieved 10 August 2013.
  9. D'Amato RJ, Loughnan MS, Flynn E, Folkman J (April 1994). "Thalidomide is an inhibitor of angiogenesis". Proceedings of the National Academy of Sciences of the United States of America. 91 (9): 4082–5. Bibcode:1994PNAS...91.4082D. doi:10.1073/pnas.91.9.4082. JSTOR 2364596. PMC 43727. PMID 7513432.
  10. Altman, David (2 April 2013). "From Thalidomide to Pomalyst: Better Living Through Chemistry".
  11. D'Amato RJ, Lentzsch S, Anderson KC, Rogers MS (December 2001). "Mechanism of action of thalidomide and 3-aminothalidomide in multiple myeloma". Seminars in Oncology. 28 (6): 597–601. doi:10.1016/S0093-7754(01)90031-4. PMID 11740816.
  12. Lentzsch S, Rogers MS, LeBlanc R, Birsner AE, Shah JH, Treston AM, et al. (April 2002). "S-3-Amino-phthalimido-glutarimide inhibits angiogenesis and growth of B-cell neoplasias in mice". Cancer Research. 62 (8): 2300–5. PMID 11956087.
  13. "Pomalyst Risk Evaluation and Mitigation Strategy (REMS) Program". Celgene Corporation. Retrieved 21 August 2016.
  14. Streetly MJ, Gyertson K, Daniel Y, Zeldis JB, Kazmi M, Schey SA (April 2008). "Alternate day pomalidomide retains anti-myeloma effect with reduced adverse events and evidence of in vivo immunomodulation". British Journal of Haematology. 141 (1): 41–51. doi:10.1111/j.1365-2141.2008.07013.x. PMID 18324965. S2CID 37073246.
  15. "Promising Results From 2 Trials Highlighting Pomalidomide Presented At ASH" (Press release). Celgene. 11 December 2008. Retrieved 28 October 2012.
  16. Tefferi, Ayalew (8 December 2008). Pomalidomide Therapy in Anemic Patients with Myelofibrosis: Results from a Phase-2 Randomized Multicenter Study. 50th ASH Annual Meeting and Exposition. San Francisco. Retrieved 28 October 2012.
  17. Miguel JS, Weisel K, Moreau P, Lacy M, Song K, Delforge M, et al. (September 2013). "Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial" (PDF). The Lancet. Oncology. 14 (11): 1055–1066. doi:10.1016/s1470-2045(13)70380-2. hdl:2318/150538. PMID 24007748. S2CID 4526729.
  • "Pomalidomide". Drug Information Portal. U.S. National Library of Medicine.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.