Chemistry:Pomalidomide

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Short description: Chemical compound
Pomalidomide
Pomalidomide enantiomers.svg
Clinical data
Trade namesPomalyst, Imnovid
AHFS/Drugs.comMonograph
MedlinePlusa613030
License data
Pregnancy
category
  • AU: X (High risk)[1]
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability73% (at least)[8]
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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC13H11N3O4
Molar mass273.248 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
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Pomalidomide, sold under the brand names Pomalyst and Imnovid,[6][7] is an anti-cancer medication used for the treatment of multiple myeloma and AIDS-related Kaposi sarcoma.[6]

Pomalidomide was approved for medical use in the United States in February 2013,[9] and in the European Union in August 2013.[7] It is available as a generic medication.[10]

Medical uses

In the European Union, pomalidomide, in combination with bortezomib and dexamethasone, is indicated in the treatment of adults with multiple myeloma who have received at least one prior treatment regimen including lenalidomide;[7] and in combination with dexamethasone is indicated in the treatment of adults with relapsed and refractory multiple myeloma who have received at least two prior treatment regimens, including both lenalidomide and bortezomib, and have demonstrated disease progression on the last therapy.[7]

In the United States, pomalidomide is indicated, in combination with dexamethasone, for people with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy;[11] and is indicated for people with AIDS-related Kaposi sarcoma after failure of highly active antiretroviral therapy (HAART) or in people with Kaposi sarcoma who are HIV-negative.[11][12][13][14]

Origin and development

The parent compound of pomalidomide, thalidomide, was originally discovered to inhibit angiogenesis in 1994.[15] Based upon this discovery, thalidomide was taken into clinical trials for cancer, leading to its ultimate FDA approval for multiple myeloma.[16] 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.[17] This dual activity of pomalidomide makes it more efficacious than thalidomide in vitro and in vivo.[18]

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.[17] 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.

Like thalidomide, pomalidomide works as a cereblon E3 ligase modulator.[19]

Side effects

Pomalidomide can cause harm to unborn babies when administered during pregnancy.[7]

Pomalidomide is present in the semen of people receiving the drug.[7][6]

Clinical trials

Phase I trial results showed tolerable side effects.[20]

Phase II clinical trials for multiple myeloma and myelofibrosis reported 'promising results'.[21][22]

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.[23]

References

  1. ↑ "Pomalidomide (Pomalyst) Use During Pregnancy". 14 May 2020. https://www.drugs.com/pregnancy/pomalidomide.html. 
  2. ↑ "Pomalidomide Medicianz/ Pomalimed/ Pomalidomide Medsurge (Medicianz Healthcare Pty Ltd)". 5 December 2022. https://www.tga.gov.au/resources/prescription-medicines-registrations/pomalidomide-medicianz-pomalimed-pomalidomide-medsurge-medicianz-healthcare-pty-ltd. 
  3. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2014". 21 June 2022. https://www.tga.gov.au/resources/resource/guidance/prescription-medicines-registration-new-chemical-entities-australia-2014. 
  4. ↑ "Pomalyst Product information". Health Canada. https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=90423. 
  5. ↑ "Imnovid 1 mg hard capsules - Summary of Product Characteristics (SmPC)". 16 June 2020. https://www.medicines.org.uk/emc/product/1262/smpc. 
  6. ↑ 6.0 6.1 6.2 6.3 "Pomalyst- pomalidomide capsule". 7 December 2017. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2b25ef01-5c9e-11e1-b86c-0800200c9a66. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 "Imnovid EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/imnovid-previously-pomalidomide-celgene.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  8. ↑ "Imnovid 1 mg Hard Capsules. Summary of Product Characteristics. 5.2 Pharmacokinetic properties". Celgene Europe Ltd.. p. 22. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002682/WC500147717.pdf. 
  9. ↑ "Drug Approval Package: Pomalyst (pomalidomide) Capsules NDA #204026". 8 February 2013. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204026Orig1s000TOC.cfm. 
  10. ↑ "2020 First Generic Drug Approvals". 23 February 2021. https://www.fda.gov/drugs/first-generic-drug-approvals/2020-first-generic-drug-approvals. 
  11. ↑ 11.0 11.1 "Pomalidomide". 13 February 2013. https://www.cancer.gov/about-cancer/treatment/drugs/pomalidomide.  This article incorporates text from this source, which is in the public domain.
  12. ↑ "FDA grants accelerated approval to pomalidomide for Kaposi sarcoma". 15 May 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pomalidomide-kaposi-sarcoma.  This article incorporates text from this source, which is in the public domain.
  13. ↑ "FDA approves pomalidomide for AIDS-related Kaposi sarcoma". National Cancer Institute (Press release). 15 May 2020. Archived from the original on 8 May 2023. Retrieved 12 May 2023.
  14. ↑ "Cancer Accelerated Approvals". 1 May 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/ongoing-cancer-accelerated-approvals. 
  15. ↑ "Thalidomide is an inhibitor of angiogenesis". Proceedings of the National Academy of Sciences of the United States of America 91 (9): 4082–5. April 1994. doi:10.1073/pnas.91.9.4082. PMID 7513432. Bibcode: 1994PNAS...91.4082D. 
  16. ↑ Altman, David (2 April 2013). "From Thalidomide to Pomalyst: Better Living Through Chemistry". https://damatolab.com/news/thalidomide-pomalyst-better-living-through-chemistry. 
  17. ↑ 17.0 17.1 "Mechanism of action of thalidomide and 3-aminothalidomide in multiple myeloma". Seminars in Oncology 28 (6): 597–601. December 2001. doi:10.1016/S0093-7754(01)90031-4. PMID 11740816. 
  18. ↑ "S-3-Amino-phthalimido-glutarimide inhibits angiogenesis and growth of B-cell neoplasias in mice". Cancer Research 62 (8): 2300–5. April 2002. PMID 11956087. 
  19. ↑ Asatsuma-Okumura, Tomoko; Ito, Takumi; Handa, Hiroshi (October 2019). "Molecular mechanisms of cereblon-based drugs". Pharmacology & Therapeutics 202: 132–139. doi:10.1016/j.pharmthera.2019.06.004. PMID 31202702. 
  20. ↑ "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. April 2008. doi:10.1111/j.1365-2141.2008.07013.x. PMID 18324965. 
  21. ↑ "Promising Results From 2 Trials Highlighting Pomalidomide Presented At ASH" (Press release). Celgene. 11 December 2008. Archived from the original on 20 September 2018. Retrieved 28 October 2012.
  22. ↑ 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. https://ash.confex.com/ash/2008/webprogram/Paper13194.html. Retrieved 28 October 2012. 
  23. ↑ "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". The Lancet. Oncology 14 (11): 1055–1066. September 2013. doi:10.1016/s1470-2045(13)70380-2. PMID 24007748. https://iris.unito.it/bitstream/2318/150538/1/1323531.pdf. Retrieved 2 September 2019. 



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