Pomalidomide: Difference between revisions

{{Short description|Chemical compound}}

{{Use dmy dates|date=May 2023}}

{{cs1 config |name-list-style=vanc |display-authors=6}}

{{Infobox drug

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 352895258

| type = <!-- empty -->

| image = Pomalidomide enantiomers.svg

| width = 200

| alt =

| caption =

| chirality = Racemic mixture

<!-- Clinical data -->

| pronounce =

| tradename = Pomalyst, Imnovid

| Drugs.com = {{drugs.com|monograph|pomalidomide}}

| MedlinePlus = a613030

| licence_EU = yes

| DailyMedID = Pomalidomide

| pregnancy_AU = X

| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Pomalidomide (Pomalyst) Use During Pregnancy | website=Drugs.com | date=14 May 2020 | url=https://www.drugs.com/pregnancy/pomalidomide.html | access-date=21 September 2020 | archive-date=25 January 2021 | archive-url=https://web.archive.org/web/20210125172209/https://www.drugs.com/pregnancy/pomalidomide.html | url-status=live }}</ref>

| pregnancy_category =

| routes_of_administration = [[Oral administration|By mouth]]

| class =

| ATC_prefix = L04

| ATC_suffix = AX06

| ATC_supplemental =

<!-- Legal status -->

| legal_AU = S4

| legal_AU_comment = <ref>{{cite web | title=Pomalidomide Medicianz/ Pomalimed/ Pomalidomide Medsurge (Medicianz Healthcare Pty Ltd) | website=Therapeutic Goods Administration (TGA) | date=5 December 2022 | url=https://www.tga.gov.au/resources/prescription-medicines-registrations/pomalidomide-medicianz-pomalimed-pomalidomide-medsurge-medicianz-healthcare-pty-ltd | access-date=9 April 2023 | archive-date=18 March 2023 | archive-url=https://web.archive.org/web/20230318044400/https://www.tga.gov.au/resources/prescription-medicines-registrations/pomalidomide-medicianz-pomalimed-pomalidomide-medsurge-medicianz-healthcare-pty-ltd | url-status=live }}</ref><ref>{{cite web | title=Prescription medicines: registration of new chemical entities in Australia, 2014 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/resource/guidance/prescription-medicines-registration-new-chemical-entities-australia-2014 | access-date=10 April 2023 | archive-date=10 April 2023 | archive-url=https://web.archive.org/web/20230410065838/https://www.tga.gov.au/resources/resource/guidance/prescription-medicines-registration-new-chemical-entities-australia-2014 | url-status=live }}</ref>

| legal_BR = C3

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-15 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>

| legal_CA = Rx-only

| legal_CA_comment = <ref>{{cite web | url=https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=90423 | title=Pomalyst Product information | publisher=Health Canada | access-date=16 December 2023}}</ref>

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = POM

| legal_UK_comment = <ref>{{cite web | title=Imnovid 1 mg hard capsules - Summary of Product Characteristics (SmPC) | website=(emc) | date=16 June 2020 | url=https://www.medicines.org.uk/emc/product/1262/smpc | access-date=21 September 2020 | archive-date=26 October 2020 | archive-url=https://web.archive.org/web/20201026072630/https://www.medicines.org.uk/emc/product/1262/smpc | url-status=live }}</ref>

| legal_US = Rx-only

| legal_US_comment = <ref name = "Pomalyst PI" />

| legal_EU = Rx-only

| legal_EU_comment = <ref name="Imnovid EPAR" />

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->

| bioavailability = 73% (at least)<ref>{{cite web|title=Imnovid 1 mg Hard Capsules. Summary of Product Characteristics. 5.2 Pharmacokinetic properties|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002682/WC500147717.pdf|publisher=Celgene Europe Ltd.|access-date=21 August 2016|page=22|archive-date=27 June 2016|archive-url=https://web.archive.org/web/20160627190420/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002682/WC500147717.pdf|url-status=live}}</ref>

| protein_bound = 12–44%

| metabolism = [[Liver]] (mostly [[CYP1A2]]- and [[CYP3A4]]-mediated; some minor contributions by [[CYP2C19]] and [[CYP2D6]])

| metabolites =

| onset =

| elimination_half-life = 7.5 hours

| duration_of_action =

| excretion = Urine (73%), faeces (15%)

<!-- Identifiers -->

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 19171-19-8

| CAS_supplemental =

| PubChem = 134780

| IUPHAR_ligand = 7348

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB08910

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 118785

| UNII_Ref = {{fdacite|changed|FDA}}

| UNII = D2UX06XLB5

| KEGG_Ref = {{keggcite|changed|kegg}}

| KEGG = D08976

| ChEBI_Ref =

| ChEBI =

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 43452

| NIAID_ChemDB =

| PDB_ligand =

| synonyms =

<!-- Chemical and physical data -->

| IUPAC_name = 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

| C=13 | H=11 | N=3 | O=4

| SMILES = C1CC(=O)NC(=O)C1N2C(=O)C3=C(C2=O)C(=CC=C3)N

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 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)

| StdInChI_comment =

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = UVSMNLNDYGZFPF-UHFFFAOYSA-N

| density =

| density_notes =

| melting_point =

| melting_high =

| melting_notes =

| boiling_point =

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| specific_rotation =

'''Pomalidomide''', sold under the brand names '''Pomalyst''' and '''Imnovid''',<ref name = "Pomalyst PI" /><ref name="Imnovid EPAR" /> is an [[anti-cancer medication]] used for the treatment of [[multiple myeloma]] and [[AIDS]]-related [[Kaposi sarcoma]].<ref name = "Pomalyst PI">{{cite web | title=Pomalyst- pomalidomide capsule | website=DailyMed | date=7 December 2017 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2b25ef01-5c9e-11e1-b86c-0800200c9a66 | access-date=21 September 2020 | archive-date=20 October 2020 | archive-url=https://web.archive.org/web/20201020205544/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2b25ef01-5c9e-11e1-b86c-0800200c9a66 | url-status=live }}</ref>

Pomalidomide was approved for medical use in the United States in February 2013,<ref>{{cite web | title=Drug Approval Package: Pomalyst (pomalidomide) Capsules NDA #204026 | website=U.S. [[Food and Drug Administration]] (FDA) | date=8 February 2013 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204026Orig1s000TOC.cfm | access-date=21 September 2020 | archive-date=29 March 2021 | archive-url=https://web.archive.org/web/20210329224959/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204026Orig1s000TOC.cfm | url-status=live }}</ref> and in the European Union in August 2013.<ref name="Imnovid EPAR" /> It is available as a [[generic medication]].<ref>{{cite web | title=2020 First Generic Drug Approvals | website=U.S. Food and Drug Administration | date=23 February 2021 | url=https://www.fda.gov/drugs/first-generic-drug-approvals/2020-first-generic-drug-approvals | access-date=12 May 2023 | archive-date=26 September 2021 | archive-url=https://web.archive.org/web/20210926025105/https://www.fda.gov/drugs/first-generic-drug-approvals/2020-first-generic-drug-approvals | url-status=live }}</ref>

== 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]];<ref name="Imnovid EPAR" /> 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.<ref name="Imnovid EPAR">{{cite web | title=Imnovid EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/imnovid-previously-pomalidomide-celgene | access-date=21 September 2020 | archive-date=27 October 2020 | archive-url=https://web.archive.org/web/20201027132039/https://www.ema.europa.eu/en/medicines/human/EPAR/imnovid-previously-pomalidomide-celgene | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref>

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;<ref name="NCI pomalidomide" /> 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.<ref name="NCI pomalidomide">{{cite web | title=Pomalidomide | website=National Cancer Institute | date=13 February 2013 | url=https://www.cancer.gov/about-cancer/treatment/drugs/pomalidomide | access-date=12 May 2023 | archive-date=15 January 2023 | archive-url=https://web.archive.org/web/20230115084913/https://www.cancer.gov/about-cancer/treatment/drugs/pomalidomide | url-status=live }} {{PD-notice}}</ref><ref>{{cite web | title=FDA grants accelerated approval to pomalidomide for Kaposi sarcoma | website=U.S. Food and Drug Administration | date=15 May 2020 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pomalidomide-kaposi-sarcoma | access-date=12 May 2023 | archive-date=9 May 2023 | archive-url=https://web.archive.org/web/20230509061138/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pomalidomide-kaposi-sarcoma | url-status=live }} {{PD-notice}}</ref><ref>{{cite press release | title=FDA approves pomalidomide for AIDS-related Kaposi sarcoma | website=National Cancer Institute | date=15 May 2020 | url=https://ccr.cancer.gov/news/article/fda-approves-pomalidomide-for-aids-related-kaposi-sarcoma | access-date=12 May 2023 | archive-date=8 May 2023 | archive-url=https://web.archive.org/web/20230508204356/https://ccr.cancer.gov/news/article/fda-approves-pomalidomide-for-aids-related-kaposi-sarcoma | url-status=live }}</ref><ref>{{cite web | title=Cancer Accelerated Approvals | website=U.S. Food and Drug Administration | date=1 May 2023 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/ongoing-cancer-accelerated-approvals | access-date=12 May 2023 | archive-date=27 April 2023 | archive-url=https://web.archive.org/web/20230427230841/https://www.fda.gov/drugs/resources-information-approved-drugs/ongoing-cancer-accelerated-approvals | url-status=live }}</ref>

==Origin and development==

The parent compound of pomalidomide, thalidomide, was originally discovered to inhibit angiogenesis in 1994.<ref>{{cite journal | vauthors = D'Amato RJ, Loughnan MS, Flynn E, Folkman J | title = Thalidomide is an inhibitor of angiogenesis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 9 | pages = 4082–5 | date = April 1994 | pmid = 7513432 | pmc = 43727 | doi = 10.1073/pnas.91.9.4082 | bibcode = 1994PNAS...91.4082D | jstor = 2364596 | doi-access = free }}</ref> Based upon this discovery, thalidomide was taken into clinical trials for cancer, leading to its ultimate FDA approval for multiple myeloma.<ref>{{cite news|last=Altman|first=David|title=From Thalidomide to Pomalyst: Better Living Through Chemistry|url=https://damatolab.com/news/thalidomide-pomalyst-better-living-through-chemistry|date=2 April 2013|access-date=14 May 2021|archive-date=14 May 2021|archive-url=https://web.archive.org/web/20210514043002/https://damatolab.com/news/thalidomide-pomalyst-better-living-through-chemistry|url-status=dead}}</ref> 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.<ref name=pmid11740816>{{cite journal | vauthors = D'Amato RJ, Lentzsch S, Anderson KC, Rogers MS | title = Mechanism of action of thalidomide and 3-aminothalidomide in multiple myeloma | journal = Seminars in Oncology | volume = 28 | issue = 6 | pages = 597–601 | date = December 2001 | pmid = 11740816 | doi = 10.1016/S0093-7754(01)90031-4 }}</ref> This dual activity of pomalidomide makes it more efficacious than thalidomide ''in vitro'' and ''in vivo''.<ref>{{cite journal | vauthors = Lentzsch S, Rogers MS, LeBlanc R, Birsner AE, Shah JH, Treston AM, Anderson KC, D'Amato RJ | title = S-3-Amino-phthalimido-glutarimide inhibits angiogenesis and growth of B-cell neoplasias in mice | journal = Cancer Research | volume = 62 | issue = 8 | pages = 2300–5 | date = April 2002 | pmid = 11956087 }}</ref>

==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 inhibitor]]s including [[rolipram]] and [[pentoxifylline]] do not inhibit myeloma cell growth or angiogenesis.<ref name=pmid11740816/> [[Downregulation and upregulation|Upregulation]] of [[interferon gamma]], [[Interleukin 2|IL-2]] and [[Interleukin 10|IL-10]] as well as downregulation of [[Interleukin 6|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.<ref>{{cite journal |last1=Asatsuma-Okumura |first1=Tomoko |last2=Ito |first2=Takumi |last3=Handa |first3=Hiroshi |title=Molecular mechanisms of cereblon-based drugs |journal=Pharmacology & Therapeutics |date=October 2019 |volume=202 |pages=132–139 |doi=10.1016/j.pharmthera.2019.06.004|pmid=31202702 |doi-access=free }}</ref>

== Side effects ==

Pomalidomide can cause [[Congenital disorder|harm to unborn babies]] when administered during pregnancy.<ref name="Imnovid EPAR" />

Pomalidomide is present in the [[semen]] of people receiving the drug.<ref name="Imnovid EPAR" /><ref name = "Pomalyst PI" />

==Clinical trials==

Phase I trial results showed tolerable side effects.<ref>{{cite journal | vauthors = Streetly MJ, Gyertson K, Daniel Y, Zeldis JB, Kazmi M, Schey SA | title = Alternate day pomalidomide retains anti-myeloma effect with reduced adverse events and evidence of in vivo immunomodulation | journal = British Journal of Haematology | volume = 141 | issue = 1 | pages = 41–51 | date = April 2008 | pmid = 18324965 | doi = 10.1111/j.1365-2141.2008.07013.x | s2cid = 37073246 }}</ref>

Phase II clinical trials for multiple myeloma and [[myelofibrosis]] reported 'promising results'.<ref>{{cite press release |title=Promising Results From 2 Trials Highlighting Pomalidomide Presented At ASH |publisher=[[Celgene]] |date=11 December 2008 |url=http://www.medicalnewstoday.com/releases/132590.php |access-date=28 October 2012 |archive-date=20 September 2018 |archive-url=https://web.archive.org/web/20180920152609/https://www.medicalnewstoday.com/releases/132590.php |url-status=live }}<!-- alternate url for identical press release: http://www.eurekalert.org/pub_releases/2008-12/wsw-prf121008.php --></ref><ref>{{cite conference |url=https://ash.confex.com/ash/2008/webprogram/Paper13194.html |title=Pomalidomide Therapy in Anemic Patients with Myelofibrosis: Results from a Phase-2 Randomized Multicenter Study |first=Ayalew |last=Tefferi |date=8 December 2008 |conference=50th ASH Annual Meeting and Exposition |location=San Francisco |access-date=28 October 2012 |archive-date=20 September 2018 |archive-url=https://web.archive.org/web/20180920152602/https://ash.confex.com/ash/2008/webprogram/Paper13194.html |url-status=live }}</ref>

Phase III results showed significant extension of [[progression-free survival]], and [[overall survival]] (median 11.9 months vs. 7.8 months; ''[[p-value|p]]'' = 0.0002) in patients taking pomalidomide and [[dexamethasone]] vs. dexamethasone alone.<ref>{{cite journal | vauthors = Miguel JS, Weisel K, Moreau P, Lacy M, Song K, Delforge M, Karlin L, Goldschmidt H, Banos A, Oriol A, Alegre A, Chen C, Cavo M, Garderet L, Ivanova V, Martinez-Lopez J, Belch A, Palumbo A, Schey S, Sonneveld P, Yu X, Sternas L, Jacques C, Zaki M, Dimopoulos M | title = 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 | journal = The Lancet. Oncology | volume = 14 | issue = 11 | pages = 1055–1066 | date = September 2013 | pmid = 24007748 | doi = 10.1016/s1470-2045(13)70380-2 | hdl = 2318/150538 | s2cid = 4526729 | url = https://iris.unito.it/bitstream/2318/150538/1/1323531.pdf | hdl-access = free | access-date = 2 September 2019 | archive-date = 20 October 2021 | archive-url = https://web.archive.org/web/20211020032825/https://iris.unito.it/retrieve/handle/2318/150538/60224/1323531.pdf | url-status = live }}</ref>

== References ==

{{reflist}}

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[[Category:Aromatic amines]]

[[Category:Drugs developed by Bristol Myers Squibb]]

[[Category:Cereblon E3 ligase modulators]]

[[Category:Glutarimides]]

[[Category:Orphan drugs]]