Pomalidomide

Pomalidomide (INN; marketed as Pomalyst in the U.S.[2] and Imnovid in the EU 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
License data
Pregnancy
category
  • AU: X (High risk)
  • US: X (Contraindicated)
    Routes of
    administration    		Oral (capsules)
    ATC code
    Legal status
    Legal status
    • UK: POM (Prescription only)
    • US: ℞-only
    • In general: ℞ (Prescription only)
    Pharmacokinetic data
    Bioavailability73% (at least)[1]
    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
    ChemSpider
    UNII
    KEGG
    ChEMBL
    ECHA InfoCard100.232.884
    Chemical and physical data
    FormulaC13H11N3O4
    Molar mass273.24 g/mol g·mol−1
    3D model (JSmol)
    ChiralityRacemic mixture
     NY (what is this?)  (verify)

    Pomalidomide was approved in February 2013 by the U.S. Food and Drug Administration (FDA) as a treatment for relapsed and refractory multiple myeloma. 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.[3] It received a similar approval from the European Commission in August 2013.[4]

    Origin and development

    The parent compound of pomalidomide, thalidomide, was originally discovered to inhibit angiogenesis in 1994.[5] Based upon this discovery, thalidomide was taken into clinical trials for cancer, leading to its ultimate FDA approval for multiple myeloma.[6] 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.[7] This dual activity of pomalidomide makes it more efficacious than thalidomide in vitro and in vivo.[8]

    Clinical trials

    Phase I trial results showed tolerable side effects.[9]

    Phase II clinical trials for multiple myeloma and myelofibrosis reported 'promising results'.[10][11]

    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.[12]

    Mechanism

    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.[7] 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.

    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 4 weeks prior to initiating treatment with pomalidomide, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of pomalidomide therapy.

    Pomalidomide is present in the semen of patients receiving the drug. 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. Male patients taking pomalidomide must not donate sperm.[2]

    Notes

      See also

      References
      1. "Imnovid 1 mg Hard Capsules. Summary of Product Characteristics. 5.2 Pharmacokinetic properties" (PDF). Celgene Europe Ltd. p. 22. Retrieved 21 August 2016.
      2. "Pomalyst (pomalidomide) Capsules, for Oral Use. Full Prescribing Information" (PDF). Celgene Corporation, Summit, NJ 07901. Retrieved 26 October 2015.
      3. "Pomalyst (Pomalidomide) Approved By FDA For Relapsed And Refractory Multiple Myeloma". The Myeloma Beacon. Retrieved 2013-08-10.
      4. "Pomalidomide Approved In Europe For Relapsed And Refractory Multiple Myeloma". The Myeloma Beacon. Retrieved 2013-08-10.
      5. D'Amato, Robert J.; Loughnan, Michael S.; Flynn, Evelyn; Folkman, Judah (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.
      6. Altman, David (2 April 2013). "From Thalidomide to Pomalyst: Better Living Through Chemistry". Boston Children's Hospital's Science and Clinical Innovation Blog. Retrieved 21 August 2016.
      7. D'Amato, R; Lentzsch, S; Anderson, KC; Rogers, MS (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.
      8. Lentzsch, S; Rogers, MS; Leblanc, R; Birsner, AE; Shah, JH; Treston, AM; Anderson, KC; D'Amato, RJ (2002). "S-3-Amino-phthalimido-glutarimide inhibits angiogenesis and growth of B-cell neoplasias in mice". Cancer Research. 62 (8): 2300–5. PMID 11956087.
      9. Streetly, Matthew J.; Gyertson, Kylie; Daniel, Yvonne; Zeldis, Jerome B.; Kazmi, Majid; Schey, Stephen A. (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.
      10. "Promising Results From 2 Trials Highlighting Pomalidomide Presented At ASH" (Press release). Celgene. December 11, 2008. Retrieved October 28, 2012.
      11. Tefferi, Ayalew (December 8, 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 October 28, 2012.
      12. San Miguel, J; Weisel, K; Moreau, P; Lacy, M; Song, K; et al. (October 2014). "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). Lancet Oncology. 14 (11): 1055–1066. doi:10.1016/s1470-2045(13)70380-2. PMID 24007748.
      13. "Pomalyst Risk Evaluation and Mitigation Strategy (REMS) Program". Celgene Corporation. Retrieved 21 August 2016.
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