Lenalidomide: Wikis

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1 : 1 mixture (racemate)
Systematic (IUPAC) name
(RS)-3-(4-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione
Identifiers
CAS number 191732-72-6
ATC code L04AX04
PubChem 216326
DrugBank APRD01303
Chemical data
Formula C 13H13N3O3  
Mol. mass 259.261 g/mol
Pharmacokinetic data
Bioavailability  ?
Protein binding 30%
Metabolism Undetermined
Half life 3 hours
Excretion Renal (67% unchanged)
Therapeutic considerations
Pregnancy cat. X
Legal status -only (US)
Routes Oral
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Lenalidomide (pronounced /lɛnəˈlɪdɵmaɪd/), initially known as CC-5013 and marketed as Revlimid by Celgene, is a derivative of thalidomide introduced in 2004. It was initially intended as a treatment for multiple myeloma, for which thalidomide is an accepted therapeutic modality, but has also shown efficacy in the class of hematological disorders known as myelodysplastic syndromes (MDS). Revlimid is also known as Revamid in the UK.

The exact mechanism of the immunomodulatory drugs (i.e., thalidomide, CC-4047/Actimid and lenalidomide) is not known. Apart from interfering with the immune system, they are also thought to act on angiogenesis.

Lenalidomide and bortezomib are considered therapeutic breakthroughs in myeloma, which generally carries a poor prognosis.

Contents

Mechanism of action

Lenalidomide has been used to successfully treat both inflammatory disorders and cancers in the past 10 years. There are multiple mechanisms of action, and they can be simplified by organizing them as mechanisms of action in vitro and in vivo.[1] In vitro, lenalidomide has three main activities: direct anti-tumour effect, inhibition of the microenvironment support for tumour cells, and immunomodulatory role. In vitro, lenalidomide induces tumour cell apoptosis directly and indirectly by inhibition of bone marrow stromal cell support, by anti-angiogenic and anti-osteoclastogenic effects, and by immunomodulatory activity. Lenalidomide has a broad range of activities that can be exploited to treat many hematologic and solid cancers.

Treatment of multiple myeloma

Multiple myeloma is a rare cancer of the blood, characterized by accumulation of a plasma cell clone in the bone marrow.[2] Lenalidomide is one of the novel drug agents used to treat multiple myeloma. It is a small molecular analogue of thalidomide that was originally found based on its ability to effectively inhibit tumour necrosis factor production. Lenalidomide is 50,000 times more potent than thalidomide in inhibiting tumour necrosis factor-alpha, and has less severe adverse drug reactions. In a phase III clinical study, Weber et al. found that lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma was superior to the old treatment of multiple myeloma consisting of high-dose dexamethasone alone.[3]

Nonetheless, lenalidomide, like its parent compound thalidomide, causes venous thromboembolism (VTE), a potentially serious complication with their use. Bennett et al. have reviewed incidents of lenalidomide-associated VTE among patients with multiple myeloma.[4] They have found that there are high rates of VTE when patients with multiple myeloma received thalidomide or lenalidomide in conjunction with dexamethasone, melphalan, or doxorubicin. When lenalidomide and dexamethasone are used to treat multiple myeloma, a median of 14% of patients had VTE (range,3-75%). Patients who took prophylaxis to treat lenalidomide-associated VTE, such as aspirin, thromboembolism rates were found to be lower than without prophylaxis, frequently lower than 10%. Clearly, thromboembolism is a serious adverse drug reaction associated with lenalidomide, as well as thalidomide. In fact, a black box warning is included in the package insert for lenalidomide, indicating that lenalidomide-dexamethasone treatment for multiple myeloma is complicated by high rates of thromboembolism.

Currently, clinical trials are underway to further test the efficacy of lenalidomide to treat multiple myeloma and how to prevent the lenalidomide associated venous thromboembolism.

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Use in USA

On June 29, 2006, lenalidomide received U.S. Food and Drug Administration (FDA) clearance for use in combination with dexamethasone in patients with multiple myeloma who have received at least one prior therapy.

Use in the UK

On 23 April 2009, The National Institute for Health and Clinical Excellence (NICE) issued a Final Appraisal Determination (FAD) approving lenalidomide, in combination with dexamethasone, as an option to treat patients who suffer from multiple myeloma who have received two or more prior therapies in England and Wales. [5] [6]

Treatment of myelodysplastic syndromes (MDS)

With myelodysplastic syndromes, the best results of lenalidomide were obtained in patients with deletion 5q (List et al. 2005).

It was approved by the FDA on December 27, 2005 for patients with low or intermediate-1 risk MDS with 5q- with or without additional cytogenetic abnormalities. A completed Phase II, multi-centre, single-arm, open-label study evaluated the efficacy and safety of Revlimid monotherapy treatment for achieving haematopoietic improvement in red blood cell (RBC) transfusion dependent subjects with low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality.

63.8% of subjects had achieved RBC-transfusion independence accompanied by a median increase of 5.8 g/dL in blood Hgb concentration from baseline to the maximum value during the response period. Major cytogenetic responses were observed in 44.2% and minor cytogenetic responses were observed in 24.2% of the evaluable subjects. Improvements in bone marrow morphology were also observed. The results of this study demonstrate the efficacy of Revlimid for the treatment of subjects with Low- or Intermediate-1-risk MDS and an associated del 5 cytogenetic abnormality.[7][8][9]

Treatment of other cancers

Lenalidomide is undergoing clinical trial as a treatment for Hodgkin's Lymphoma.[10]

Risks

Lenalidomide is related to thalidomide which is known to be teratogenic. While laboratory tests have suggested lenalidomide is not teratogenic it is categorized as such because of its structural similarities with thalidomide. It therefore has the pregnancy category X and cannot be prescribed for women who are pregnant or who might be conceiving. For this reason, the drug is only available through a restricted distribution system called RevAssistSM.

Other potential side effects are thrombosis, pulmonary embolus, and hepatotoxicity, as well as bone marrow toxicity resulting in neutropenia and thrombocytopenia. Myelosuppression is the major dose-limiting toxicity, which is contrary to experience with thalidomide.[11]

In March 2008, the U.S. Food and Drug Administration (FDA) included lenalidomide on a list of 20 prescription drugs under investigation for potential safety problems. The drug is being investigated for possibly increasing the risk of developing Stevens-Johnson syndrome, a life-threatening condition affecting the skin.[12]

References

  1. ^ Vallet S, Palumbo A, Raje N, Boccadoro M, Anderson KC (July 2008). "Thalidomide and lenalidomide: Mechanism-based potential drug combinations". Leukemia & Lymphoma 49 (7): 1238–45. doi:10.1080/10428190802005191. PMID 18452080.  
  2. ^ Armoiry X, Aulagner G, Facon T (June 2008). "Lenalidomide in the treatment of multiple myeloma: a review". Journal of Clinical Pharmacy and Therapeutics 33 (3): 219–26. doi:10.1111/j.1365-2710.2008.00920.x. PMID 18452408.  
  3. ^ Weber DM, Chen C, Niesvizky R, et al. (November 2007). "Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America". The New England Journal of Medicine 357 (21): 2133–42. doi:10.1056/NEJMoa070596. PMID 18032763.  
  4. ^ Bennett CL, Angelotta C, Yarnold PR, et al. (December 2006). "Thalidomide- and lenalidomide-associated thromboembolism among patients with cancer". JAMA : the Journal of the American Medical Association 296 (21): 2558–60. doi:10.1001/jama.296.21.2558-c. PMID 17148721.  
  5. ^ REVLIMID Receives Positive Final Appraisal Determination from National Institute for Health and Clinical Excellence (NICE) for Use in the National Health Service (NHS) in England and Wales, Reuters, April 23, 2009, http://www.reuters.com/article/pressRelease/idUS83290+23-Apr-2009+BW20090423  
  6. ^ http://www.nice.org.uk/nicemedia/pdf/MMLenalidomideFAD.pdf
  7. ^ List A, Kurtin S, Roe DJ, et al. (February 2005). "Efficacy of lenalidomide in myelodysplastic syndromes". The New England Journal of Medicine 352 (6): 549–57. doi:10.1056/NEJMoa041668. PMID 15703420.  
  8. ^ List AF (August 2005). "Emerging data on IMiDs in the treatment of myelodysplastic syndromes (MDS)". Seminars in Oncology 32 (4 Suppl 5): S31–5. doi:10.1053/j.seminoncol.2005.06.020. PMID 16085015.  
  9. ^ List A, Dewald G, Bennett J, et al. (October 2006). "Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion". The New England Journal of Medicine 355 (14): 1456–65. doi:10.1056/NEJMoa061292. PMID 17021321.  
  10. ^ "Phase II Study of Lenalidomide for the Treatment of Relapsed or Refractory Hodgkin's Lymphoma". ClinicalTrials.gov. US National Institutes of Health. 2009 February. http://clinicaltrials.gov/ct2/show/NCT00478959.  
  11. ^ Rao KV (September 2007). "Lenalidomide in the treatment of multiple myeloma". American Journal of Health-system Pharmacy : AJHP : Official Journal of the American Society of Health-System Pharmacists 64 (17): 1799–807. doi:10.2146/ajhp070029. PMID 17724360.  
  12. ^ "Potential Signals of Serious Risks/New Safety Information Identified from the Adverse Event Reporting System (AERS) between January - March 2008". US Department of Health & Human Services. FDA. Marc 2008. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm085914.htm.  

Further reading

External links


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