Lenalidomide

drugbox
IUPAC_name = 3-(4-amino-1-oxo-3"H"-isoindol-2-yl)piperidine-2,6-dione



width = 188
CAS_number = 191732-72-6
ATC_prefix = L04
ATC_suffix = AX04
PubChem = 216326
DrugBank = APRD01303
C = 13 | H = 13 | N = 3 | O = 3
molecular_weight = 259.261 g/mol
bioavailability =
protein_bound = 30%
metabolism = Undetermined
elimination_half-life = 3 hours
excretion = Renal (67% unchanged)
pregnancy_category = X
legal_US = Rx-only
routes_of_administration = Oral

Lenalidomide (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.

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.

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

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". [Vellet, S et al Thalidomide and lenalidomide: mechanism-based potential drug combinations Leukemia and Lymphoma 2008;49(7):1238-1245] "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.

Lenalidomide and Multiple Myeloma

Multiple myeloma is a rare cancer of the blood, characterized by accumulation of a plasma cell clone in the bone marrow. [Armoiry, X et al. Lenalidomide in the treatment of multiple myeloma: a review J of Clin Pharmacy & Therapeutics 2008;33:219-226] 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. Unlike thalidomide, lenalidomide is 50,000 more potent than its parent molecule 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. [Weber, DM et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America N Engl Med 2007;357(21):2133-2142]

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. [Thalidomide- and lenalidomide-associated thromboembolism among patients with cancer JAMA 2006;296(21):2558-2560] 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.

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 [http://www.medscape.com/viewarticle/562417_3] , which is contrary to experience with thalidomide.

In September 2008, the United States FDA included lenalidomide on a list of 20 prescription drugs under investigation for potential safety problems. [http://www.fda.gov/cder/aers/potential_signals/potential_signals_2008Q1.htm] The drug is being investigated for possibly increasing the risk of developing Stevens-Johnson syndrome, a life-threatening condition affecting the skin.

References

* Bennett et al. Thalidomide- and lenalidomide-associated thromboembolism among patients with cancer JAMA 2006;296(21):2558-2560
* List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, Rimsza L, Heaton R, Knight R, Zeldis JB. Efficacy of lenalidomide in myelodysplastic syndromes. "N Engl J Med" 2005;352:549-57. PMID 15703420.
* Chang DH, Liu N, Klimek V, Hassoun H, Mazumder A, Numer SD, Jagannath S, Dhodapkar MV. "Enhancement of ligand dependent activation of human natural killer T cells by lenalidomide: therapeutic implications." Blood 2006;epub ahead of print. PMID 16569772.
* Anderson KC. Lenalidomide and thalidomide: mechanisms of action--similarities and differences. "Semin Hematol" 2005;42(4 Suppl 4):S3-8. PMID 16344099.
* Armoiry, X et al. Lenalidomide in the treatment of multiple myeloma: a review J of Clin Pharmacy & Therapeutics 2008;33:219-226
* Vellet, S et al Thalidomide and lenalidomide: mechanism-based potential drug combinations Leukemia and Lymphoma 2008;49(7):1238-1245
* Weber, DM et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America N Engl Med 2007;357(21):2133-2142

External links

* [http://www.revlimid.com Official website]
* [http://www.myeloma.org/main.jsp?source=link&source_link_id=2048&type=article&tab_id=13&menu_id=94&id=1706 International Myeloma Foundation article on Revlimid]
* [http://www.revlimid.com/pdf/REVLIMID_PI.pdf Prescribing Information]
* [http://www.multiplemyeloma.org/treatments/3.08.02.html IMiDs] Immunomodulatory Drugs are a group of oral drugs that are chemically similar to thalidomide"
* [http://www.news-medical.net/?id=6741 Medical News]


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