| Systematic (IUPAC) name | |
|---|---|
| (RS)-3-(4-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione | |
| Clinical data | |
| Trade names | Revlimid |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a608001 |
| Pregnancy cat. | X |
| Legal status | ℞-only (US) |
| Routes | Oral |
| Pharmacokinetic data | |
| Protein binding | 30% |
| Metabolism | Undetermined |
| Half-life | 3 h |
| Excretion | Renal (67% unchanged) |
| Identifiers | |
| CAS number | 191732-72-6 |
| ATC code | L04AX04 |
| PubChem | CID 216326 |
| DrugBank | APRD01303 |
| ChemSpider | 187515 |
| UNII | F0P408N6V4 |
| KEGG | D04687 |
| ChEMBL | CHEMBL848 |
| Chemical data | |
| Formula | C13H13N3O3 |
| Mol. mass | 259.261 g/mol |
| SMILES | eMolecules & PubChem |
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Lenalidomide ( /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 treatment. Lenalidomide has also shown efficacy in the class of hematological disorders known as myelodysplastic syndromes (MDS). Lenalidomide and bortezomib are considered therapeutic breakthroughs in the treatment of myeloma, which generally carries a poor prognosis.
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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-tumor effect, inhibition of the microenvironment support for tumor cells, and immunomodulatory role. In vivo, lenalidomide induces tumor 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.
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 analog of thalidomide that was originally found based on its ability to effectively inhibit tumor necrosis factor production. Lenalidomide is 50,000 times more potent than thalidomide in inhibiting tumor 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, may cause 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.
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.
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]
With myelodysplastic syndromes (MDS), the best results of lenalidomide were obtained in patients with deletion 5q.[7]
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]
Lenalidomide is undergoing clinical trial as a treatment for Hodgkin's Lymphoma,[10] as well as non-Hodgkin's Lymphoma, Chronic Lymphocytic Leukemia and solid tumor cancers, such as carcinoma of the pancreas.[11]
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 in the United States (under the name Revlimid) 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.[12]
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.[13]