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Sunday, 24 February 2013

New Drug Approvals 2013 - Pt. III - Pomalidomide (PomalystTM)

ATC Code: L04A (partial)
Wikipedia: Pomalidomide

On February 8th, the FDA approved Pomalidomide (Tradename: Pomalyst; Research Code: CC-4047, IMiD 3), a thalidomide analogue, indicated for the treatment of multiple myeloma in patients who failed to respond to previous therapies (e.g. lenalidomide and bortezomib).

Multiple myeloma is a form of blood cancer that primarily affects older adults, and arises from the accumulation of abnormal plasma cells in the bone marrow. These abnormal plasma cells produce large amounts of unneeded antibodies, which are then deposited in various organs, causing renal failure, polyneuropathy and other myeloma-associated symptoms.

Pomalidomide, an analogue of thalidomide, is an immunomodulatory agent with antineoplastic activity. Like other thalidomide analogs, the exact mechanism of action is yet not fully understood, however in vitro assays demonstrated that pomalidomide inhibited proliferation and induced apoptosis of hematopoietic tumor cells, including lenalidomide-resistant multiple myeloma cell lines. It has also been shown that pomalidomide enhanced T cell and natural killer (NK) cell-mediated immunity and inhibited production of pro-inflammatory cytokines (e.g., TNF-α and IL-6). For more information take a look at this review.

Pomalidomide, like other thalidomide derivatives, belongs to the -domide USAN/INN stem. Members of this class are thalidomide, lenalidomide (both approved drugs and licensed by Celgene Corporation), and Mitindomide and Endomide. Pomalidomide is a result of a quest for safer analogs of thalidomide, and has a higher potency than any of its predecessors.

Pomalidomide (IUPAC Name: 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione; Canonical smiles: Nc1cccc2C(=O)N(C3CCC(=O)NC3=O)C(=O)c12 ; ChEMBL: CHEMBL43452; PubChem: 134780; ChemSpider: 118785; Standard InChI Key: UVSMNLNDYGZFPF-UHFFFAOYSA-N) is a derivative of thalidomide, with a molecular weight of 273.2 Da, 5 hydrogen bond acceptors, 2 hydrogen bond donors, and has an ALogP of -0.65. The compound is therefore fully compliant with the rule of five.

Pomalidomide is available in the capsular form, and the recommended daily dose is 4 mg on days 1-21 of repeated 28-day cycles until disease progression. Following administration of single oral doses in patients with multiple mieloma, the systematic exposure was characterized by an AUC(Τ) of 400 mL and maximum plasma concentration (Cmax) of 75 ng/mL. At steady state, the mean apparent volume of distribution (Vd/F) was 62-138 L. Pomalidomide is weakly bound to human plasma proteins (12-44%).

Pomalidomide is primarily metabolized in the liver by CYP1A2 and CYP3A4, with additional minor contributions from CYP2C19 and CYP2D6. Pomalidomide is also a substrate for P-glycoprotein (P-gp). The elimination median plasma half-life (t1/2) for pomalidomide is approximately 9.5 hours in healthy subjects and 7.5 in patients with multiple mieloma. Pomalidomide has a mean total body clearance (CL/ F) of 7-10 L/hr.

Pomalidomide has been issued with a black box warning due to its teratogenic profile, i.e., it can cause severe life-threatening birth defects, and also due to its higher risk for venous thromboembolism in patients exposed to the drug. Because of Pomalyst’s embryo-fetal risk, it is available only through the Pomalyst Risk Evaluation and Mitigation Strategy (REMS) Program.

The license holder for PomalystTM is Celgene Corporation, and the full prescribing information can be found here.

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