Lenalidomide

Lenalidomide is an analogue of thalidomide. It has immunomodulatory, antiangiogenic and antineoplastic properties. Its cellular effects work through its target, cereblon, which is part of a cullin ring E3 ubiquitin ligase enzyme complex. When the drug is present, substrate proteins (including Aiolos, Ikaros and CK1α) are marked for ubiquitination and then broken down, and this leads to direct cytotoxic and immunomodulatory effects. These findings come from in vitro work.

Lenalidomide inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells, including MM, mantle cell lymphoma and del (5q) myelodysplastic syndromes, as seen in vitro. It also delays tumor growth in some nonclinical hematopoietic tumor models in vivo, including MM. Its immunomodulatory properties include a higher number and more activation of T cells and natural killer (NK) cells. This leads to direct and enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) through greater secretion of interleukin-2 and interferon-gamma, more NKT cells, and inhibition of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. For MM cells, Lenalidomide and Dxamethasone together act synergistically, both on inhibiting cell proliferation and on inducing apoptosis.

Absorption: Lenalidomide is absorbed rapidly after oral administration. After single and multiple doses in patients with MM or MDS, maximum plasma concentrations occurred between 0.5 and 6 hours post-dose. The pharmacokinetics are linear for single and multiple doses, with AUC and Cmax rising in proportion to the dose. Multiple doses at the recommended dosage do not cause the drug to accumulate. A single 25 mg dose taken with a high-fat meal in healthy subjects reduced the extent of absorption, with an approximate 20% decrease in AUC and 50% decrease in Cmax. The trials that established efficacy and safety gave the drug without regard to food intake, so Lenalidomide can be taken with or without food. Oral absorption in patients with MCL is similar to that seen in patients with MM or MDS.

Distribution: Binding of [14 C]-Lenalidomide to plasma proteins in vitro is approximately 30%. Lenalidomide is present in semen at 2 hours (1379 ng/ejaculate) and at 24 hours (35 ng/ejaculate) after Lenalidomide 25 mg is given daily.

Elimination: The mean half-life of Lenalidomide is 3 hours in healthy subjects and 3 to 5 hours in patients with MM, MDS or MCL.

Metabolism: Lenalidomide is metabolised only to a limited extent. Unchanged Lenalidomide is the main component circulating in humans. Two metabolites have been identified, 5¬ Hydroxy-Lenalidomide and N-Acetyl Lenalidomide, and each makes up less than 5% of parent levels in circulation.

Excretion: Elimination is mainly through the kidneys. After a single oral dose of [14 C]-Lenalidomide 25 mg in healthy subjects, approximately 90% of the radioactive dose was eliminated in urine and 4% in feces within ten days. About 82% of the radioactive dose was excreted as Lenalidomide in urine within 24 hours. Hydroxy-Lenalidomide and N-Acetyl-Lenalidomide accounted for 4.6% and 1.8% of the excreted dose, respectively. Renal clearance of Lenalidomide is higher than the glomerular filtration rate.