Linadex Mechanism of Action

Pharmacology: Mechanism of action: The Lenalidomide mechanism of action includes anti-neoplastic, anti-angiogenic, pro-erythropoietic, and immunomodulatory properties. Specifically, Lenalidomide inhibits proliferation of certain hematopoietic tumour cells (including MM plasma tumour cells and those with deletions of chromosome 5), enhances T cell- and Natural Killer (NK) cell-mediated immunity and increases the number of NK T cells, inhibits angiogenesis by blocking the migration and adhesion of endothelial cells and the formation of microvessels, augments foetal hemoglobin production by CD34+ hematopoietic stem cells, and inhibits production of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes.
In MDS Del (5q), Lenalidomide was shown to selectively inhibit the abnormal clone by increasing the apoptosis of Del (5q) cells.
Lenalidomide binds directly to cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex that includes deoxyribonucleic acid (DNA) damage-binding protein 1(DDB1), cullin 4 (CUL4), and regulator of cullins 1 (Roc1). In the presence of Lenalidomide, cereblon binds substrate proteins Aiolos and Ikaros which are lymphoid transcriptional factors, leading to their ubiquitination and subsequent degradation resulting in cytotoxic and immunomodulatory effects.
Pharmacokinetics: The study was an open label, balanced, randomized, two-treatment, two-period, two-sequence, single oral dose, crossover, bioequivalence study in 43 healthy, adult, human male subjects under fasting condition. The study was conducted following an oral administration of one capsule 25 mg of the test drug or one capsule 25 mg of the reference drug.
Based on the pharmacokinetic parameters of Lenalidomide (N = 43), mean ± SD for Test Drug and Reference Drug showed: T_max values were 0.750 (0.500 - 2.000) and 0.767 (0.500 - 2.750) hour, respectively; C_max values were 568.077 ± 123.4757 and 573.912 ± 141.9003 ng/mL, respectively; AUC_0-t values were 2219.402 ± 541.0999 and 2237.919 ± 503.2726 ng.h/mL, respectively; AUC_0-∞ values were 2237.632 ± 559.1299 and 2255.280 ± 518.8979 ng.h/mL, respectively; λ_z values were 0.203 ± 0.0278 and 0.209 ± 0.0298 (l/h), respectively; T_½ values were 3.469 ± 0.4813 and 3.375 ± 0.4715 hours, respectively; AUC_%Extrap_obs (%) values were 0.724 ± 0.4454 and 0.696 ± 0.4303, respectively.
Relative bioavailability results for Test Drug and Reference Drug of Lenalidomide were as following: 90.00% Confidence Intervals of C_max, AUC_0-t, AUC_0-∞ were 94.24 - 105.49, 97.39 - 100.38, 97.42 - 100.41, respectively. Intra subject CV (%) of C_max, AUC_0-t, AUC_0-∞ were 15.6, 4.2 and 4.2%, respectively.
Conclusion: These results showed that Lenalidomide capsule 25 mg was bioequivalent to the reference product.