Lenangio Mechanism of Action

Pharmacotherapeutic group: Other immunosuppressants. ATC code: L04AX04.
Pharmacology: Pharmacodynamics: Mechanism of action: The lenalidomide mechanism of action includes anti-neoplastic, anti-angiogenic, pro-erythropoietic, and immunomodulatory properties. Specifically, lenalidomide inhibits proliferation of certain haematopoietic 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 haemoglobin production by CD34+ haematopoietic stem cells, and inhibits production of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes.
Pharmacokinetics: Lenalidomide has an asymmetric carbon atom and can therefore exist as the optically active forms S(-) and R(+). Lenalidomide is produced as a racemic mixture. Lenalidomide is generally more soluble in organic solvents but exhibits the greatest solubility in 0.1N HCl buffer.
Absorption: Lenalidomide is rapidly absorbed following oral administration under fasting conditions, with maximum plasma concentrations occurring between 0.5 and 2 hours post-dose. In patients, the maximum concentration (C_max) and area-under-the-concentration time curve (AUC) increase proportionally with increases in dose. Multiple dosing does not cause marked drug accumulation. In plasma, the relative exposures of the S- and R- enantiomers of lenalidomide are approximately 56% and 44%, respectively.
Co-administration with a high-fat and high-calorie meal reduces the extent of absorption, resulting in an approximately 20% decrease in area under the concentration versus time curve (AUC) and 50% decrease in C_max in plasma. However, it has been shown that the drug can be administered without regard to food intake. Thus, lenalidomide can be administered with or without food.
Distribution: (¹⁴C)-lenalidomide binding to plasma proteins was low in both multiple myeloma patients and healthy patients.
Lenalidomide is present in human semen (< 0.01% of the dose) after administration of 25 mg/day and the drug is undetectable in semen of a healthy male 3 days after stopping the substance.
Biotransformation and elimination: Lenalidomide has no inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A.
A majority of lenalidomide is eliminated through urinary excretion. The contribution of renal excretion to total clearance in patients with normal renal function was 90%, with 4% of lenalidomide eliminated in faeces.
Lenalidomide is poorly metabolized as 82% of the dose is excreted unchanged in urine. Hydroxy- lenalidomide and N-acetyl-lenalidomide represent 4.59% and 1.83% of the excreted dose, respectively. The renal clearance of lenalidomide exceeds the glomerular filtration rate and therefore is at least actively secreted to some extent.
At recommended doses (5 to 25 mg/day), half-life in plasma is approximately 3 hours in healthy person and patients with multiple myeloma.
It is indicated that as renal function decreases (< 50 ml/min), the total drug clearance decreases proportionally resulting in an increase in AUC. The half-life of lenalidomide increased from approximately 3.5 hours in patients with creatinine clearance > 50 ml/min to more than 9 hours in patients with reduced renal function < 50 ml/min. However, renal impairment did not alter the oral absorption of lenalidomide. The C_max was similar between healthy subjects and patients with renal impairment. Recommended dose adjustments in patients with impaired renal function are described in Dosage & Administration.