Lenalidomide - How It Works
Clinical pharmacology details from the US FDA-approved label: how Lenalidomide works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Cellular activities of lenalidomide are mediated through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex. In vitro , in the presence of drug, substrate proteins (including Aiolos, Ikaros, and CK1α) are targeted for ubiquitination and subsequent degradation leading to direct cytotoxic and immunomodulatory effects. Lenalidomide inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells including MM, mantle cell lymphoma, and del (5q) myelodysplastic syndromes, follicular lymphoma and marginal zone lymphoma in vitro . Lenalidomide causes a delay in tumor growth in some in vivo nonclinical hematopoietic tumor models including MM. Immunomodulatory properties of lenalidomide include increased number and activation of T cells and natural killer (NK) cells leading to direct and enhanced antibody-dep
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties.
Cellular activities of lenalidomide are mediated through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex.
In vitro , in the presence of drug, substrate proteins (including Aiolos, Ikaros, and CK1α) are targeted for ubiquitination and subsequent degradation leading to direct cytotoxic and immunomodulatory effects.
Lenalidomide inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells including MM, mantle cell lymphoma, and del (5q) myelodysplastic syndromes, follicular lymphoma and marginal zone lymphoma in vitro .
Lenalidomide causes a delay in tumor growth in some in vivo nonclinical hematopoietic tumor models including MM.
Immunomodulatory properties of lenalidomide include increased number and activation of T cells and natural killer (NK) cells leading to direct and enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) via increased secretion of interleukin-2 and interferon-gamma, increased numbers of NKT cells, and inhibition of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes.
In MM cells, the combination of lenalidomide and dexamethasone synergizes the inhibition of cell proliferation and the induction of apoptosis.
The combination of lenalidomide and rituximab increases ADCC and direct tumor apoptosis in follicular lymphoma cells and increases ADCC in marginal zone lymphoma cells compared to rituximab alone in vitro .
12.2 Pharmacodynamics Cardiac Electrophysiology The effect of lenalidomide on the QTc interval was evaluated in 60 healthy male subjects in a thorough QT study.
At a dose two times the maximum recommended dose, lenalidomide did not prolong the QTc interval.
The largest upper bound of the two-sided 90% CI for the mean differences between lenalidomide and placebo was below 10 ms.
12.3 Pharmacokinetics Absorption Following single and multiple doses of lenalidomide in patients with MM or MDS, the maximum plasma concentrations occurred between 0.5 hour and 6 hours post-dose.
The single and multiple dose pharmacokinetic disposition of lenalidomide is linear with AUC and C max values increasing proportionally with dose.
Multiple doses of lenalidomide at the recommended dosage does not result in drug accumulation.
Administration of a single 25 mg dose of lenalidomide with a high-fat meal in healthy subjects reduces the extent of absorption, with an approximate 20% decrease in AUC and 50% decrease in C max .
In the trials where the efficacy and safety were established for lenalidomide, the drug was administered without regard to food intake.
Lenalidomide can be administered with or without food.
The oral absorption rate of lenalidomide in patients with MCL is similar to that observed in patients with MM or MDS.
Distribution In vitro [ 14 C]-lenalidomide binding to plasma proteins is approximately 30%.
Lenalidomide is present in semen at 2 hours (1,379 ng/ejaculate) and 24 hours (35 ng/ejaculate) after the administration of lenalidomide 25 mg daily.
Pharmacokinetics
12.3 Pharmacokinetics Absorption Following single and multiple doses of lenalidomide in patients with MM or MDS, the maximum plasma concentrations occurred between 0.5 hour and 6 hours post-dose. The single and multiple dose pharmacokinetic disposition of lenalidomide is linear with AUC and C max values increasing proportionally with dose. Multiple doses of lenalidomide at the recommended dosage does not result in drug accumulation. Administration of a single 25 mg dose of lenalidomide with a high-fat meal in healthy subjects reduces the extent of absorption, with an approximate 20% decrease in AUC and 50% decrease in C max . In the trials where the efficacy and safety were established for lenalidomide, the drug was administered without regard to food intake. Lenalidomide can be administered with or without food. The oral absorption rate of lenalidomide in patients with MCL is similar to that observed in patients with MM or MDS. Distribution In vitro [ 14 C]-lenalidomide binding to plasma proteins is approximately 30%. Lenalidomide is present in semen at 2 hours (1,379 ng/ejaculate) and 24 hours (35 ng/ejaculate) after the administration of lenalidomide 25 mg daily. Elimination The mean half-life of lenalidomide is 3 hours in healthy subjects and 3 hours to 5 hours in patients with MM, MDS or MCL. Metabolism Lenalidomide undergoes limited metabolism. Unchanged lenalidomide is the predominant circulating component in humans. Two identified metabolites are 5-hydroxy-lenalidomid