Lenalid 5/Lenalid 10/Lenalid 15/Lenalid 25 Mechanism of Action

Pharmacology: Pharmacodynamics: In healthy volunteers, multiple dosing with lenalidomide appeared to have an effect upon the immune response. The highest dose was 200 mg/day. Dosing occurred once on the morning of Days 1 and 8 and twice daily on Days 2 to 7 inclusive. Statistically significant dose-related decrease in both CD4 and CD8 blood counts was observed from Day 4 onwards. For CD4 counts, the magnitude of the decreases was relatively constant (approximately 300/mm³) on Days 4, 6 and 8, with values approaching 433/mm³. The decrease in mean CD8 counts were up to 242/mm³ on Day 8, with levels still considerably lower than the baseline value at the post-study assessment.
Electrocardiography: A double-blind, randomised, placebo- and active-controlled, single-dose, four-period crossover study was performed to investigate the effects of lenalidomide 10 mg and 50 mg on ECG parameters in healthy male subjects (N=52). Lenalidomide at 10 mg and 50 mg single doses was not observed to affect the QTcF interval, the QRS duration, the PR interval, or heart rate in a treatment related manner.
Multiple Myeloma: Treatment with lenalidomide in MM patients is associated with the induction of antiproliferative effects and apoptosis in malignant myeloma cells due to direct antitumor activity, the alteration of the bone marrow microenvironment, and immune modulation.
Myelodysplastic Syndromes: Treatment with lenalidomide in MDS patients is associated with apoptosis of dysplastic cells in the bone marrow of these patients. Whether long-term lenalidomide therapy affects the CD4 and CD8 counts in MDS patients is not yet known.
Pharmacokinetics: The pharmacokinetics of lenalidomide were evaluated in a single-blind, placebo-controlled, ascending single oral-dose study (see Table 2 as follows). Single oral doses of 5, 20, 50, 100, 200 and 400 mg were administered in the fasted state. Nineteen subjects entered the study and 15 completed the study. (See Table 2.)

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No formal bioavailability studies were performed in humans.
The pharmacokinetics of lenalidomide were evaluated in MDS subjects who received a single 10 mg dose of lenalidomide or multiple doses of lenalidomide (see Table 3 as follows) (see Table 3).

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Geometric mean (CV%) data are presented for all parameters; AUC = area under the concentration versus time curve from time zero to 5 hours; Cmax = maximum concentration; t1/2,z = terminal half-life.
Absorption: Lenalidomide, in healthy volunteers, is rapidly absorbed following oral administration with maximum plasma concentrations occurring between 0.625 and 1.5 hours post-dose. Co-administration with food does not alter the extent of absorption (AUC) but does reduce the maximal plasma concentration (Cmax) by 36%. The pharmacokinetic disposition of lenalidomide is linear. Cmax and AUC increase proportionately with increases in dose. Multiple dosing at the recommended dose-regimen does not result in drug accumulation.
In MM patients maximum plasma concentrations occurred between 0.5 and 4.0 hours post-dose both on Days 1 and 28. AUC and Cmax values increase proportionally with dose following single and multiple doses. Exposure (AUC) in multiple myeloma patients was 57% higher than in healthy male volunteers.
In patients with low- or intermediate-1-risk MDS, a single 10 mg oral dose of lenalidomide is rapidly absorbed with the Cmax observed at around 1 hour post-dose. There is no accumulation of lenalidomide in plasma with multiple does at 10 mg per day. The mean exposure (AUC∞) in MDS patients is approximately 57% higher than healthy male subjects, possibly related to reduced renal function associated with the MDS disease state and secondary to increased age in this patient population. In two subjects with 30 ≤CrCL <50 mL/min, the 5-hour exposure (AUC) on Day 14 was increased by more than 70%, compared with the subjects with CrCL >80 mL/min.
Distribution: In vitro (14C)-lenalidomide binding to plasma proteins is approximately 23-29%.
Lenalidomide is present in semen (<0.01% of the dose) after the administration of 25 mg/day. Lenalidomide is undetectable in the semen of healthy volunteers three days after discontinuation of the drug.
Metabolism: Lenalidomide is not a substrate of hepatic metabolic enzymes in vitro. Unchanged lenalidomide is the predominant circulating component in vivo in humans. Two identified metabolites are hydroxy-lenalidomide and N-acetyl-lenalidomide; each constitutes less than 5% of parent levels in circulation.
In vitro in human liver preparations lenalidomide does not undergo oxidative (cytochrome P450) or conjugative metabolism. Non-enzymatic hydrolysis of lenalidomide occurs in aqueous media and plasma. In vitro lenalidomide does not inhibit or induce cytochrome P450 enzymes, suggesting that clinically relevant drug-drug interactions with cytochrome P450 substrates are unlikely.
Excretion: In healthy volunteers, approximately two-thirds of lenalidomide is eliminated unchanged through urinary excretion. The process exceeds the glomerular filtration rate and therefore active secretion may have some contribution in the overall renal excretion of lenalidomide. Lenalidomide is a weak substrate, but not an inhibitor of P-glycoprotein, suggesting that drug-drug interactions are unlikely with P-glycoprotein substrates and inhibitors.
In MDS patients, urinary excretion of unchanged lenalidomide in 24 hours post-dose averages approximately 65% of the administered dose.
At recommended doses (5 to 25 mg/day), half-life in plasma is approximately 3 hours in healthy volunteers and ranged from 3 to 5 hours in patients with multiple myeloma or MDS.
Special Populations and Conditions: Pediatrics: No pharmacokinetic (PK) data are available in patients below the age of 18 years.
Geriatrics: No dedicated clinical studies have been conducted to evaluate pharmacokinetics of lenalidomide in the elderly. Population PK analyses included patients with ages ranging from 39 to 85 years old, of which 40.8 % were older than 65 years of age, and show that age does not influence the disposition of lenalidomide.
Gender: Based on a population PK analysis of pooled PK dataset containing 147 patients (M/F, 102/45) gender has no effect on lenalidomide pharmacokinetics.
Race: Based on PK studies in Asian patients, there are no clinically relevant differences in the lenalidomide PK parameters when compared to PK parameters obtained in Caucasian patients.
Hepatic Insufficiency: Population PK analyses included patients with mild hepatic impairment (N=16, total bilirubin >1.0 to ≤1.5 x ULN or AST >ULN) and show that mild hepatic impairment does not influence the disposition of lenalidomide. There are no data available for patients with moderate to severe hepatic impairment.
Renal Insufficiency: The pharmacokinetics of lenalidomide were studied in patients with renal impairment due to nonmalignant conditions. In this study, 5 patients with mild renal function impairment (CrCL 56-74 mL/min), 6 patients with moderate renal function impairment (CrCL 33-46 mL/min), 6 patients with severe renal function impairment (CrCL 17-29 mL/min), and 6 patients with end stage renal disease requiring dialysis were administered a single oral 25 mg dose of lenalidomide. As a control group comparator, 7 healthy subjects of similar age with normal renal function (CrCL 83-145 mL/min) were also administered a single oral 25 mg dose of lenalidomide. The pharmacokinetic parameters of lenalidomide were similar in patients with mild impairment and healthy subjects. Patients with moderate and severe renal impairment had a 3-fold increase in half-life and up to 75% decrease in clearance compared to healthy subjects. Patients with end stage renal disease on hemodialysis had an approximately 4.5-fold increase in half-life and an 80% decrease in clearance compared to healthy subjects. Approximately 30% of the drug in the body was removed by a 4-hour dialysis session.
Mean AUC∞ was increased by 137%, 274% and 372% in patients with moderate, severe and end stage renal disease, respectively, as compared to that of normal and mild groups combined (n=12). Renal impairment had no effect on oral absorption (Cmax and tmax).
After a single 10 mg dose of lenalidomide in MDS patients with mild renal impairment, the drug exposure (AUC∞) was increased by 55% and the apparent total clearance was reduced by 35% compared to those observed in MDS patients with normal renal function.
In two MDS patients with moderate renal impairment, lenalidomide exposure after multiple doses was increased to a greater degree (Cmax increased by 41-51% and AUC5 by (74-95%) while renal clearance was decreased by 65-92%. A starting dose adjustment is recommended for MDS patients with moderate renal impairment.