Pharmacokinetic sampling in myelodysplastic syndromes patients was not performed. In multiple myeloma 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 is 57% higher than in healthy male volunteers.

Distribution

In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%.

Metabolism and Excretion

The metabolic profile of lenalidomide in humans has not been studied. In healthy volunteers, approximately two-thirds of lenalidomide is eliminated unchanged through urinary excretion. The process exceeds the glomerular filtration rate and therefore is partially or entirely active. Half life of elimination is approximately 3 hours.

Special Populations

Patients with Renal Impairment: 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 (creatinine clearance 57-74 mL/min), 6 patients with moderate renal function impairment (creatinine clearance 33-46 mL/min), 6 patients with severe renal function impairment (creatinine clearance 17-29 mL/min), and 6 patients with end stage renal disease requiring dialysis were administered a single oral 25-mg dose of REVLIMID. As a control group comparator, 7 healthy subjects of similar age with normal renal function (creatinine clearance 83-145 mL/min) were also administered a single oral 25-mg dose of REVLIMID. As creatinine clearance decreased from mild to severe impairment, half-life increased and drug clearance decreased linearly. Patients with moderate and severe renal impairment had a 3-fold increase in half-life and a 66% to 75% decrease in drug clearance compared to healthy subjects. Patients on hemodialysis (n=6) given a single, 25-mg dose of lenalidomide has an approximate 4.5-fold increase in half-life and an 80% decrease in drug clearance compared to healthy subjects. Approximately 40% of the administered dose was removed from the body during a single dialysis session.

In multiple myeloma patients, those patients with mild renal impairment had an AUC 56% greater than those with normal renal function.

Adjustment of the starting dose of REVLIMID is recommended in patients with moderate or severe (CLcr < 60 mL/min) renal impairment and in patients on dialysis. [see Dosage and Administration (2.1, 2.2)].

Patients with Hepatic Disease: The pharmacokinetics of lenalidomide in patients with hepatic impairment have not been studied.

Age: The effects of age on the pharmacokinetics of lenalidomide have not been studied.

Pediatric: No pharmacokinetic data are available in patients below the age of 18 years.

Gender: The effects of gender on the pharmacokinetics of lenalidomide have not been studied.

Race: Pharmacokinetic differences due to race have not been studied.

13. NONCLINICAL TOXICOLOGY
13.1.Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity: Carcinogenicity studies with lenalidomide have not been conducted.

Mutagenesis: Lena