Pharmacokinetics of lenalidomide in subjects with various degrees of renal function

Abstract

2520 Background: Lenalidomide is a novel oral immunomodulatory drug approved for treating myelodysplastic syndrome (MDS) and multiple myeloma (MM). As unchanged lenalidomide is eliminated predominantly by urinary excretion, the present study investigated the effect of renal impairment (RI) on pharmacokinetics (PK) of lenalidomide. Results were used to refine initial dosing recommendations based on a subject’s estimated creatinine clearance. Methods: The study was conducted at 3 clinical centers. Thirty male and female subjects aged 39–76 years were stratified into 5 groups based on their creatinine clearance (CLCr) values: normal renal function (NRF) (CLCr > 80 mL/min; N = 7), mild RI (50 = CLCr = 80 mL/min; N = 5), moderate RI (30 = CLCr < 50 mL/min; N = 6), severe RI (CLCr < 30 mL/min, but not on dialysis; N = 6), and end stage renal disease (ESRD, requiring dialysis; N = 6). Subjects with NRF, mild, moderate or severe RI received a single 25-mg oral dose of lenalidomide. Subjects with ESRD received 2 single 25 mg doses which were separated by 7–10 days: one dose on a non-dialysis day and the other dose 3 hours before a 4-hour haemodialysis. Assessments included PK and safety parameters. Results: All subjects completed the study. Total and renal clearance of lenalidomide were strongly correlated with CLCr (R > 0.9, p < 0.01). As a result, AUC8 increased with decreasing CLCr. The mean difference in AUC8 between NRF and mild RI was < 20%. Compared with the pooled data from NRF and mild RI groups, mean AUC8 increased approximately 140% in moderate RI, 240% in severe RI, and 360% in ESRD (off dialysis). There was no correlation between Cmax or Tmax and CLCr. Approximately 10% of the dose was recovered in the dialysate of subjects with ESRD. Protein binding of lenalidomide was not markedly affected by RI (∼35 - 44%). The drug was well tolerated. On the basis of these data, recommendations for initial starting doses were made ( Table below). Conclusions: Lenalidomide dosage adjustment should be considered for patients with CLCr < 50 mL/min. [Table: see text] No significant financial relationships to disclose.