Pharmacokinetics of Lenalidomide in Subjects With Various Degrees of Renal Impairment and in Subjects on Hemodialysis

Abstract

The present study investigated the effect of renal impairment and hemodialysis on the pharmacokinetics of lenalidomide following a single 25-mg oral dose in 30 subjects aged 39 to 76 years. A single 25-mg dose was well tolerated by renally impaired subjects. Renal impairment did not alter the oral absorption, protein binding, or nonrenal elimination of lenalidomide. Mean urinary recovery of unchanged lenalidomide was 84% of the dose in subjects with normal renal function (creatinine clearance [CL(Cr)] > 80 mL/min), and it declined to 69%, 38%, and 43% in subjects with mild (50 < or = CL(Cr) < or = 80 mL/min), moderate (30 < or = CL(Cr) < 50 mL/min), and severe (CL(Cr) < 30 mL/min) renal impairment, respectively. The differences in pharmacokinetic parameters between normal renal function and mild renal impairment were minor to modest (11%-32%). As renal impairment progressed to moderate, severe, or end-stage renal disease, total and renal lenalidomide clearance decreased drastically, area under the concentration-time curve increased by approximately 185% to 420%, and t((1/2)) was prolonged by approximately 6 to 12 hours. A 4-hour hemodialysis removed 31% of lenalidomide in the body. Therefore, lenalidomide dose adjustments should be considered for patients with CL(Cr) < 50 mL/min, and the recommendations are given for the starting doses.

A pharmacokinetics and safety phase 1/1b study of oral ixazomib in patients with multiple myeloma and severe renal impairment or end‐stage renal disease requiring haemodialysis

“…Haemodialysis clearance (CLHD) was calculated using the following equation: CLHD = QBIN × R × f. In this equation, QBIN is the blood flow rate into the dialyser, R is the plasma‐to‐blood ratio [estimated using the blood‐to‐plasma AUC ratio (12·7) following single‐dose administration], and f is the fraction of ixazomib removed during haemodialysis, calculated as (AUC in  – AUC out )/AUC in , where AUC in and AUC out are the area under the concentration‐time curve during the haemodialysis interval using samples collected at the entry and exit of the dialyser, respectively (Chen et al , 2007; Khadzhynov et al , 2012; Dahlke et al , 2016). …”

Kidney Disease and Multiple Myeloma

“…Lenalidomide needs to be used with caution in the setting of CKD, and dose reduction is mandatory, because the drug is renally cleared. Despite this information, myelosuppression and other adverse events are more common in this setting (76)(77)(78). Nonetheless, it is not directly nephrotoxic, and therefore, a low dose (e.g., 5-10 mg/d) can be used.…”

Pathogenesis and treatment of renal failure in multiple myeloma

“…On the basis of these data, the following dose modifications for lenalidomide are recommended according to renal function: no dose reduction for creatinine clearance X50 ml/min; reduce dose to 10 mg per day for creatinine clearance 30-50 ml/min; 15 mg every other day for patients with creatinine clearance o30 ml/ min but not on dialysis; and 15 mg thrice per week after each dialysis in patients requiring dialysis. 79 However, more safety data are needed for lenalidomide in patients with moderate or severe renal failure before definite recommendations are made.…”