Chen Nianhang, Lau Henry, Kong Linghui, Kumar Gondi, Zeldis Jerome B, Knight Robert, Laskin Oscar L
Celgene Corporation, 86 Morris Avenue, Summit, NJ 07091, USA.
J Clin Pharmacol. 2007 Dec;47(12):1466-75. doi: 10.1177/0091270007309563. Epub 2007 Oct 22.
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.
本研究调查了肾功能损害和血液透析对30名年龄在39至76岁的受试者单次口服25毫克来那度胺后药代动力学的影响。肾功能受损的受试者对单次25毫克剂量耐受性良好。肾功能损害未改变来那度胺的口服吸收、蛋白结合或非肾清除率。在肾功能正常（肌酐清除率[CL(Cr)]>80 mL/min）的受试者中，未改变的来那度胺的平均尿回收率为给药剂量的84%，而在轻度（50≤CL(Cr)≤80 mL/min）、中度（30≤CL(Cr)<50 mL/min）和重度（CL(Cr)<30 mL/min）肾功能损害的受试者中，该回收率分别降至69%、38%和43%。肾功能正常与轻度肾功能损害之间药代动力学参数的差异较小至中等（11%-32%）。随着肾功能损害进展至中度、重度或终末期肾病，来那度胺的总清除率和肾清除率急剧下降，浓度-时间曲线下面积增加约185%至420%，半衰期延长约6至12小时。4小时的血液透析清除了体内31%的来那度胺。因此，对于CL(Cr)<50 mL/min的患者应考虑调整来那度胺剂量，并给出了起始剂量的建议。
