Frank Bridoux1,2, Nianhang Chen3, Stephane Moreau4,5, Bertrand Arnulf6, Eric Moumas7,4, Julie Abraham4,5, Estelle Desport7,4, Arnaud Jaccard4,5, Jean Paul Fermand6. 1. Department of Nephrology, Hôpital Jean Bernard CHU Poitiers, 2, rue de la Milétrie 86021 Poitiers France and INSERM CIC 1402, University Hospital, University of Poitiers, Poitiers, France. f.bridoux@chu-poitiers.fr. 2. Centre national de reference amylose AL et autres maladies à depots d'immunoglobulines monoclonales, University Hospital, University of Poitiers, Poitiers, France. f.bridoux@chu-poitiers.fr. 3. Department of Clinical Pharmacology, Translational Development, Celgene, Summit, NJ, USA. 4. Centre national de reference amylose AL et autres maladies à depots d'immunoglobulines monoclonales, University Hospital, University of Poitiers, Poitiers, France. 5. Department of Clinical Hematology, University Hospital, University of Limoges, Limoges, France. 6. Department of Hematology and Immunology and EA 3963, Hôpital Saint Louis, Paris, France. 7. Department of Nephrology, Hôpital Jean Bernard CHU Poitiers, 2, rue de la Milétrie 86021 Poitiers France and INSERM CIC 1402, University Hospital, University of Poitiers, Poitiers, France.
Abstract
PURPOSE: Renal impairment (RI) is a common comorbidity in multiple myeloma (MM). Current dose adjustments recommended for renally excreted lenalidomide are based on data from noncancer patients. This study evaluated the pharmacokinetics, safety, efficacy, and exposure-response for lenalidomide plus dexamethasone in patients with relapsed/refractory MM and stable RI using the recommended dose adjustments. METHODS: This phase 2 multicenter, open-label study stratified patients into 5 groups based on creatinine clearance (CrCl) calculated by Cockcroft-Gault equation: normal renal function (CrCl > 80 mL/min), mild RI (50 ≤ CrCl ≤ 80 mL/min), moderate RI (30 ≤ CrCl < 50 mL/min), severe RI (CrCl < 30 mL/min), and end-stage renal disease requiring hemodialysis. Dosing was based on the lenalidomide label. RESULTS: Among 38 patients, the median age was 68 (range 62-74) years, and poorer renal function was associated with older age, more advanced disease, and more lines of prior therapy. Lenalidomide clearance declined with decreased CrCl. Mean lenalidomide area under plasma concentration-time curve (AUC) was within ±25 % of the target AUC in each group. Overall response was 76 %, and safety profiles were similar across groups, with no exposure-dependent trend in efficacy or toxicity. Estimated glomerular filtration rates calculated using the simplified Modification of Diet in Renal Disease equation highly correlated with lenalidomide clearance and, in 87 % of patients, would lead to assigning the same starting dose of lenalidomide as CrCl. CONCLUSIONS: In patients with stable renal function, the recommended dose adjustments achieved proper plasma exposure and similar safety and efficacy across renal groups.
PURPOSE:Renal impairment (RI) is a common comorbidity in multiple myeloma (MM). Current dose adjustments recommended for renally excreted lenalidomide are based on data from noncancer patients. This study evaluated the pharmacokinetics, safety, efficacy, and exposure-response for lenalidomide plus dexamethasone in patients with relapsed/refractory MM and stable RI using the recommended dose adjustments. METHODS: This phase 2 multicenter, open-label study stratified patients into 5 groups based on creatinine clearance (CrCl) calculated by Cockcroft-Gault equation: normal renal function (CrCl > 80 mL/min), mild RI (50 ≤ CrCl ≤ 80 mL/min), moderate RI (30 ≤ CrCl < 50 mL/min), severe RI (CrCl < 30 mL/min), and end-stage renal disease requiring hemodialysis. Dosing was based on the lenalidomide label. RESULTS: Among 38 patients, the median age was 68 (range 62-74) years, and poorer renal function was associated with older age, more advanced disease, and more lines of prior therapy. Lenalidomide clearance declined with decreased CrCl. Mean lenalidomide area under plasma concentration-time curve (AUC) was within ±25 % of the target AUC in each group. Overall response was 76 %, and safety profiles were similar across groups, with no exposure-dependent trend in efficacy or toxicity. Estimated glomerular filtration rates calculated using the simplified Modification of Diet in Renal Disease equation highly correlated with lenalidomide clearance and, in 87 % of patients, would lead to assigning the same starting dose of lenalidomide as CrCl. CONCLUSIONS: In patients with stable renal function, the recommended dose adjustments achieved proper plasma exposure and similar safety and efficacy across renal groups.
Authors: Zaiwei Song; Lan Ma; Li Bao; Yi Ma; Ping Yang; Dan Jiang; Aijun Liu; Lu Zhang; Yan Li; Yinchu Cheng; Fei Dong; Rongsheng Zhao; Hongmei Jing Journal: Front Pharmacol Date: 2022-06-23 Impact factor: 5.988
Authors: Jim H Hughes; Richard N Upton; Stephanie E Reuter; Darlene M Rozewski; Mitch A Phelps; David J R Foster Journal: Cancer Chemother Pharmacol Date: 2019-09-06 Impact factor: 3.333