Hyeonji Kim1,2,3, Seunghoon Han4, Sungpil Han4, Suein Choi4, Sung-Soo Park5, Donghyun Kim1,2,3, Hyeon Su Kim1,2,3, Seungwon Yang1,2,3, Eun Kyoung Chung1,2,3,6,7
1Department of Pharmacy, College of Pharmacy, Kyung Hee University, 2Department of Regulatory Science, Graduate School, Kyung Hee University, 3Institute of Regulatory Innovation through Science, Kyung Hee University, 4Department of Pharmacology, College of Medicine, The Catholic University of Korea, 5Hematology Hospital, Seoul St. Mary’s Hospital, The Catholic University of Korea, 6Department of Pharmacy, Kyung Hee University Hospital at Gangdong, 7Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University
Objectives Chronic kidney disease (CKD) is a common complication in multiple myeloma (MM) due to immunoglobulin-induced kidney damage. Lenalidomide, a first-line therapy for MM, is primarily excreted through the kidneys and requires dose adjustments based on renal function [1]. Altered renal function may lead to changes in clearance (CL) and volume of distribution (Vd), particularly for renally eliminated drugs such as lenalidomide. As a result, previous studies reported increases in half-life (up to 3 folds) and area under the concentration-time curve (AUC) [2,3]. Consequently, the risk for adverse events of lenalidomide such as hematologic toxicity might increase, highlighting the need for precision dosing in CKD patients. This study aimed to evaluate the population pharmacokinetics (pop-PK) of lenalidomide in CKD patients, identify significant covariates, and suggest model-informed precision dosing regimen. Methods A prospective clinical trial was conducted in Korea for MM patients with CKD treated with lenalidomide as maintenance regimen. Upon the discretion of treating clinicians, patients received lenalidomide at doses of 5 mg, 7.5 mg, or 10 mg daily. Serial blood samples were collected on the third day of treatment at pre-dose and 2, 4, 8, 12, and 24 hours after oral administration of the study dose. Total and unbound plasma concentrations of lenalidomide were measured using a previously developed high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) method [4]. Pop-PK analysis was performed using NONMEM 7.5.1 (Globomax LLC, Ellicott, MD), incorporating allometric scaling on CL/F and Vd/F. The covariate analysis followed forward inclusions and backward elimination steps, using an OFV difference of >3.84 (P <0.05) and >6.63 (P <0.01) for statistical significance, respectively. Covariates of interest including demographics, markers of renal and liver functions, hematological parameters were evaluated in this study. The final PK model was selected based on goodness-of-fit criteria, including clinical plausibility, successful minimization, objective function value (OFV), relative standard error (RSE), and graphical diagnostics. Results A total of 360 plasma concentrations from 30 patients (12 males) were analyzed to develop a pop-PK model of lenalidomide; including 12 patients with CrCL <30 mL/min (1 patient undergoing dialysis), 12 patients with CrCL 30~60 mL/min, and 6 patients with CrCL 60~90 mL/min. A two-compartment PK model with time-dependent first-order oral absorption and time-independent first-order elimination best described the concentration-time data. The time-dependent first-order oral absorption rate constant was adjusted using a sigmoidal Emax equation. Interindividual variability (IIV, ?) of pop-PK parameters was assumed to follow a log-normal distribution, with a mean of zero and variance of ?^2. IIV was estimated for CL/F and Vd/F. Residual error (e) was best modelled by the proportional form for total concentrations and the combinational form with both proportional and additive terms for unbound concentrations. The concentrations of total and unbound lenalidomide were linked using a linear protein binding model. CL/F and V/F were allometrically scaled using a fixed exponent based on estimated body surface area (BSA). CL/F was significantly correlated with creatinine clearance (P < 0.05, ?OFV = -36.96). Therefore, the final established Pop-PK model parameters for lenalidomide were as follows: CL/F (L/h) = 9.15 · [1+0.0174 · (CRCL-37.2)] · (BSA/1.64)^0.75 · exp(?CL/F) Vc/F (L) = 65 · (BSA/1.64)^1 · exp(?Vc/F) Vp/F (L) = 9.66 · exp(?Vp/F) Q/F (L/h) = 1.83 · exp(?Q/F) Ka (1/h) = 3.21 Fu (%) = 61.1 TT50 (h) = 40.7 GAM = 7.84 Conclusions Pop-PK model of lenalidomide for MM patients with CKD can be described by a two-compartment model with time-dependent absorption. Our model might inform individualized dose adjustments of lenalidomide in MM patients with CKD based on patient factors such as BSA, CrCL.
[1] Chen, N., Lau, H., Kong, L., Kumar, G., Zeldis, J. B., Knight, R., & Laskin, O. L. (2007). Pharmacokinetics of Lenalidomide in Subjects With Various Degrees of Renal Impairment and in Subjects on Hemodialysis. The Journal of Clinical Pharmacology, 47(12), 1466-1475. https://doi.org/10.1177/0091270007309563 [2] U.S. Food and Drug Administration Prescribing Information for REVLIMID® (lenalidomide) Tablets, for Oral Use. [(accessed on 06 March 2025)];2005. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021880s057lbl.pdf [3] Borrello, I. (2009). Lenalidomide in renal insufficiency – balancing the risks and benefits. British Journal of Haematology, 144(3), 446-447. https://doi.org/10.1111/j.1365-2141.2008.07002.x [4] Lee, S., Yang, S., Shim, W.-S., Song, E., Han, S., Park, S.-S., Choi, S., Joo, S. H., Park, S. J., Shin, B., Kim, D., Kim, H., Jung, Y., Lee, K.-T., & Chung, E. K. (2024). Development and Validation of an Improved HPLC-MS/MS Method for Quantifying Total and Unbound Lenalidomide in Human Plasma. Pharmaceutics, 16(10), 1340. https://doi.org/10.3390/pharmaceutics16101340
Reference: PAGE 33 (2025) Abstr 11504 [www.page-meeting.org/?abstract=11504]
Poster: Drug/Disease Modelling - Oncology