Push Forward Clinical Management of Hematological Toxicity due to Lenalidomide Overexposure: Model-Informed Precision Dosing for Chinese Population With Renal Insufficiency

Abstract

Dose-dependent hematological toxicity of lenalidomide has been reported previously, and thus, there is a clinical need for dose individualization to manage toxicities. The objectives of this study were to explore optimal individualized dosing regimens for Chinese B-cell malignancies patients with varying degrees of renal function, and to push forward clinical management of hematological toxicity due to lenalidomide overexposure. A total of 164 plasma concentrations of lenalidomide were obtained from 97 Chinese patients with multiple myeloma (MM) and B-cell non-Hodgkin lymphoma (NHL) from a multicenter prospective study. A population pharmacokinetic (PopPK) model for lenalidomide was developed by nonlinear mixed effect modeling. A Monte Carlo simulation was conducted to recommend model-informed precision dosing (MIPD) for patients with varying degrees of renal function. A one-compartment model with first-order elimination best described the pharmacokinetics of lenalidomide. The population typical values of lenalidomide were as follows: absorption rate constant (Ka) of 8.34 h^-1, apparent volume of distribution (V/F) of 37.4 L, and apparent clearance (CL/F) of 7.4 L/h. Creatinine clearance (CCr) was identified as a major covariate for CL/F, whereas other demographics or clinical characteristics had no significant effect on the model. When given the identical dose, Chinese patients exhibited a higher exposure than the predominantly non-Asian population at all dosage regimens, especially in patients with severe renal damage (CCr < 30 mL/min). For Chinese patients with CCr of 15-30 mL/min who do not require dialysis usually, compared to the dosing regimen of 15 mg every other day recommended by drug instructions, there exists a relatively lower risk of hematotoxicity when administered with 5 or 10 mg/day. For Chinese patients with CCr < 15 mL/min requiring dialysis, there was still a certain level of hematotoxicity risk associated with the dosing regimen of 5 mg/day recommended by drug instructions. The PopPK Model-based simulation suggests that Chinese patients may exhibit a higher exposure than the predominantly non-Asian population. For patients with severely impaired renal function, compared to dose adjustment in accordance with drug instructions, an individualized dosage strategy based on therapeutic drug monitoring (TDM) and MIPD would be preferable from a safety perspective.

Keywords: B‐cell malignancies; lenalidomide; model‐informed precision dosing; population pharmacokinetics; therapeutic drug monitoring.

FIGURE 1

Diagnostic goodness‐of‐fit plots of the final model. (A) Concentration observations versus individual predictions (IPRED); (B) concentration observations versus population predictions (PRED); (C) conditional weighted residuals (CWRES) versus PRED; (D) CWRES versus time after dose (TAD). The solid lines in (A) and (B) represent the line of agreement and in (C) and (D) the axis with residuals of 0. The dashed lines in (C) and (D) represent the ideal range of CWRES (y = ±2). The blue lines are the linear regression lines.

FIGURE 2

Prediction‐corrected visual prediction check of the final model. Blue dots represent observed concentrations, red lines represent the 5th, 50th and 95th quartiles of observed concentrations, black lines represent the 5th, 50th and 95th quartiles of simulated values, and shaded areas represent 90% confidence intervals for the 5th, 50th and 95th quartiles of simulated values.

FIGURE 3

Comparison of C_min estimates in Chinese patients taking different dosage regimens of lenalidomide. (A) Patients with varying CCr (15–90 mL/min); (B) Patients with severely impaired renal function. The 25th and 75th quartiles (box), median (black line in the box) and upper and lower limits of normal (error bar) are displayed. The red dashed line running parallel to the X‐axis denotes a C_min level of 10.95 ng/mL. Qd, Once a day; Qod, Once every other day.

FIGURE 4

Comparison of C_min estimates among ethnic groups with different levels of renal function. (A) Severe renal injury, CCr < 30 mL/min; (B) moderate renal injury, CCr of 30–60 mL/min range; (C) mild renal injury or normal renal function, CCr of 60‐90 mL/min range. The 25th and 75th quartiles (box), median (black line in the box) and upper and lower limits of normal (error bar) are displayed. The red dashed line running parallel to the X‐axis denotes a C_min level of 10.95 ng/mL. The red box is the Chinese population, and the blue box is the predominantly non‐Asian population.

FIGURE 5

Comparison of PK exposure estimates by racial groups with normal renal function. The bold horizontal bars represent the median value of the estimated _{AUC024 h}.