Population Pharmacokinetics and Model-Informed Precision Dosing of Lenalidomide Incorporating Total and Unbound Plasma Concentrations in Renally Impaired Patients with Multiple Myeloma

Purpose: To develop a population pharmacokinetic (PK) model of lenalidomide and propose model-informed precision dosing based on total and unbound concentrations in multiple myeloma (MM) patients with moderate-to-severe renal impairment (RI). Patients and Methods: Thirty MM patients orally receiving lenalidomide were prospectively enrolled with the following stratification based on renal function: 11 with an estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m 2 , 11 with eGFR ≥ 30 to < 60 mL/min/1.73 m 2 , and 8 with eGFR ≥ 60 mL/min/1.73 m 2 . Serial plasma samples were collected at steady state. Total and unbound concentrations were analyzed simultaneously by population PK modeling using NONMEM. Monte Carlo simulations were performed to identify dosing regimens targeting the reference systemic exposure (area under the plasma concentration-time curve, AUC) for patients with normal renal function receiving 25 mg/day. Results: A two-compartment model with linear protein binding best described both total and unbound plasma lenalidomide concentration-time data. Apparent unbound clearance (CL/F) increased with higher eGFR and body surface area (BSA), while apparent central volume of distribution (V 1 /F) increased with higher BSA ( P < 0.05). No other PK parameters were significantly associated with patient characteristics including ABCB1 genotypes. Simulation results indicated that although labeled dosing was generally adequate, BSA-stratified adjustments offered improved precision. Specifically, dose reduction is recommended for patients with BSA < 1.6 m 2 to maintain therapeutic exposure while minimizing toxicity; conversely, dose escalation is warranted for patients with BSA ≥ 2.0 m 2 to prevent underexposure. Conclusion: Our model identifies eGFR and BSA as critical covariates for precision dosing of lenalidomide to optimize therapeutic exposure in MM patients with RI. The infographic illustrates the population pharmacokinetics and model-informed precision dosing of lenalidomide for patients with multiple myeloma and renal impairment. It begins with a prospectively conducted clinical study in patients receiving lenalidomide, followed by simultaneous measurement of total and unbound plasma concentrations and genetic analysis. These data were used in population pharmacokinetic modeling and simulation. The lower section shows that apparent unbound clearance (CL/F) was significantly influenced by eGFR and body surface area (BSA), while apparent central volume of distribution (V₁/F) was associated with BSA, and the unbound fraction (Fu) was estimated at 61.4%. Based on the final model, virtual patient populations were generated across renal function and BSA strata, and Monte Carlo simulations were performed to evaluate drug exposure. The simulation results guide dosing adjustments based on BSA, indicating dose reduction for BSA less than 1.6 m² and dose escalation for BSA greater than or equal to 2.0 m².Lenalidomide dosing for renally impaired multiple myeloma patients using population pharmacokinetics.