Population Pharmacokinetics and Model-Informed Precision Dosing of Lenalidomide Incorporating Total and Unbound...

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).

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 m², 11 with eGFR ≥ 30 to < 60 mL/min/1.73 m², and 8 with eGFR ≥ 60 mL/min/1.73 m². 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.

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 (V₁/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 m² to maintain therapeutic exposure while minimizing toxicity; conversely, dose escalation is warranted for patients with BSA ≥ 2.0 m² to prevent underexposure.

Our model identifies eGFR and BSA as critical covariates for precision dosing of lenalidomide to optimize therapeutic exposure in MM patients with RI.