Nonlinear Mixed-Effects Modeling to Characterize the Pharmacokinetics of a Novel Mithramycin Analogue for Ewing Sarcoma in Mice

Purpose To develop a pharmacokinetic model for a novel mithramycin analogue, MTMSA-Trp, in mice and characterize dose-dependent disposition to support future pharmacokinetic-pharmacodynamic (PK/PD) and exposure-efficacy analyses. Methods Non-linear mixed-effects modeling was used to develop a population pharmacokinetic (popPK) model in MonolixSuite 2024R1 using 121 plasma concentrations from 70 female athymic nude mice after single IV bolus doses of 0.3, 1, 3, 5, and 10 mg/kg. Model selection was guided by the objective function value (OFV), parameter precision, and diagnostic plots. The final model was evaluated using bootstrap resampling (1000 replicates) and visual predictive checks (VPC; 1000 simulated datasets). Results A one-compartment model with first-order elimination and an empirical power relationship between dose and clearance best described the data. Including dose as a covariate in the clearance model significantly improved model fit relative to the linear base model (ΔOFV = − 26.19). Typical clearance and volume of distribution were 39.18 mL/h/kg (at 3 mg/kg) and 53.06 mL/kg, respectively, and the dose-clearance exponent was β = −0.30, indicating decreasing clearance with increasing dose. Fixed-effect parameters were estimated with high precision (RSE ≤ 11%). Shrinkage was high for clearance (81%) and moderate for volume of distribution (39.1%). Bootstrap and VPC results supported model robustness and predictive performance. Conclusion A robust popPK model describing dose-dependent MTMSA-Trp disposition in mice was developed and is suitable for simulation to support subsequent PK/PD and exposure-efficacy analyses.