Abstract

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-e cacy 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 nal model was evaluated using bootstrap resampling (1000 replicates) and visual predictive checks (VPC; 1000 simulated datasets).

Results

A one-compartment model with rst-order elimination and an empirical power relationship between dose and clearance best described the data. Including dose as a covariate in the clearance model signi cantly improved model t 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-e cacy analyses.

By Kumar Kulldeep Niloy, Jamie Horn, Nazmul Hasan Bhuiyan, Khaled A Shaaban, Suhas S Bhosale, Thomas Prisinzano, Jon S Thorson, Jurgen Rohr, Markos Leggas