Population pharmacokinetic-pharmacodynamic model of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid in cancer patients

Purpose: To develop a population pharmacokinetic-pharmacodynamic (PK-PD) model that defines the dose-concentration-effect relationship of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), using plasma 5-hydroxyindole-3-acetic acid (5-HIAA) as a biomarker for the antivascular effect of DMXAA. Experimental Design: The plasma DMXAA and 5-HIAA concentration data were obtained from 124 patients receiving DMXAA monotherapy as a 20-minute i.v. infusion weekly or every 3 weeks at doses of 6 to 4,900 mg/m(2). The PK and PD data were analyzed by nonlinear mixed effects modeling with NONMEM version 5. Results: DMXAA concentration-time profiles were well described by a three-compartment model with saturable elimination (Michaelis-Menten kinetics). Body surface area (BSA) and sex were significant covariates on the volume of distribution of the central compartment (V-1) and the maximum elimination rate (V-m), respectively. Population estimates for Vm, Km (concentration at which half Vm is achieved), and V, were 112[1 + 0.474(2 - sex)] mu mol/L/h, 102 mu mol/L, and 8.19(BSA/1.8)(0.857) liters, respectively (sex in Vm is equal to 1 for males and equal to 2 for females). The effect of DMXAA on plasma 5-HIAA was described by the stimulatory E-max model, where population estimates for baseline, E-max, and EC50 were 46.3 mu mol/L, 2.62-fold increase of the baseline value, and 631 mu mol/L, respectively. Conclusions: DMXAA plasma disposition is characterized by a saturable elimination process. BSA-guided dosing is important. The present PK-PD model, with 5-HIAA as a biomarker, supports the use of DMXAA doses of 1,000 to 2,000 mg/m(2) in phase II studies, and provides an example of how PK-PD models can be used to aid in selection of drug doses for phase 11 evaluation.