Pharmacokinetics of 5,6-dimethylxanthenone-4-acetic acid (AS1404), a novel vascular disrupting agent, in phase I clinical trial

Purpose 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) (AS1404) is a novel antitumour agent that selectively disrupts tumour vasculature and induces cytokines. The purpose of this study was to determine the pharmacokinetics (PK) of DMXAA in cancer patients enrolled in a phase I clinical trial. Methods DMXAA was administered as a 20-min i.v. infusion every 3 weeks and doses were escalated in cohorts of patients according to a predefined schema. PK samples were taken over the first 24 h of at least the first cycle. Results DMXAA was administered to 63 patients at 19 dose levels from 6 to 4,900 mg m⁻², and 3,700 mg m⁻² was established as the maximum tolerated dose. The PK observed over the dose range showed a non-linear fall in clearance from 16.1 to 1.42 l h⁻¹ m⁻² and resultant increase in the area under the concentration–time curve (AUC) from 1.29 to 12,400 μM h. In contrast, the increase in peak plasma concentrations from 2.17 to 1,910 μM approximated linearity. DMXAA was highly protein-bound to albumin (>99%) until saturation occurred at higher doses, leading to a rapid increase in the free fraction (up to 20%) and greater concentrations of DMXAA bound to non-albumin proteins. However, the main determinant of the non-linearity of the PK appeared to be sequential saturation of elimination mechanisms, which include hydroxylation, glucuronidation and perhaps hepatic transport proteins. This resulted in an exaggerated non-linear increase in free DMXAA plasma concentrations and AUC compared to total drug. Conclusions The PK of DMXAA are well-defined, with a consistent degree of non-linearity across a very large dose range.