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 microM h. In contrast, the increase in peak plasma concentrations from 2.17 to 1,910 microM 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.
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 cancerpatients 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 microM h. In contrast, the increase in peak plasma concentrations from 2.17 to 1,910 microM 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.
Authors: Parmeswaran Diagaradjane; Anil Shetty; James C Wang; Andrew M Elliott; Jon Schwartz; Shujun Shentu; Hee C Park; Amit Deorukhkar; R Jason Stafford; Sang H Cho; James W Tunnell; John D Hazle; Sunil Krishnan Journal: Nano Lett Date: 2008-04-16 Impact factor: 11.189