5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent: phase I clinical and pharmacokinetic study

The purpose of this phase I, dose-escalation study was to determine the toxicity, maximum tolerated dose, pharmacokinetics, and pharmacodynamic end points of 5,6-dimethylxanthenone acetic acid (DMXAA). In all, 46 patients received a total of 247 infusions of DMXAA over 15 dose levels ranging from 6 to 4900 mg m(−2). The maximum tolerated dose was established at 3700 mg m(−2); dose-limiting toxicities in the form of urinary incontinence, visual disturbance, and anxiety were observed at the highest dose level (4900 mg m(−2)). The pharmacokinetics of DMXAA were dose dependent. Peak concentrations and area under the curve level increased from 4.8 μM and 3.2 μM h, respectively, at 6 mg m(−2) to 1290 μM and 7600 μM h at 3700 mg m(−2), while clearance declined from 7.4 to 1.7 l h(−1) m(−2) over the same dose range. The terminal half-life was 8.1±4.3 h. More than 99% of the drug was protein bound at doses up to 320 mg m(−2); at higher doses the percent free drug increased to a maximum of 6.9% at 4900 mg m(−2). Dose-dependent increases in the serotonin metabolite 5-hydroxyindoleacetic acid were observed at dose levels of 650 mg m(−2) and above. There was one unconfirmed partial response at 1300 mg m(−2). In conclusion, DMXAA is a novel vascular targeting agent and is well tolerated.