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

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Abstract
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 μ M and 3.2 μ M h, respectively, at 6 mg m−2 to 1290 μ M and 7600 μ M 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.

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