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

Rustin GJ, Bradley C, Galbraith S, Stratford M, Loadman P, Waller S, Bellenger K, Gumbrell L, Folkes L, Halbert G, Phase I/II Trials Committee of Cancer Research - Br. J. Cancer (2003)

Bottom Line: Dose-dependent increases in the serotonin metabolite 5-hydroxyindoleacetic acid were observed at dose levels of 650 mg x m(-2) and above.There was one unconfirmed partial response at 1300 mg x m(-2).In conclusion, DMXAA is a novel vascular targeting agent and is well tolerated.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Mount Vernon Hospital, Northwood, Middlesex, UK. rustin@mtvern.co.uk

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 x m(-2). The maximum tolerated dose was established at 3700 mg x m(-2); dose-limiting toxicities in the form of urinary incontinence, visual disturbance, and anxiety were observed at the highest dose level (4900 mg x m(-2)). The pharmacokinetics of DMXAA were dose dependent. Peak concentrations and area under the curve level increased from 4.8 microM and 3.2 microM h, respectively, at 6 mg x m(-2) to 1290 microM and 7600 microM h at 3700 mg x m(-2), while clearance declined from 7.4 to 1.7 l h(-1) x 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 x m(-2); at higher doses the percent free drug increased to a maximum of 6.9% at 4900 mg x m(-2). Dose-dependent increases in the serotonin metabolite 5-hydroxyindoleacetic acid were observed at dose levels of 650 mg x m(-2) and above. There was one unconfirmed partial response at 1300 mg x m(-2). In conclusion, DMXAA is a novel vascular targeting agent and is well tolerated.

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Related in: MedlinePlus

Effect of DMXAA dose on 5-HIAA plasma concentration and AUC.
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fig3: Effect of DMXAA dose on 5-HIAA plasma concentration and AUC.

Mentions: There was a dose-dependent increase in plasma 5-HIAA at DMXAA doses of 650 mg m−2 and above, which became more marked both in extent and duration, as the dose of DMXAA increased, as shown in Figure 3Figure 3


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

Rustin GJ, Bradley C, Galbraith S, Stratford M, Loadman P, Waller S, Bellenger K, Gumbrell L, Folkes L, Halbert G, Phase I/II Trials Committee of Cancer Research - Br. J. Cancer (2003)

Effect of DMXAA dose on 5-HIAA plasma concentration and AUC.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2747563&req=5

fig3: Effect of DMXAA dose on 5-HIAA plasma concentration and AUC.
Mentions: There was a dose-dependent increase in plasma 5-HIAA at DMXAA doses of 650 mg m−2 and above, which became more marked both in extent and duration, as the dose of DMXAA increased, as shown in Figure 3Figure 3

Bottom Line: Dose-dependent increases in the serotonin metabolite 5-hydroxyindoleacetic acid were observed at dose levels of 650 mg x m(-2) and above.There was one unconfirmed partial response at 1300 mg x m(-2).In conclusion, DMXAA is a novel vascular targeting agent and is well tolerated.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Mount Vernon Hospital, Northwood, Middlesex, UK. rustin@mtvern.co.uk

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 x m(-2). The maximum tolerated dose was established at 3700 mg x m(-2); dose-limiting toxicities in the form of urinary incontinence, visual disturbance, and anxiety were observed at the highest dose level (4900 mg x m(-2)). The pharmacokinetics of DMXAA were dose dependent. Peak concentrations and area under the curve level increased from 4.8 microM and 3.2 microM h, respectively, at 6 mg x m(-2) to 1290 microM and 7600 microM h at 3700 mg x m(-2), while clearance declined from 7.4 to 1.7 l h(-1) x 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 x m(-2); at higher doses the percent free drug increased to a maximum of 6.9% at 4900 mg x m(-2). Dose-dependent increases in the serotonin metabolite 5-hydroxyindoleacetic acid were observed at dose levels of 650 mg x m(-2) and above. There was one unconfirmed partial response at 1300 mg x m(-2). In conclusion, DMXAA is a novel vascular targeting agent and is well tolerated.

Show MeSH
Related in: MedlinePlus