title: 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent: phase I clinical and pharmacokinetic study.
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.
authors.affiliation: Department of Medical Oncology, Mount Vernon Hospital, Northwood, Middlesex, UK. rustin@mtvern.co.uk
authors.forename: G J S
authors.initials: GJ
authors.lastname: Rustin
authors.forename: C
authors.initials: C
authors.lastname: Bradley
authors.forename: S
authors.initials: S
authors.lastname: Galbraith
authors.forename: M
authors.initials: M
authors.lastname: Stratford
authors.forename: P
authors.initials: P
authors.lastname: Loadman
authors.forename: S
authors.initials: S
authors.lastname: Waller
authors.forename: K
authors.initials: K
authors.lastname: Bellenger
authors.forename: L
authors.initials: L
authors.lastname: Gumbrell
authors.forename: L
authors.initials: L
authors.lastname: Folkes
authors.forename: G
authors.initials: G
authors.lastname: Halbert
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D002648:Child; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D044004:Xanthones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D044004:Xanthones; C066668:vadimezan