Pharmacokinetics of 5,6-dimethylxanthenone-4-acetic acid (AS1404), a novel vascular disrupting agent, in phase I clinical trial.
OBJECTIVE
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.
Jameson
M B
MB
Department of Clinical Oncology, Auckland Hospital, Private Bag 92024, Auckland, New Zealand. jameson@waikatodhb.govt.nz
Baguley
B C
BC
Kestell
P
P
Zhao
L
L
Paxton
J W
JW
Thompson
P I
PI
Waller
S
S
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006801:Humans; D016014:Linear Models; D017711:Nonlinear Dynamics; D044004:Xanthones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D044004:Xanthones; C066668:vadimezan