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Population Pharmacokinetic-Pharmacodynamic Model of the Vascular-Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid in Cancer Patients

Authors' Affiliations: ¹ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland; ² Waikato Hospital, Hamilton, New Zealand; and ³ Auckland Cancer Society Research Center, University of Auckland, Auckland, New Zealand

Requests for reprints: Jing Li, Barbara Ann Karmanos Cancer Institute, Wayne State University, 4100 John R, HWCRC/Room 523, Detroit, MI 48201. Phone: 313-576-8258; E-mail: lijin{at}karmanos.org.

Purpose: To develop a population pharmacokinetic-pharmacodynamic (PK-PD) model that defines the dose-concentration-effect relationship of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), using plasma 5-hydroxyindole-3-acetic acid (5-HIAA) as a biomarker for the antivascular effect of DMXAA.

Experimental Design: The plasma DMXAA and 5-HIAA concentration data were obtained from 124 patients receiving DMXAA monotherapy as a 20-minute i.v. infusion weekly or every 3 weeks at doses of 6 to 4,900 mg/m². The PK and PD data were analyzed by nonlinear mixed effects modeling with NONMEM version 5.

Results: DMXAA concentration-time profiles were well described by a three-compartment model with saturable elimination (Michaelis-Menten kinetics). Body surface area (BSA) and sex were significant covariates on the volume of distribution of the central compartment (V₁) and the maximum elimination rate (V_m), respectively. Population estimates for V_m, K_m (concentration at which half V_m is achieved), and V₁ were 112[1 + 0.474(2 – sex)] µmol/L/h, 102 µmol/L, and 8.19(BSA/1.8)^0.857 liters, respectively (sex in V_m is equal to 1 for males and equal to 2 for females). The effect of DMXAA on plasma 5-HIAA was described by the stimulatory E_max model, where population estimates for baseline, E_max, and EC₅₀ were 46.3 µmol/L, 2.62-fold increase of the baseline value, and 631 µmol/L, respectively.

Conclusions: DMXAA plasma disposition is characterized by a saturable elimination process. BSA-guided dosing is important. The present PK-PD model, with 5-HIAA as a biomarker, supports the use of DMXAA doses of 1,000 to 2,000 mg/m² in phase II studies, and provides an example of how PK-PD models can be used to aid in selection of drug doses for phase II evaluation.