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 receivingDMXAA monotherapy as a 20-minute i.v. infusion weekly or every 3 weeks at doses of 6 to 4,900 mg/m(2). 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 (V(1)) and the maximum elimination rate (V(m)), respectively. Population estimates for V(m), K(m) (concentration at which half V(m) is achieved), and V(1) were 112[1 + 0.474(2-sex)] micromol/L/h, 102 micromol/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 EC(50) were 46.3 micromol/L, 2.62-fold increase of the baseline value, and 631 micromol/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/m(2) 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.
RCT Entities:
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/m(2). 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 (V(1)) and the maximum elimination rate (V(m)), respectively. Population estimates for V(m), K(m) (concentration at which half V(m) is achieved), and V(1) were 112[1 + 0.474(2-sex)] micromol/L/h, 102 micromol/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 EC(50) were 46.3 micromol/L, 2.62-fold increase of the baseline value, and 631 micromol/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/m(2) 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.
Authors: Jian-Feng Lu; Erik Rasmussen; Beth Y Karlan; Ignace B Vergote; Lynn Navale; Mita Kuchimanchi; Rebeca Melara; Daniel E Stepan; David M Weinreich; Yu-Nien Sun Journal: Cancer Chemother Pharmacol Date: 2012-01-01 Impact factor: 3.333
Authors: Kari Ann Shirey; Quan M Nhu; Kevin C Yim; Zachary J Roberts; John R Teijaro; Donna L Farber; Jorge C Blanco; Stefanie N Vogel Journal: J Leukoc Biol Date: 2010-11-17 Impact factor: 4.962
Authors: Sam Salman; Sherwin K B Sy; Kenneth F Ilett; Madhu Page-Sharp; Michael J Paech Journal: Eur J Clin Pharmacol Date: 2011-03-11 Impact factor: 2.953