TY - JOUR
T1 - Population pharmacokinetic-pharmacodynamic model of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acidin cancer patients
AU - Li, Jing
AU - Jameson, Michael B.
AU - Baguley, Bruce C.
AU - Pili, Roberto
AU - Baker, Sharyn D.
PY - 2008/4/1
Y1 - 2008/4/1
N2 - 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 (Vm), respectively. Population estimates for V m, Km (concentration at which half Vm 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 Emax model, where population estimates for baseline, Emax, 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.
AB - 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 (Vm), respectively. Population estimates for V m, Km (concentration at which half Vm 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 Emax model, where population estimates for baseline, Emax, 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.
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U2 - 10.1158/1078-0432.CCR-07-1475
DO - 10.1158/1078-0432.CCR-07-1475
M3 - Article
C2 - 18381951
AN - SCOPUS:42249093188
SN - 1078-0432
VL - 14
SP - 2102
EP - 2110
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7
ER -