Cancer Chemother Pharmacol. 2005
Mar;55(3):237-43. Epub 2004 Oct 19.
Population pharmacokinetic analysis of 17AAG in adult
patients with advanced malignancies.
Chen X, Bies RR, Ramanathan RK, Zuhowski EG, Trump DL, Egorin
MJ.
Department of Medical Oncology and Hematology, Princess
Margaret Hospital, Room 5-221A, 610 University Ave., Toronto,
ON, Canada, M5G 2M9. eric.chen@uhn.on.ca
PURPOSE: 17-(Allylamino)-17-demethoxygeldanamycin (17AAG) is a
novel anticancer agent in clinical development. The objectives
of this study were to develop a population pharmacokinetic model
for 17AAG and its major metabolite, 17AG, and to investigate
influences of patient characteristics and biochemical markers on
pharmacokinetic parameters estimated for 17AAG and 17AG.
EXPERIMENTAL DESIGN: In a phase I clinical study, 17AAG was
administered by intravenous infusion to 43 patients with
refractory, advanced malignancies. Plasma concentrations of
17AAG and 17AG were determined by high-performance liquid
chromatography. Plasma concentration vs time data were modeled
using NONMEM. Nine covariates (age, sex, performance status,
weight, height, body surface area, AST, bilirubin and serum
creatinine) were investigated for their influences on individual
pharmacokinetic parameters. RESULTS: Plasma concentration vs
time data were best described by a two-compartment model for
17AAG and a one-compartment model for 17AG. Volumes of
distribution were 24.2 and 89.6 l for 17AAG. Total elimination
clearances were 26.7 and 21.3 l/h for 17AAG and 17AG,
respectively. Both fixed and random effects pharmacokinetic
parameters were well estimated. None of the covariates explained
the interindividual variability in 17AAG and 17AG
pharmacokinetic parameters or improved the fit of the model
based on objective function changes. CONCLUSIONS: A population
pharmacokinetic model was developed to describe 17AAG and 17AG
population pharmacokinetic parameters and interindividual
variabilities. There were substantial interindividual
variabilities in 17AAG and 17AG pharmacokinetic parameters
despite BSA-normalized dosing.
PMID: 15503027
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