Population pharmacokinetic analysis of 17-(allylamino)-17- demethoxygeldanamycin (17AAG) in adult patients with advanced malignancies

Xueyu Chen, Robert Bies, Ramesh K. Ramanathan, Eleanor G. Zuhowski, Donald L. Trump, Merrill J. Egorin

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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 89.61 for 17AAG. Total elimination clearances were 26.7 and 21.3 1/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.

Original languageEnglish (US)
Pages (from-to)237-243
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume55
Issue number3
DOIs
StatePublished - Mar 2005
Externally publishedYes

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tanespimycin
Pharmacokinetics
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Neoplasms
Plasmas

Keywords

  • Geldanamycin
  • NONMEM
  • Population pharmacokinetics

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Population pharmacokinetic analysis of 17-(allylamino)-17- demethoxygeldanamycin (17AAG) in adult patients with advanced malignancies. / Chen, Xueyu; Bies, Robert; Ramanathan, Ramesh K.; Zuhowski, Eleanor G.; Trump, Donald L.; Egorin, Merrill J.

In: Cancer Chemotherapy and Pharmacology, Vol. 55, No. 3, 03.2005, p. 237-243.

Research output: Contribution to journalArticle

Chen, Xueyu ; Bies, Robert ; Ramanathan, Ramesh K. ; Zuhowski, Eleanor G. ; Trump, Donald L. ; Egorin, Merrill J. / Population pharmacokinetic analysis of 17-(allylamino)-17- demethoxygeldanamycin (17AAG) in adult patients with advanced malignancies. In: Cancer Chemotherapy and Pharmacology. 2005 ; Vol. 55, No. 3. pp. 237-243.
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N2 - 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 89.61 for 17AAG. Total elimination clearances were 26.7 and 21.3 1/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.

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