Population pharmacokinetic analysis of 17-dimethylaminoethylamino-17- demethoxygeldanamycin (17-DMAG) in adult patients with solid tumors

Abdulateef O. Aregbe, Eric A. Sherer, Merrill J. Egorin, Howard I. Scher, David B. Solit, Ramesh K. Ramanathan, Suresh Ramalingam, Chandra P. Belani, Percy S. Ivy, Robert Bies

Research output: Contribution to journalArticle

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Abstract

Purpose: To identify sources of exposure variability for the tumor growth inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) using a population pharmacokinetic analysis. Methods: A total 67 solid tumor patients at 2 centers were given 1 h infusions of 17-DMAG either as a single dose, daily for 3 days, or daily for 5 days. Blood samples were extensively collected and 17-DMAG plasma concentrations were measured by liquid chromatography/mass spectrometry. Population pharmacokinetic analysis of the 17-DMAG plasma concentration with time was performed using nonlinear mixed effect modeling to evaluate the effects of covariates, inter-individual variability, and between-occasion variability on model parameters using a stepwise forward addition then backward elimination modeling approach. The inter-individual exposure variability and the effects of between-occasion variability on exposure were assessed by simulating the 95 % prediction interval of the AUC per dose, AUC 0-24 h, using the final model and a model with no between-occasion variability, respectively, subject to the five day 17-DMAG infusion protocol with administrations of the median observed dose. Results: A 3-compartment model with first order elimination (ADVAN11, TRANS4) and a proportional residual error, exponentiated inter-individual variability and between occasion variability on Q2 and V1 best described the 17-DMAG concentration data. No covariates were statistically significant. The simulated 95% prediction interval of the AUC 0-24 h for the median dose of 36 mg/m 2 was 1,059-9,007 mg/L h and the simulated 95 % prediction interval of the AUC 0-24 h considering the impact of between-occasion variability alone was 2,910-4,077 mg/L h. Conclusions: Population pharmacokinetic analysis of 17-DMAG found no significant covariate effects and considerable inter-individual variability; this implies a wide range of exposures in the population and which may affect treatment outcome. Patients treated with 17-DMAG may require therapeutic drug monitoring which could help achieve more uniform exposure leading to safer and more effective therapy.

Original languageEnglish
Pages (from-to)201-205
Number of pages5
JournalCancer Chemotherapy and Pharmacology
Volume70
Issue number1
DOIs
StatePublished - Jul 2012

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17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
Pharmacokinetics
Tumors
Population
Area Under Curve
Neoplasms
Plasmas
Growth Inhibitors
Drug Monitoring
Liquid chromatography
Liquid Chromatography
Mass spectrometry

Keywords

  • 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG)
  • 3-compartment model
  • Heat shock protein-90
  • Objective function values

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this

Population pharmacokinetic analysis of 17-dimethylaminoethylamino-17- demethoxygeldanamycin (17-DMAG) in adult patients with solid tumors. / Aregbe, Abdulateef O.; Sherer, Eric A.; Egorin, Merrill J.; Scher, Howard I.; Solit, David B.; Ramanathan, Ramesh K.; Ramalingam, Suresh; Belani, Chandra P.; Ivy, Percy S.; Bies, Robert.

In: Cancer Chemotherapy and Pharmacology, Vol. 70, No. 1, 07.2012, p. 201-205.

Research output: Contribution to journalArticle

Aregbe, AO, Sherer, EA, Egorin, MJ, Scher, HI, Solit, DB, Ramanathan, RK, Ramalingam, S, Belani, CP, Ivy, PS & Bies, R 2012, 'Population pharmacokinetic analysis of 17-dimethylaminoethylamino-17- demethoxygeldanamycin (17-DMAG) in adult patients with solid tumors', Cancer Chemotherapy and Pharmacology, vol. 70, no. 1, pp. 201-205. https://doi.org/10.1007/s00280-012-1859-1
Aregbe, Abdulateef O. ; Sherer, Eric A. ; Egorin, Merrill J. ; Scher, Howard I. ; Solit, David B. ; Ramanathan, Ramesh K. ; Ramalingam, Suresh ; Belani, Chandra P. ; Ivy, Percy S. ; Bies, Robert. / Population pharmacokinetic analysis of 17-dimethylaminoethylamino-17- demethoxygeldanamycin (17-DMAG) in adult patients with solid tumors. In: Cancer Chemotherapy and Pharmacology. 2012 ; Vol. 70, No. 1. pp. 201-205.
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abstract = "Purpose: To identify sources of exposure variability for the tumor growth inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) using a population pharmacokinetic analysis. Methods: A total 67 solid tumor patients at 2 centers were given 1 h infusions of 17-DMAG either as a single dose, daily for 3 days, or daily for 5 days. Blood samples were extensively collected and 17-DMAG plasma concentrations were measured by liquid chromatography/mass spectrometry. Population pharmacokinetic analysis of the 17-DMAG plasma concentration with time was performed using nonlinear mixed effect modeling to evaluate the effects of covariates, inter-individual variability, and between-occasion variability on model parameters using a stepwise forward addition then backward elimination modeling approach. The inter-individual exposure variability and the effects of between-occasion variability on exposure were assessed by simulating the 95 {\%} prediction interval of the AUC per dose, AUC 0-24 h, using the final model and a model with no between-occasion variability, respectively, subject to the five day 17-DMAG infusion protocol with administrations of the median observed dose. Results: A 3-compartment model with first order elimination (ADVAN11, TRANS4) and a proportional residual error, exponentiated inter-individual variability and between occasion variability on Q2 and V1 best described the 17-DMAG concentration data. No covariates were statistically significant. The simulated 95{\%} prediction interval of the AUC 0-24 h for the median dose of 36 mg/m 2 was 1,059-9,007 mg/L h and the simulated 95 {\%} prediction interval of the AUC 0-24 h considering the impact of between-occasion variability alone was 2,910-4,077 mg/L h. Conclusions: Population pharmacokinetic analysis of 17-DMAG found no significant covariate effects and considerable inter-individual variability; this implies a wide range of exposures in the population and which may affect treatment outcome. Patients treated with 17-DMAG may require therapeutic drug monitoring which could help achieve more uniform exposure leading to safer and more effective therapy.",
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AU - Sherer, Eric A.

AU - Egorin, Merrill J.

AU - Scher, Howard I.

AU - Solit, David B.

AU - Ramanathan, Ramesh K.

AU - Ramalingam, Suresh

AU - Belani, Chandra P.

AU - Ivy, Percy S.

AU - Bies, Robert

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N2 - Purpose: To identify sources of exposure variability for the tumor growth inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) using a population pharmacokinetic analysis. Methods: A total 67 solid tumor patients at 2 centers were given 1 h infusions of 17-DMAG either as a single dose, daily for 3 days, or daily for 5 days. Blood samples were extensively collected and 17-DMAG plasma concentrations were measured by liquid chromatography/mass spectrometry. Population pharmacokinetic analysis of the 17-DMAG plasma concentration with time was performed using nonlinear mixed effect modeling to evaluate the effects of covariates, inter-individual variability, and between-occasion variability on model parameters using a stepwise forward addition then backward elimination modeling approach. The inter-individual exposure variability and the effects of between-occasion variability on exposure were assessed by simulating the 95 % prediction interval of the AUC per dose, AUC 0-24 h, using the final model and a model with no between-occasion variability, respectively, subject to the five day 17-DMAG infusion protocol with administrations of the median observed dose. Results: A 3-compartment model with first order elimination (ADVAN11, TRANS4) and a proportional residual error, exponentiated inter-individual variability and between occasion variability on Q2 and V1 best described the 17-DMAG concentration data. No covariates were statistically significant. The simulated 95% prediction interval of the AUC 0-24 h for the median dose of 36 mg/m 2 was 1,059-9,007 mg/L h and the simulated 95 % prediction interval of the AUC 0-24 h considering the impact of between-occasion variability alone was 2,910-4,077 mg/L h. Conclusions: Population pharmacokinetic analysis of 17-DMAG found no significant covariate effects and considerable inter-individual variability; this implies a wide range of exposures in the population and which may affect treatment outcome. Patients treated with 17-DMAG may require therapeutic drug monitoring which could help achieve more uniform exposure leading to safer and more effective therapy.

AB - Purpose: To identify sources of exposure variability for the tumor growth inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) using a population pharmacokinetic analysis. Methods: A total 67 solid tumor patients at 2 centers were given 1 h infusions of 17-DMAG either as a single dose, daily for 3 days, or daily for 5 days. Blood samples were extensively collected and 17-DMAG plasma concentrations were measured by liquid chromatography/mass spectrometry. Population pharmacokinetic analysis of the 17-DMAG plasma concentration with time was performed using nonlinear mixed effect modeling to evaluate the effects of covariates, inter-individual variability, and between-occasion variability on model parameters using a stepwise forward addition then backward elimination modeling approach. The inter-individual exposure variability and the effects of between-occasion variability on exposure were assessed by simulating the 95 % prediction interval of the AUC per dose, AUC 0-24 h, using the final model and a model with no between-occasion variability, respectively, subject to the five day 17-DMAG infusion protocol with administrations of the median observed dose. Results: A 3-compartment model with first order elimination (ADVAN11, TRANS4) and a proportional residual error, exponentiated inter-individual variability and between occasion variability on Q2 and V1 best described the 17-DMAG concentration data. No covariates were statistically significant. The simulated 95% prediction interval of the AUC 0-24 h for the median dose of 36 mg/m 2 was 1,059-9,007 mg/L h and the simulated 95 % prediction interval of the AUC 0-24 h considering the impact of between-occasion variability alone was 2,910-4,077 mg/L h. Conclusions: Population pharmacokinetic analysis of 17-DMAG found no significant covariate effects and considerable inter-individual variability; this implies a wide range of exposures in the population and which may affect treatment outcome. Patients treated with 17-DMAG may require therapeutic drug monitoring which could help achieve more uniform exposure leading to safer and more effective therapy.

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