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

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.

• Authors: 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 R Bies
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 70 Issue 1 Pg. 201-5 (Jul 2012) ISSN: 1432-0843 [Electronic] Germany
• PMID: 22450873 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Benzoquinones
• Lactams, Macrocyclic
• 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin

Topics

• Adult
• Aged
• Aged, 80 and over
• Algorithms
• Area Under Curve
• Benzoquinones (administration & dosage, pharmacokinetics)
• Drug Administration Schedule
• Drug Monitoring (methods)
• Female
• Humans
• Infusions, Intravenous
• Lactams, Macrocyclic (administration & dosage, pharmacokinetics)
• Male
• Middle Aged
• Models, Biological
• Monte Carlo Method
• Neoplasms (drug therapy, metabolism)
• Time Factors