Population pharmacokinetic analysis of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in adult patients with solid tumors
Year: 2012
Type: article
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.
Institutions: Indiana University Indianapolis, Indiana University School of Medicine, Indiana University – Purdue University Indianapolis, Richard L. Roudebush VA Medical Center, University of Pittsburgh, UPMC Hillman Cancer Center, Memorial Sloan Kettering Cancer Center, Translational Genomics Research Institute, Emory University, Winship Cancer Institute, Penn State Cancer Institute, Penn State Milton S. Hershey Medical Center, National Institutes of Health
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,390
Funders: Indiana Clinical and Translational Sciences Institute, University of Pittsburgh, Indiana University-Purdue University Indianapolis, Deutsches Krebsforschungszentrum, National Institutes of Health, Cancer Institute, University of Pittsburgh, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Biomedical Imaging and Bioengineering, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G2519210884, Early Clinical Trials of New Anti-Cancer Agents with Phase I Emphasis, General Clinical Research Center, G352457742, G3633146589, G3764349871, G3771559836, Resource Facility for Population Kinetics, G422284981, G424558205, G4441976884, G583498415, Cancer Biology Training Program, G614725904, G661928818, G741073515, G830266829, PHASE I CLINICAL TRIALS OF ANTICANCER AGENTS, G9000015325, G9000092902, Indiana University Comprehensive Training in Clinical Pharmacology, SPORE in Prostate Cancer
OpenAlex ID: W2094068462