Population pharmacokinetic analysis of 17-dimethylaminoethylamino-17- demethoxygeldanamycin (17-DMAG) in adult patients with solid tumors Journal Article
| Authors: | Aregbe, A. O.; Sherer, E. A.; Egorin, M. J.; Scher, H. I.; Solit, D. B.; Ramanathan, R. K.; Ramalingam, S.; Belani, C. P.; Ivy, P. S.; Bies, R. R. |
| Article Title: | 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. © 2012 The Author(s). |
| Keywords: | adult; aged; aged, 80 and over; middle aged; major clinical study; area under the curve; solid tumor; outcome assessment; neoplasms; mass spectrometry; models, biological; drug administration schedule; algorithms; time factors; cancer inhibition; blood sampling; single drug dose; area under curve; drug monitoring; drug blood level; liquid chromatography; infusions, intravenous; concentration response; drug exposure; benzoquinones; lactams, macrocyclic; monte carlo method; drug elimination; alvespimycin; 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-dmag); 3-compartment model; heat shock protein-90; objective function values |
| Journal Title: | Cancer Chemotherapy and Pharmacology |
| Volume: | 70 |
| Issue: | 1 |
| ISSN: | 0344-5704 |
| Publisher: | Springer |
| Date Published: | 2012-07-01 |
| Start Page: | 201 |
| End Page: | 205 |
| Language: | English |
| DOI: | 10.1007/s00280-012-1859-1 |
| PROVIDER: | scopus |
| PMCID: | PMC3383947 |
| PUBMED: | 22450873 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 August 2012" - "CODEN: CCPHD" - "Source: Scopus" |
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