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

• Published in: Cancer chemotherapy and pharmacology Vol. 70; no. 1; pp. 201 - 205
• Main Authors: 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 R.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.07.2012; Springer; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Algorithms; Antineoplastic agents; Area Under Curve; Benzoquinones - administration & dosage; Benzoquinones - pharmacokinetics; Biological and medical sciences; Cancer Research; Drug Administration Schedule; Drug Monitoring - methods; Female; Humans; Infusions, Intravenous; Lactams, Macrocyclic - administration & dosage; Lactams, Macrocyclic - pharmacokinetics; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Models, Biological; Monte Carlo Method; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Neoplasms - metabolism; Oncology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Short Communication; Time Factors; Tumors; Heat shock protein-90; 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG); 3-compartment model; Objective function values; Human; Population pharmacokinetics; Solid tumor; Patient; Malignant tumor; Analysis; Heat shock protein; Adult; Models; Objective function; 17-dimethylaminoethylamino-17demethoxygeldanamycin (17-DMAG); Cancer; Heat shock protein 90
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-012-1859-1

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.