title: Population pharmacokinetic analysis of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in adult patients with solid tumors.
abstract: OBJECTIVE
  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.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, 1001 W. 10th Street, WD W7123, Indianapolis, IN 46202, USA. aaregbe@iupui.edu
authors.forename: Abdulateef O
authors.initials: AO
authors.lastname: Aregbe
authors.forename: Eric A
authors.initials: EA
authors.lastname: Sherer
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.forename: Suresh
authors.initials: S
authors.lastname: Ramalingam
authors.forename: Chandra P
authors.initials: CP
authors.lastname: Belani
authors.forename: Percy S
authors.initials: PS
authors.lastname: Ivy
authors.forename: Robert R
authors.initials: RR
authors.lastname: Bies
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D019540:Area Under Curve; D016227:Benzoquinones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009010:Monte Carlo Method; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013997:Time Factors
chemical_list: D016227:Benzoquinones; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin