Population pharmacokinetic analysis of 17-(allylamino)-17-demethoxygeldanamycin (17AAG) in adult patients with advanced malignancies.
OBJECTIVE
17-(Allylamino)-17-demethoxygeldanamycin (17AAG) is a novel anticancer agent in clinical development. The objectives of this study were to develop a population pharmacokinetic model for 17AAG and its major metabolite, 17AG, and to investigate influences of patient characteristics and biochemical markers on pharmacokinetic parameters estimated for 17AAG and 17AG.


METHODS
In a phase I clinical study, 17AAG was administered by intravenous infusion to 43 patients with refractory, advanced malignancies. Plasma concentrations of 17AAG and 17AG were determined by high-performance liquid chromatography. Plasma concentration vs time data were modeled using NONMEM. Nine covariates (age, sex, performance status, weight, height, body surface area, AST, bilirubin and serum creatinine) were investigated for their influences on individual pharmacokinetic parameters.


RESULTS
Plasma concentration vs time data were best described by a two-compartment model for 17AAG and a one-compartment model for 17AG. Volumes of distribution were 24.2 and 89.6 l for 17AAG. Total elimination clearances were 26.7 and 21.3 l/h for 17AAG and 17AG, respectively. Both fixed and random effects pharmacokinetic parameters were well estimated. None of the covariates explained the interindividual variability in 17AAG and 17AG pharmacokinetic parameters or improved the fit of the model based on objective function changes.


CONCLUSIONS
A population pharmacokinetic model was developed to describe 17AAG and 17AG population pharmacokinetic parameters and interindividual variabilities. There were substantial interindividual variabilities in 17AAG and 17AG pharmacokinetic parameters despite BSA-normalized dosing.
Chen
Xueyu
X
Department of Medical Oncology and Hematology, Princess Margaret Hospital, Room 5-221A, 610 University Ave., Toronto, ON, Canada, M5G 2M9. eric.chen@uhn.on.ca
Bies
Robert R
RR
Ramanathan
Ramesh K
RK
Zuhowski
Eleanor G
EG
Trump
Donald L
DL
Egorin
Merrill J
MJ
D000328:Adult; D000367:Age Factors; D000368:Aged; D000970:Antineoplastic Agents / Q000378:metabolism*; D016227:Benzoquinones; D015415:Biomarkers; D001827:Body Height; D001835:Body Weight; D005260:Female; D006801:Humans; D047029:Lactams, Macrocyclic; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000097:blood / Q000378:metabolism*; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D012737:Sex Factors
D000970:Antineoplastic Agents; D016227:Benzoquinones; D015415:Biomarkers; D047029:Lactams, Macrocyclic; D017828:Rifabutin; C112765:tanespimycin