D. Hille(1) , R. Bruno(2) , S. Durrleman1, L. Sheiner(3) ,
Statistics(1) , Drug Metabolism and Pharmacokinetics(2) ,
Rhone-Poulenc Rorer, Antony, France
University of California,(3) San Francisco, U.S.A.
A sparse pharmacokinetic sampling strategy was implemented during
the first cycle of docetaxel treatment in 24 Phase II studies to
perform a prospective population pharmacokinetic/pharmacodynamic
(PK/PD) evaluation. The studies included breast cancer (8
studies, 320 patients, 234 with PK data), non small cell lung
cancer (6 studies, 268 patients, 189 with PK data) and other
tumor types (10 studies, 351 patients, 220 with PK data). The PK
analysis consisted of building a population model relating
docetaxel clearance to physio- pathological covariates, and
generating individual PK estimates. The primary objective was to
explore whether the inter-patient variability, as evidenced in
the pharmacokinetic parameters clearance, AUC and peak,
translates into different pharmacodynamic effects. For the
analysis of efficacy, only the breast patients and the non small
cell lung cancer patients were analyzed, separately. For the
analysis of safety, all patients were considered. For the
outcomes, respond and incidence of grade IV neutropenia at first
cycle, a logistic regression model was used. For the outcomes
time to first response, and time to onset of fluid retention a
Cox regression model was used. All models were developed with a
stepwise procedure using clinical covariates, and the PK
parameters to assess the influence of pharmacokinetics.
Statistical significance was determined with an 
level of
0.05. No evidence was found that inter-individual PK variability
would significantly affect the efficacy of docetaxel. An elevated
-1-acid glycoprotein (AAG) plasma level is an unfavorable
prognostic feature for response in breast and NSCL cancer, and in
time to first response in NSCL cancer. (It was not significant in
the model for time to first response in breast cancer.) An
elevated AAG plasma level is also associated with lower odds of
experiencing grade IV neutropenia at first cycle, and a lower
risk of developing fluid retention throughout the study. Patients
with a lower docetaxel clearance have higher odds of having grade
IV neutropenia at first cycle, and a higher risk of developing
fluid retention syndrome. For a subgroup of patients with
elevated hepatic enzymes, for which the population PK model
predicted a 30% decrease in clearance, there was no statistical
evidence of an increased risk of grade IV neutropenia at first
cycle. However, these patients have been found to have a higher
incidence of severe toxicites such as febrile neutropenia, and
treatment discontinuation due to adverse events.