René Bruno, N. Vivier, J.C. Vergniol, G. Montay and L.B. Sheiner(1)
Rhone-Poulenc Rorer R & D, Antony, France; (1)University of California, San Francisco
A limited sampling strategy has been designed and implemented in Phase II studies of docetaxel to perform a prospective population pharmacokinetic/pharmacodynamic (PK/PD) evaluation. The sampling strategy consisted of four protocols of three sampling times each randomly assigned to patients.
The data set comprised 549 patients from 22 studies and 1890 plasma concentrations (3.4 per patient). NONMEM analysis of an index set of 282 patients demonstrated that docetaxel clearance (CL) is related to α1-acid glycoprotein (AAG) level, hepatic function (HEP), age (AGE) and body surface area (BSA). The population model (PM) was evaluated both qualitatively and quantitatively using a validation set of 267 patients. Validation of the model consisted in addressing the two following questions:
- Are (most or all) sub-populations at risk properly identified?
- Does use of the population model improve the prediction of clearance in sub-populations (potentially) at risk (as compared to a naive predictor: NP)?
Graphical and statistical evaluations will be presented that permitted the definition of the sub-populations likely to benefit from a priori dosage adjustments (if warranted) using the PM. In the whole population of 267 patients, the performance (bias, precision) of the PM was good (7 %, 21 %, resp.) although not better than that of the NP. However, in all the sub-populations with decreased CL, the PM performed better than the NP; the more the CL differed from the population avarage, the better the performance. For example, in the sub-population of patients with AAG levels > 2.27 g/L (n = 26, average 33 % decrease in CL), bias and precision of the PM predictions were: 7 % and 30 %, resp. The prediction of CL using the PM was better (than that of the NP) in 77 % of the patients. PK is currently being evaluated as a prognostic factor for drug response to help identify the clinical relevance of the results and to assess the need for a priori dosage adjustment.
Reference: PAGE 3 (1994) Abstr 876 [www.page-meeting.org/?abstract=876]
Poster: oral presentation