D.M. Reith (1), W. Hooper (2), M Franklin (2).
(1) Dunedin School of Medicine, University of Otago, Dunedin, New Zealand; (2) Q-Pharm Pty Limited, Queensland Institute of Medical Research, Brisbane, Australia
Objectives: NONMEM has been validated primarily using simulated datasets and there are relatively few studies comparing the two-stage and population approaches using real patient or volunteer data. The aim of the present study was to compare the two approaches using a large dataset accumulated during the conduct of bioequivalence studies.
Methods: One hundred volunteers were observed to ingest 40 mg of the same formulation of fluoxetine. Each subject had 19 plasma samples collected between time 0 and 26 days post-dose. Plasma fluoxetine and norfluoxetine levels were determined using a GC-MS assay. The two-stage approach was used to determine Ka and Ke for each subject by nonlinear curve fitting using WinNonLin™ and Ke for each subject by fitting the terminal elimination phase using Stemkinetics™ and Stata , and the mean values were determined for the 100 volunteers. A one compartment, first order absorption and elimination model (ADVAN2) was used to determine Ka and Ke using NONMEM and first order conditional estimation. The POSTHOC command was used to provide individual estimates of Ka and Ke to determine if NONMEM can detect a bimodal distribution of Ke. Starting with all 19 observations per subject, and randomly removing one observation per subject at each step, Ka and Ke were determined for the reduced datasets.
Results: NONMEM estimated similar values for Ka and Ke to the two-stage approach down to three observations per subject. The CV% for ETA1, ETA2 and EPS were acceptable (< 30%) down to 2 observations per subject. There was no deterioration in the precision or bias of the models with the progressive reduction in observations. Posthoc estimates of Ke were normally distributed rather than demonstrating the bimodal distribution of Ke from the two-stage approach. NONMEM and WinNonLin determined similar estimates for Ke and Ka. Stemkinetics™ and Stata determined similar estimates of Ke to each other but differed to the two other programs.
Conclusions: NONMEM produced acceptable estimates of the pharmacokinetic parameters when there were three or more observations per volunteer but, in contrast to the two-stage approach, did not detect the bimodal distribution of the Ke for fluoxetine.
Reference: PAGE 12 () Abstr 390 [www.page-meeting.org/?abstract=390]
Poster: poster