C. Laveille Pharm.D., M. Malbezin M.D, D. Guez M.D., R. Jochemsen Ph.D.
IRIS, 6 place des Pleiades, 92415 Courbevoie cedex, France
S-12024 is an original compound with cognitive enhancing properties in animals. After Phase I studies in healthy volunteers, three Phase IIa double blind versus placebo studies in dementia of the Alzheimer type were achieved for tolerance assessment in the target populations. A prospective population approach was performed using the NONMEM software in order to analyse the pharmacokinetics at steady-state of these Phase IIa studies.
Because only a small number of blood samples could be taken per patient, it was important to improve the power of the analysis by increasing the variability among blood sampling times. To reach this objective, we attributed randomly to each patient two to three blood sampling times, in addition to the Cmin.
Analysis by NONMEM was performed in a first step for each study separately. Then the three Phase IIa studies were combined and analyzed together in a second step. For these two steps, structural and error models were built and, furthermore, the influence of several covariates on pharmacokinetic parameters was investigated (Gender, weight, age, creatinine clearance …).
A one-compartment model with first order absorption was used to describe the data of each of the three Phase II studies and no covariates were found to influence the pharmacokinetic parameters. However, mean population clearances were different for each study.
A validation of the pharmacokinetic model was realized on the Phase I study after repeated administration in the elderly, by comparison of clearance predicted by bayesian estimation from the population approach, and clearance calculated by a non compartmental approach. Bias and precision for estimated clearance of the Phase I study were less than 10%.
The next step was to analyse simultaneously the three studies and to reassess the influence of the covariables. This analysis is still going on.
All results will be presented in the PAGE meeting in June 1994.
Reference: PAGE 3 (1994) Abstr 856 [www.page-meeting.org/?abstract=856]
Poster: poster