Results and validation of a population pharmacodynamic model for cognitive effects in Alzheimer patients treated with tacrine.
Tacrine has been studied in two clinical trials of identical design in patients with probable Alzheimer disease. One trial enrolled patients in the United States, while the other enrolled patients in France. A population pharmacodynamic model has been used to describe the cognitive component of the Alzheimer disease assessment scale (ADASC) using mixed effects nonlinear regression. The model parameters and their population variability and covariance were estimated by using NONMEM. During an observation period of up to 5 months, the rate of disease progression was 6.17 ADASC units/year. The effect of tacrine was described best by a shift in the disease progress curve (-2.99 ADASC units or 177.6 days at a dose of 80 mg/day). The placebo effects associated with tacrine and placebo treatment were similar in magnitude and time course. There was no evidence of tolerance to tacrine but tolerance to the placebo treatment developed during the study. The size of the placebo effect in the French population was 76% larger than in the United States population, and the response to placebo diminished more slowly in the French population.
Holford
N H
NH
Department of Pharmacology and Clinical Pharmacology, University of Auckland, New Zealand.
Peace
K E
KE
D000544:Alzheimer Disease / Q000188:drug therapy*; D003071:Cognition / Q000187:drug effects*; D004311:Double-Blind Method; D005602:France; D006801:Humans; D016013:Likelihood Functions; D008954:Models, Biological; D015990:Placebo Effect; D013619:Tacrine / Q000494:pharmacology / Q000627:therapeutic use*; D014481:United States
D013619:Tacrine