The bridging concept: optimizing dose for phase II/III in Alzheimer's disease.
Our research has shown that the tolerance of Alzheimer's disease (AD) patients for anti-dementia compounds is frequently higher but occasionally lower than the tolerance of healthy young or elderly populations. Such differences can either pose safety problems in later efficacy studies if patients cannot tolerate the dosages previously deemed 'safe' in healthy populations, or interfere with determining efficacy if inadequate doses are employed. We recommend use of a 'bridging study', which optimizes dosage early in development by determining the maximum tolerated dose of a compound in patients. Consecutive panels of patients each receive higher doses of study drug until a minimum intolerated dose is reached. The dose immediately below this one is then considered the maximum tolerated dose. Careful subject selection, adequate facilities, and highly qualified, experienced personnel, are critical to the successful implementation of a bridging study. Correctly done, bridging can streamline the overall drug development process while making Phase II and III trials safer for patients, and has immense potential for accelerating the search for compounds that have efficacy in AD.
Cutler
N R
NR
International Clinical Trials, London, UK.
Sramek
J J
JJ
Kilborn
J R
JR
D000544:Alzheimer Disease / Q000188:drug therapy*; D018678:Cholinergic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D006801:Humans
D018678:Cholinergic Agents