The Role of Bridging Studies in the Development of Cholinesterase Inhibitors for Alzheimer’s Disease

The impairment of cognitive function that is seen in patients with Alzheimer’s disease is widely considered to be a consequence of cortical deficiencies in cholinergic transmission. Numerous cholinesterase inhibitors have been investigated for treatment of the disease, aiming to bolster the cholinergic system by blocking the degradation of acetylcholine and prolonging its ability to transmit a signal. The improvement of cognitive impairment that is achieved with cholinesterase inhibitors is dose dependent; however, the administration of clinically beneficial doses is sometimes associated with the development of intolerable cholinergic adverse effects. The poor tolerability of efficacious doses creates a narrow therapeutic index for some cholinesterase inhibitors, posing a difficult obstacle in both the development and clinical use of these agents. Bridging studies, in which the maximum tolerated dose of the compound is determined in a patient population in the early stages of development, can significantly reduce the time and cost of developing new cholinesterase inhibitors. This is achieved by identifying the upper limit of the dose range in the target population before phase II efficacy studies are initiated. Bridging studies accelerate and facilitate the process of development of new compounds by obviating the need for repeated redesign of phase II studies in the search for an optimal dose.