RBC cholinesterase inhibition: A useful surrogate marker for cholinesterase inhibitor activity in Alzheimer disease therapy?

Red blood cell (RBC) acetylcholinesterase (AChE) inhibition has been used a s a peripheral surrogate marker for the activity of centrally acting AChE i nhibitors (AChEIs) in the treatment of Alzheimer disease. As a valid periph eral surrogate marker, RBC AChE inhibition should reflect the central pharm acodynamic activity of the compound and should demonstrate a relation with cognitive or global improvement in patients with Alzheimer disease. As a us eful clinical tool, RBC AChE inhibition should also provide an advantage in dose optimization. However, the application of surrogate markers in resear ch and clinical use is controversial (Prentice, 1989; Gotzsche, 1996; Colbu rn, 1997; De Gruttola et al., 1997). For instance, surrogate markers that h ave been identified or applied inappropriately can lead to erroneous conclu sions, slowing the drug development process (Colburn, 1997). Also, the vali dation of surrogate markers for the pharmacodynamic activity of central ner vous system drugs is not always possible because samples of brain tissue ca nnot be analyzed in humans. Finally, although validation of peripheral mark ers for central nervous system drugs has been approached via analysis of ce rebrospinal fluid (Cutler et al., 1998a), few markers have been subjected t o such rigorous evaluation in clinical studies. The extent to which measure s of peripheral AChE inhibition accurately model central drug activity and therapeutic effectiveness of AChEIs, both as individual agents and as a dru g class, is the focus of this review. AChEIs comprise a group of structural ly diverse compounds with a wide range of relative specificities for the va rious molecular species of cholinesterase found in plasma, RBCs, and the br ain. Studies of RBC AChE inhibition after administration of AChEIs in anima ls are of limited utility because of the differential sensitivity of AChEIs for human versus animal forms of AChE, the poor correlation between effect ive doses in animals and humans, and the lock of standardized measurements of effectiveness. Although clinical studies of donepezil, metrifonate, and eptastigmine have suggested the potential use of RBC AChE inhibition as a p redictor of clinical response, the degree of inhibition yielding maximum co gnitive improvements was highly variable from compound to compound (30-80%) . Further, investigators did not prove a relation between central and perip heral pharmacodynamics or demonstrate an advantage over dose in the ability of RBC AChE inhibition to predict clinical response. A study of rivastigmi ne in patients with Alzheimer disease revealed that cerebrospinal fluid ACh E inhibition correlated well with cognitive performance, whereas peripheral inhibition did not. Therefore, RBC cholinesterase inhibition is not a reli able surrogate marker for the activity of AChEIs as a class of drugs, and i ts usefulness as a dose optimization tool for individual agents has yet to be demonstrated clearly.