How the FDA forgot the evidence: the case of donepezil 23 mg

Schwartz and Woloshin (1) argue convincingly that Eisai and Pfizer investigated a 23 mg donepezil (Aricepttm) tablet for efficacy motivated by commercial interest in obtaining FDA approval to market the new dosage as a strategy to compete after patent expiration with the soon to be generic donepezil. The selection of a patented 23 mg tablet seems based on providing practitioners a therapeutic option not achievable with the approved 5 an 10 mg tablets and patients the convenience of a single daily dose. Neither of these assumptions makes any scientific sense to us; in fact, each is contradicted by current knowledge of acetylcholine pharmacology in brain and the pharmacokinetics of donepezil and other acetylcholinesterase inhibitors (AChEI)

A difference of 23 mg from 25 mg or 20 mg dosing almost certainly has no significance for this therapeutic since it has already been shown that wide variations in tissue concentrations of drug and levels of enzyme inhibition occur in a population after administration of 5 and 10 mg doses of donepezil as with other AChEI (2). What has been lacking for the last decades of therapy with donepezil and other ACHEIs is a clear understanding of the relations between dose and AChE inhibition levels, needed to optimize target engagement by the drug and between AChE inhibition levels and patient benefits, the clinical efficacy available with an optimal target engagement. The study by Farlow et al. (3) could have been designed to clarify these issues and to justify a higher than 10 mg qd dose but unfortunately it was not. Eisai and Pfizer instead sponsored a randomized double blind study with 1371 patients at two fixed doses of donepezil 10mg daily or 23 mg daily for 24 weeks. As could be predicted from prior experiences of having to reduce donepezil 10 mg q.d. doses back to 5 mg q.d., patients showing adverse events in the high dose group doubled from 300 (10mg) to 710 and nausea and vomiting, the most common adverse events, were 5-10 times more common in the high dose group.

These classical cholinergic adverse events, increased nausea and vomiting, could have been predicted for a single 23 mg. donepezil from past experiences with AChEI drugs (2). Cholinergic adverse events are already increased with a move from 5 to 10 mg doses of donepezil (2) and in the original developments of AChEI drugs as potential therapies for AD investigators first had to gain control over cholinergic adverse events before efficacy could be demonstrated for the class (2). In our own research we selected to work with metrifonate to take advantage of its irreversible inhibition that provided drug concentration independent stable levels of AChE inhibition over time. We were able to demonstrate that higher levels of ACHE inhibition could be obtained without incurring classical cholinergic adverse events by limiting the reductions in AChE activity to 20% following a dosing of drug (4).There is support for achieving optimal clinical responses with dose increases of AChEI (5) and we do not disagree with research into using higher doses of donepezil to document these benefits and provide to practitioners guidelines for best evidence care. Unfortunately the 23 mg donepezil experience does not achieve this end. Even though donepezil is a long acting AChEI because of its prolonged t ½ elimination, we would be surprised if the 23 mg. tablet did not produce excessive acute percentage reductions in ACHE activity such as we found associated with the onset of classical cholinergic adverse events.

Eisai and Pfizer have done AD patients no service by resurrecting adverse events as an additional incentive to avoid the inconvenience of taking a medication for a chronic illness. It is most probable that that a certain number of patients who have not shown a clinical effect at a lower dose i.e. 10 mg ("non responders" and " weak responders") may show a clinically significant effect at a higher dose; however, the introduction of a 23 mg. tablet does nothing to further this appropriate use of donepezil or other ACHEIs among AD patients.

- A Nordberg, Alzheimer Neurobiology Center, Karolinska Institutet, Stockholm, Sweden
- RE Becker, Aristea Translational Corporation, Freeport, ME, USA
- E Giacobini, Department of Internal Medicine, Rehabilitation and Geriatrics, University of Geneva Faculty of Medicine, Geneva, Switzerland

References
1. Schwartz LM, Woloshin S. How the FDA forgot the evidence: the case of donepezil 23 mg. BMJ 344e, 1086doi, 2012
2. Giacobini E. Cholinesterase in human brain: the effect of cholinesterase inhibitors on Alzheimer´s disease and related disorders. In: Giacobini E, Pepeu G. The brain cholinergic system in health and disease p. 235-264. Informa Healthcare, 2006.
3. Farlow MR, Salloway S, Tariot PN, Yardley J, Moline ML, Wang Q, et al. Effectiveness and tolerability of high-dose (23 mg/d) versus standard-dose (10 mg/d) donepezil in moderate to severe Alzheimer’s disease: a 24-week, randomized, double-blind study. Clin Ther, 2010; 32:1234-51.
4. Becker RE, Colliver JA, Markwell SJ, Moriearty PL, Unni LK, Vicari S. A Double-Blind, Placebo-Controlled Study of Metrifonate, an Acetylcholinesterase Inhibitor for Alzheimer’s Disease. Alzheimer’s Disease and Associated Disorders. 1996; 10(3):124-131.
5. Nordberg A, Amberla K, Shigeta M, Lundqvist H, Viitanen M, Hellström-Lindahl E, Johansson M, Anderson J, Hartvig P, Lilja A, Långström B and Winblad B. Long-term Tacrine treatment in three mild Alzheimer patients: effects on nicotinic receptors, cerebral blood flow, glucose metabolism and cognitive abilities. Alzheimer Disease and Associated Disorders, 1998;12(3);228-237.