Lack of pharmacokinetic or pharmacodynamic interaction between memantine and donepezil

BACKGROUND: Memantine, a low- to moderate-affinity, uncompetitive N-methyl-D-aspartate receptor antagonist, was approved in the US for treatment of moderate to severe Alzheimer's disease in October 2003. OBJECTIVE: To determine whether an in vivo pharmacokinetic interaction exists between memantine and the acetylcholinesterase (AChE) inhibitor donepezil. METHODS: In this open-label, multiple-dose study, 24 healthy subjects (aged 18-35 y) received oral administration of memantine 10 mg on day 1. Following a 14-day washout period, subjects were orally administered donepezil 5 mg once daily for 7 days on an outpatient basis. Beginning on day 22, the donepezil dosage was doubled for 22 days to the target dose of 10 mg once daily, with the last donepezil dose concomitantly administered with memantine 10 mg on day 43. Assessments included pharmacokinetic as well as safety parameters. In addition, AChE inhibition was measured in red blood cells by radiolabeled-enzyme assay following administration of donepezil alone and after a single memantine dose. RESULTS: Data from 19 subjects who completed the study indicated no significant pharmacokinetic interactions between a single dose of memantine and multiple doses of donepezil. Percent maximum inhibition of AChE activity (mean +/- SD) by donepezil was 77.8 +/- 7.3% and not significantly different upon coadministration of a single dose of memantine (81.1 +/- 5.7%). Two subjects withdrew due to adverse events while taking donepezil alone. Single memantine doses administered with multiple donepezil doses were well tolerated. CONCLUSIONS: The pharmacokinetic and pharmacodynamic data from this study indicated a lack of interaction between memantine and donepezil, suggesting that memantine and donepezil may be safely and effectively used in combination.