Objective: Memantine, a moderate affinity, uncompetitive NMDA receptor antagonist, is approved in Europe for Alzheimer's disease and under investigation for this indication in the US. Our objective was to determine whether an in vivo pharmacokinetic and pharmacodynamic interaction exists between memantine and the acetylcholinesterase inhibitor (AChE) donepezil.
Design/Methods: In an open-label multiple-dose study, 24 healthy subjects (age 18-35 years) received 10 mg memantine orally on Day 1. Following a 14-day washout, subjects received 5 mg donepezil orally once daily for 7 days (outpatient). Beginning on Day 22, donepezil dosage was doubled for 22 days, and the last donepezil dose was concomitantly administered with 10 mg memantine on Day 43. Assessments included pharmacokinetic, pharmacodynamic (AChE inhibition) and safety parameters (adverse events, ECG, vital signs, clinical laboratory tests).
Results: The rate and extent of memantine absorption was not significantly altered with daily dosing of donepezil, nor was the bioavailability of multiple-dose donepezil altered with single-dose memantine. Percent maximum inhibition of AChE activity by donepezil averaged 77.8% and was not statistically different upon co-administration of memantine (81.1%). Two patients withdrew due to adverse events while treated with donepezil. Of 19 subjects who completed the study, single memantine doses administered with multiple donepezil doses were well tolerated.
Conclusion: Memantine and donepezil did not interact pharmacokinetically or pharmacodynamically, suggesting that they can be safely co-administered.
Supported by Forest Laboratories, Inc.
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