Investigation of the pharmacokinetic and pharmacodynamic interactions between memantine and glyburide/metformin in healthy young subjects: a single-center, multiple-dose, open-label study.
BACKGROUND
The high prevalence rates of both Alzheimer's disease (AD) and type 2 diabetes mellitus in the elderly population suggest that concomitant pharmacotherapy is likely. Given the renal tubular transport and extensive urinary excretion of memantine and metformin, it was of interest to assess the pharmacokinetic and pharmacodynamic interaction with glyburide/metformin.


OBJECTIVE
The primary goal of this study was to determine whether an in vivo pharmacokinetic or pharmacodynamic interaction exists between memantine (an uncompetitive, moderate-affinity, N-methyl-D-aspartate receptor antagonist with fast blocking/unblocking kinetics that is available in the United States for moderate to severe AD) and glyburide/metformin (a combination pharmacotherapy formulation approved for glycemic control in patients with type 2 diabetes mellitus).


METHODS
In this single-center, multiple-dose, open-label study, healthy adult subjects received a single oral dose of memantine hydrochloride (20 mg) on day 1. After a 14-day washout period, subjects were orally administered 1.25-mg glyburide/250-mg metformin BID with food for 6 days. On day 21, subjects were coadministered memantine (20 mg) and glyburide/metformin with food. Assessments included determination of pharmacokinetic parameters for memantine and the antidiabetic agents when administered alone and in combination, pharmacodynamic measurements of blood glucose levels, and analyses of tolerability.


RESULTS
The study population consisted of 24 subjects (13 women, 11 men; 79.2% white) with a mean (SD) age of 26.1 (5.6) years and a mean (SD) weight of 69.5 (11.3) kg. Twenty-one subjects completed the study: 2 discontinued due to adverse events judged unrelated to study medication, and 1 withdrew consent. No significant pharmacokinetic or pharmacodynamic interactions were observed between memantine and glyburide/metformin. Adverse events included dizziness (41.7% of patients) with memantine administration and gastrointestinal effects (nausea, 9.1 %; vomiting, 9.1%; abdominal cramps, 13.6%) with glyburide/metformin administration.


CONCLUSIONS
No pharmacokinetic interactions between memantine and glyburide/metformin were detected in this study of healthy young volunteers. Memantine had no effect on the pharmacodynamic activities of glyburide and metformin, and the drug combination was well tolerated in this population.
Rao
Niranjan
N
Forest Research Institute, Forest Laboratories, Inc., Jersey City, New Jersey, USA. rao.niranjan@kyowa-kpi.com
Chou
Thomas
T
Ventura
Daniel
D
Abramowitz
Wattanaporn
W
D000328:Adult; D000544:Alzheimer Disease / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D005905:Glyburide / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008559:Memantine / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008687:Metformin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*
D004338:Drug Combinations; D008687:Metformin; D005905:Glyburide; D008559:Memantine