Investigation of the pharmacokinetic and pharmacodynamic interactions between memantine and glyburide/metformin in healthy young subjects: A single-center, multiple-dose, open-label study

• Published in: Clinical therapeutics Vol. 27; no. 10; pp. 1596 - 1606
• Main Authors: Rao, Niranjan, Chou, Thomas, Ventura, Daniel, Abramowitz, Wattanaporn
• Format: Journal Article
• Language: English
• Published: Belle Mead, NJ EM Inc USA 01.10.2005; Excerpta Medica; Elsevier Limited
• Subjects: Adult; Alzheimer Disease - drug therapy; Alzheimer's disease; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; diabetes mellitus; Diabetes Mellitus, Type 2 - drug therapy; Diabetes. Impaired glucose tolerance; Drug Combinations; Drug Interactions; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; glyburide; Glyburide - administration & dosage; Glyburide - pharmacokinetics; Glyburide - pharmacology; Humans; Male; Medical sciences; memantine; Memantine - pharmacokinetics; Memantine - pharmacology; metformin; Metformin - administration & dosage; Metformin - pharmacokinetics; Metformin - pharmacology; Neurology; pharmacokinetics/pharmacodynamics; Pharmacology. Drug treatments; metformin; diabetes mellitus; memantine; glyburide; Alzheimer's disease; pharmacokinetics/pharmacodynamics; Endocrinopathy; Sulfanilamide derivatives; Alzheimer disease; Glutamate receptor; Multiple dose; Hypoglycemic agent; Biguanides; Degenerative disease; Antagonist; Glibenclamide; Human; Nervous system diseases; Healthy subject; Diabetes mellitus; Interaction; Single dose; Antialzheimer agent; Antiparkinson agent; Biological activity; Cerebral disorder; Memantine; Amantadine dérivatives; Sulfonylureas; Central nervous system disease; Metformin; NMDA receptor; Pharmacokinetics
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2005.10.006

The high prevalence rates of both 1026 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. The primary goal of this study was to determine1026 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). In this single-center, multiple-dose, open-label1026 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 coad-ministered 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. The study population consisted of 24 subjectResults:026 (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. No pharmacokinetic interactions between1026 memantine and glyburide/metformin were detected in this study of healthy young volunteers. Memantme had no effect on the pharmacodynamic activities of glyburide and metformin, and the drug combination was well tolerated in this population.