title: A novel once-daily fixed-dose combination of memantine extended release and donepezil for the treatment of moderate to severe Alzheimer's disease: two phase I studies in healthy volunteers.
abstract: BACKGROUND
  Combining two standard-of-care medications for Alzheimer's disease (AD) into a single once-daily dosage unit may improve treatment adherence, facilitate drug administration, and reduce caregiver burden. A new fixed-dose combination (FDC) capsule containing 28 mg memantine extended release (ER) and 10 mg donepezil was evaluated for bioequivalence with co-administered commercially available memantine ER and donepezil, and for bioavailability with regard to food intake.
  
  
  METHODS
  Two phase I, single-dose, randomized, open-label, crossover studies were conducted in 18- to 45-year-old healthy individuals. In MDX-PK-104 study, fasting participants (N = 38) received co-administered memantine ER and donepezil or the FDC. In MDX-PK-105 study, participants (N = 36) received three treatments: intact FDC taken while fasting or after a high-fat meal, or FDC contents sprinkled on applesauce while fasting. Standard pharmacokinetic parameters for memantine and donepezil were calculated from the plasma concentration time-curve using non-compartmental analyses. Linear mixed-effects models were used to compare: (a) FDC versus co-administered individual drugs; (b) FDC fasted versus with food; and (c) FDC sprinkled on applesauce versus FDC intact, both fasted. Safety parameters were also evaluated.
  
  
  RESULTS
  The FDC capsule was bioequivalent to co-administered memantine ER and donepezil. There was no significant food effect on the bioavailability of the FDC components. There were no clinically relevant differences in time to maximum plasma concentration or safety profiles across treatments.
  
  
  CONCLUSIONS
  An FDC capsule containing 28 mg memantine ER and 10 mg donepezil is bioequivalent to commercially available memantine ER and donepezil, and bioavailability is not affected by food intake or sprinkling of capsule contents on applesauce.
authors.affiliation: Forest Research Institute, an affiliate of Actavis, Inc., Harborside Financial Center, Plaza V, Floor 19, Jersey City, NJ, 07311, USA, Ramesh.Boinpally@actavis.com.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Boinpally
authors.forename: Laishun
authors.initials: L
authors.lastname: Chen
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Zukin
authors.forename: Natalie
authors.initials: N
authors.lastname: McClure
authors.forename: Robert K
authors.initials: RK
authors.lastname: Hofbauer
authors.forename: Antonia
authors.initials: A
authors.lastname: Periclou
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000188:drug therapy*; D001682:Biological Availability; D018592:Cross-Over Studies; D000077265:Donepezil; D004359:Drug Therapy, Combination; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007189:Indans / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008559:Memantine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D007189:Indans; D010880:Piperidines; D000077265:Donepezil; D008559:Memantine