title: Estimation of the absolute bioavailability of rivastigmine in patients with mild to moderate dementia of the Alzheimer's type.
abstract: OBJECTIVE
  To investigate the bioavailability of rivastigmine, an approved therapy for patients with mild to moderate dementia of the Alzheimer's type, at the highest approved single dose of 6 mg.
  
  
  METHODS
  Randomised, two-period crossover, single-centre, non-blinded, inpatient study.
  
  
  METHODS
  Eleven patients (five females and six males) with mean age 69.5 years.
  
  
  METHODS
  The 6 mg oral dose was compared with a 2 mg intravenous dose of rivastigmine infused over a 1-hour period. Plasma concentrations of rivastigmine and its metabolite NAP 226-90 were measured with a gas chromatographic/mass spectrometric method.
  
  
  RESULTS
  Following oral administration of a single 6 mg capsule, rivastigmine is rapidly absorbed with an average time to peak plasma concentration of about 1 hour and an average peak concentration of about 25.6 g/L. By a noncompartmental approach, the absolute bioavailability of the 6 mg oral dose of rivastigmine was 71.7% when compared with a 2mg intravenous infusion normalised for dose. By using a population pharmacokinetic model with Michaelis-Menten elimination, absolute bioavailability was estimated at 60.2%. The average terminal elimination half-life of rivastigmine ranged from 1.4 to 1.7 hours for both treatments. Plasma concentrations of the major metabolite, NAP 226-90, formed by the hydrolysis of rivastigmine by cholinesterase are lower than those of the parent compound following oral and intravenous administration.
  
  
  CONCLUSIONS
  A noncompartmental approach and a compartmental approach based on a population pharmacokinetic model with Michaelis-Menten elimination yielded comparable values, 71.7% and 60.2% respectively, for the absolute bioavailability of a single 6 mg oral dose of rivastigmine. Comparison with previous studies confirmed that the oral form of the drug exhibits increased bioavailability with increasing dose, consistent with its nonlinear pharmacokinetics..
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hossain
authors.forename: Stanford S
authors.initials: SS
authors.lastname: Jhee
authors.forename: Thomas
authors.initials: T
authors.lastname: Shiovitz
authors.forename: Craig
authors.initials: C
authors.lastname: McDonald
authors.forename: Greg
authors.initials: G
authors.lastname: Sedek
authors.forename: Francoise
authors.initials: F
authors.lastname: Pommier
authors.forename: Neal R
authors.initials: NR
authors.lastname: Cutler
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy*; D019540:Area Under Curve; D001682:Biological Availability; D002219:Carbamates / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D048448:Phenylcarbamates; D000068836:Rivastigmine
chemical_list: D002219:Carbamates; D002800:Cholinesterase Inhibitors; D048448:Phenylcarbamates; D000068836:Rivastigmine