title: Steady-state pharmacokinetics and safety of donepezil HCl in subjects with moderately impaired renal function.
abstract: OBJECTIVE
  To characterize the pharmacokinetic, pharmacodynamic and safety profiles of donepezil in subjects with moderate renal impairment and matched healthy controls during single-dose and multiple-dose phases.
  
  
  METHODS
  This open-label study enrolled subjects with moderate renal impairment (creatinine clearance [CL(Cr)] 17-33 ml min(-1) 1.73 m(-2) body surface area) and age, weight and sex-matched healthy controls. A single-dose (5 mg donepezil) phase was followed by a 23-day multiple dose (5 mg day(-1) donepezil) steady-state phase. The pharmacokinetic and pharmacodynamic parameters of donepezil were determined for up to 144 h after the first dose and 168 h after the last dose.
  
  
  RESULTS
  Thirty-six subjects were enrolled, 19 renally impaired and 17 healthy controls. All pharmacokinetic and pharmacodynamic parameters were similar between groups after a single dose of donepezil (C(max) 5.17 +/- 0.36 and 6.07 +/- 0.49 ng ml(-1); AUC(0-24) 76.05 +/- 5.54 and 77.45 +/- 4.49 ng.h ml(-1); mean maximum percentage inhibition [I(max)] red blood cell (RBC) AChE activity 32.07 +/- 2.00 and 31.69 +/- 2.45%; for subjects with renal impairment and healthy subjects, respectively). Pharmacokinetic parameters under steady-state conditions did not differ between renally impaired and healthy subjects (C(SS) 20.83 +/- 1.78 and 18.38 +/- 1.52 ng ml(-1); AUC(0-24) 500.0 +/- 42.8 and 441.1 +/- 36.4 ng.h ml(-1); degree of accumulation [R(A)] 6.98 +/- 0.59 and 5.94 +/- 0.53; for subjects with renal impairment and healthy subjects, respectively). Main pharmacodynamic parameters were also similar in renally impaired and healthy subjects at steady state (average percentage inhibition [I(SS)] RBC AChE activity 65.11 +/- 2.52 and 60.62 +/- 2.95, respectively). Protein binding was also similar between groups (% free donepezil 23.54 +/- 1.96 and 20.23 +/- 0.64, respectively). Donepezil was well tolerated by both groups.
  
  
  CONCLUSIONS
  These results indicate that the pharmacokinetics of donepezil are not altered after dosing to steady state, and that donepezil can be administered safely to subjects with moderate renal impairment.
authors.affiliation: Clinical Pharmacology, Eisai Medical Research Inc., Ridgefiled Park, NJ 07660, USA. christa_nagy@eisai.com
authors.forename: Christa F
authors.initials: CF
authors.lastname: Nagy
authors.forename: Dinesh
authors.initials: D
authors.lastname: Kumar
authors.forename: Edward I
authors.initials: EI
authors.lastname: Cullen
authors.forename: W Kline
authors.initials: WK
authors.lastname: Bolton
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Marbury
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Gutierrez
authors.forename: H Wayne
authors.initials: HW
authors.lastname: Hutman
authors.forename: Raymond D
authors.initials: RD
authors.lastname: Pratt
mesh_terms: D000328:Adult; D000368:Aged; D002800:Cholinesterase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D015331:Cohort Studies; D000077265:Donepezil; D005260:Female; D006801:Humans; D007189:Indans / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D007674:Kidney Diseases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D011485:Protein Binding
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil