Arzneimittelforschung 2010; 60(3): 116-123
DOI: 10.1055/s-0031-1296259
CNS-active Drugs · Hypnotics · Psychotropics · Sedatives
Editio Cantor Verlag Aulendorf (Germany)

Bioequivalence study of two different tablet formulations of donepezil using truncated areas under the curve

A single-center, single-dose, randomized, open-label, 2-way crossover study under fasting conditions
Susana Almeida
1   Medical Department, Grupo Tecnimede, Sintra, Portugal
2   Department of Pharmacology and Therapeutics, Universidad Autònoma de Barcelona, Spain
Augusto Filipe
1   Medical Department, Grupo Tecnimede, Sintra, Portugal
Rita Neves
1   Medical Department, Grupo Tecnimede, Sintra, Portugal
Isabelle Desjardins
3   Anapharm, Québec (Québec), Canada
Eric Shink
3   Anapharm, Québec (Québec), Canada
Araceli Castillo
4   Anapharm Europe S.L., Barcelona, Spain
› Institutsangaben
Weitere Informationen


02. Dezember 2011 (online)



Donepezil hydrochloride (CAS 120014-06-4) is a piperidine-based, reversible inhibitor of the enzyme acetylcholinesterase (AChE). It is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine (ACh) through reversible inhibition of its hydrolysis by AChE.


The aim of this study was to assess the bioequivalence of a new donepezil 10 mg formulation (test formulation) vs. the reference product, as required by European regulatory authorities for the marketing of a generic product. Additionally, the applicability of the truncated area under the plasma concentration curve (AUC) approach to this drug and under these test conditions was determined.


This was a single center, randomized, single-dose, open-label, 2-way crossover study in healthy volunteers under fasting conditions. Plasma samples were collected up to 288 h post-dosing and (+)-donepezil and (−)-donepezil plasma levels were determined by reverse liquid chromatography and by tandem mass spectrometry detection (ie, the LCMS/MS method). Pharmacokinetic parameters were calculated using non-compartmental analysis. Area under the concentration-time curve from time zero to the time of the last non-zero concentration (AUClast) and maximum observed concentration (Cmax) were the main evaluation criteria, while area under the concentration-time curve from time zero to infinity (AUCinf) was also analyzed for additional information. For the assessment of the applicability of the truncated AUC approach, AUCs truncated at 24, 48, 72, 96, 144, 192, 240, and 288 h were calculated. All of the abovementioned pharmacokinetic parameters were analyzed using 90% geometric confidence interval of the ratio (T/R) of least-squares means from the ANOVA of the In-transformed parameter. Tolerability was monitored using physical examination, including vital sign measurements and laboratory analysis.


According to the classical approach, the 90% geometric confidence intervals obtained by analysis of variance for AUClast, Cmax and AUCinf were within the predefined ranges (80.00–125.00%) for both analytes. Truncated AUCs were also in all cases within the predefined ranges for acceptance of bioequivalence.


Bioequivalence between test and reference formulations, both in terms of rate and extension of absorption, under fasting conditions, was concluded according to European guidelines. Both formulations were well tolerated. The conclusion of bioequivalence was also supported using the truncated AUCs approach.

  • References

  • 1 Electronic Medicines Compendium (eMC). Datapharm Communications Ltd. [online]. [cited 2008/07/09]; available from:
  • 2 Canadian Pharmacists Association, 2008. Compendium of Pharmaceuticals and Specialties, online version (e-CPS). [online]. 2008 [cited 2008/07/09]; available from:
  • 3 Rogers SL, Friedhoff LT. Pharmacokinetic and pharmacodynamic profile of donepezil HCl following oral doses. Br J Pharmacol. 1998; 46 (Suppl 1) 1-6
  • 4 Tiseo PJ, Perdomo CA, Friedhoff LT. Metabolism and elimination of 14C-donepezil in healthy volunteers: A single-dose study. Br J Pharmacol. 1998; 46 (01) 19-24
  • 5 Xie Z, Liao Q, Xu X, Yao M, Wan J, Liu D. Rapid and sensitive determination of donepezil in human plasma by liquid chromatography/tandem mass spectrometry: application to a pharmacokinetic study. Rapid Commun Mass Spectrometry. 2006; 20: 3193-8
  • 6 Park EJ, Lee HW, Ji HY, Kim HY, Lee MH, Park ES et al. Hydrophilic interaction chromatography-tandem mass spectrometry of donepezil in human plasma: application to a pharmacokinetic study of donepezil in volunteers. Arch Pharm Res. 2008; 31 (9) 1205-11
  • 7 Seltzer B. Donepezil: an update. Expert Opin Pharmacother. 2007; 8 (7) 1011-23
  • 8 Jann MW, Shirley KL, Small GW. Clinical pharmacokinetics and pharmacodynamics of Cholinesterase inhibitors. Clin Pharmacokinet. 2002; 41 (10) 719-39
  • 9 Note For Guidance on the Investigation of Bioavailability and Bioequivalence. CPMP (Committee for Proprietary Medicinal Products) 2001
  • 10 Good Clinical Practice Consolidated Guideline. International Conference on Harmonisation, E6 1996
  • 11 Guideline on the investigation of bioequivalence. Committee for Medicinal Products for Human Use (CHMP), Doc. Ref. CPMP/EWP/QWP/1401/98 Rev. 1 2010