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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.

BACKGROUND
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.


OBJECTIVE
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.


METHODS
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 (AUC(last)) and maximum observed concentration (C(max)) were the main evaluation criteria, while area under the concentration-time curve from time zero to infinity (AUC(inf)) 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.


RESULTS
According to the classical approach, the 90% geometric confidence intervals obtained by analysis of variance for AUC(last), C(max) and AUC(inf) 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.


CONCLUSION
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.