The Use of Truncated Area under the Curves in the Bioequivalence Evaluation of Long Half-Life Drugs

Abstract

The bioequivalence of long terminal half-life drugs, donepezil (CAS 120014-06-4) 10 mg and memantine (CAS 19982-08-2) 10 mg, was evaluated by comparing the results obtained for the total areas under the concentration time curves (AUC(0–inf)) with those for partial AUCs: AUC(0–216h), AUC(0–72h) and AUC(0–48h). Pharmacokinetic endpoints were determined by standard formulas from the concentration-time courses of the parent compounds donepezil and memantine.

The results of the bioequivalence assessment based on the 90% confidence intervals calculated by means of ANOVA for logarithmically transformed values (ANOVA log) led to exactly the same decision irrespective of the type of AUC used. The 90% confidence intervals for all types of AUCs were practically identical within each product. These results prove that truncated AUCs, e.g. AUC(0–72h) or even AUC(0–48h), can be adequately used in assessing the relative bioavailability of long terminal half-life drugs. The findings suggest that even for drugs with half-lives between 24 and 60 h and thus shorter than those of donepezil and memantine an AUC truncated to 48 h post dose can be successfully used for the assessment of bioequivalence as this sample collection time ensures a proper comparison of the absorption process as recommended in the CPMP Note for Guidance on the Investigation of Bioavailability and Bioequivalence.

Key words

CAS 19982-08-2 - CAS 120014-06-4 - CNS-active drugs - Bioequivalence, long terminal half-life drugs, truncated AUC - Donepezil, bioequivalence - Memantine, bioequivalence

• References

• 1 CPMP Note for Guidance on the Investigation of Bioavailability and Bioequivalence. CPMP/EWP/QWP/1401/98, 26 July 2001.
• 2 FDA Guidance for Industry. Bioavailability and Bioequivalence. Studies for Orally Administered Drug Products -General Considerations. March 2003.
• 3 Health Canada TPD. Notice to Industry. Bioequivalence Requirements for Long Half-life Drugs. June 2005.
• 4 NIHS Guideline for Bioequivalence Studies of Generic Products. Japan, December 1997.
• 5 Physician’s Desk Reference (PDR) Information of Aricept®, 2006.
• 6 Heydorn WE. Donepezil (E2020): a new acetylcholinesterase inhibitor. Review of its pharmacology, pharmacokinetics, and utility in the treatment of Alzheimer’s disease. Expert Opin Investig Drugs. 1997; Oct 6 (10) 1527-1535
• 7 Lundback Pharma, Prescribing Information of Ebixa, 2006.
• 8 ICH Topic E 6. Guideline for Good Clinical Practice. Step 5, Consolidated Guideline from 01.05.1996. Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) Jan. 1997.
• 9 Shah VP, Midha KK, Findlay JWA, Hill HM, Hulse JD, McGilveray LJ et al. Bioanalytical method validation. A revist with a decade of progress. Pharm Res. 2000; 17: 1551-1557
• 10 FDA Guidance for Industry. Bioanalytical Method Validation. May 2001.
• 11 Endrenyi L, Tothfalusi L. Truncated AUC evaluates effectively the bioequivalence of drugs with long half-lives. IntJ Clin Pharmacol Ther. 1997; Apr 35 (4) 142-150
• 12 Gaudreault J, Potvin D, Lavigne J, Lalonde RL. Truncated area under the curve as a measure of relative extent of bioavailability: evaluation using experimental data and Monte Carlo simulations. Pharm Res. 1998; Oct 15 (10) 1621-1629