The use of truncated area under the curves in the bioequivalence evaluation of long half-life drugs. Studies with donepezil and memantine.
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.
Erkent
Ulkem
U
Eczacibasi Pharmaceuticals Co., Istanbul, Turkey.
Koytchev
Rossen
R
D000293:Adolescent; D000328:Adult; D000465:Algorithms; D019540:Area Under Curve; D018592:Cross-Over Studies; D000077265:Donepezil; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D006801:Humans; D007189:Indans / Q000008:administration & dosage / Q000493:pharmacokinetics; D016014:Linear Models; D008297:Male; D008559:Memantine / Q000008:administration & dosage / Q000493:pharmacokinetics; D008875:Middle Aged; D015233:Models, Statistical; D018697:Nootropic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics; D013608:Tablets, Enteric-Coated; D013810:Therapeutic Equivalency
D018691:Excitatory Amino Acid Antagonists; D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D013608:Tablets, Enteric-Coated; D000077265:Donepezil; D008559:Memantine