Pharmacokinetics and Bioequivalence of Two Amoxicillin 500 mg Products: Effect of Food on Absorption and Supporting Scientific Justification for Biowaiver

Purpose Aims of this study were to compare the bioequivalence of two formulations of amoxicillin 500 mg capsules under fasted and fed conditions in the same set of healthy volunteers, compare pharmacokinetics of amoxicillin under the two conditions and to assess the possibility of predicting in vivo bioequivalence of the two formulations using in vitro dissolution data. Method The innovator product of amoxicillin was used as the reference formulation and a test product, which showed in vitro equivalence after a biowaiver study with the same reference product was used in the bioequivalence study. Altogether 16 subjects were randomized to the reference and test products in the fasted study and 12 of them participated in the fed study. Plasma concentration of amoxicillin was analyzed by a validated Liquid chromatography coupled with two mass spectrometry (LC-MS/MS) method. Noncompartmental analysis was used to determine the pharmacokinetic parameters. Average bioequivalence method was used to evaluate the bioequivalence of the two formulations and statistical significance of the pharmacokinetic parameters were tested to study the effect of food on amoxicillin absorption. Results The Geometric Mean Ratio (GMR) for the test/reference product for the maximum drug concentrations (Cmax) was 102.77% and 97.38% in fasted and fed conditions respectively which was within 80.00–125.00% range required to demonstrate bioequivalence. The GMR for test/reference products for the area under the curve (AUC0-8,) was 100.05% and 96.91% in fasted and fed conditions respectively meeting the bioequivalence criteria. For the reference product, the Cmax was 9.38 and 7.61 µg x mL−1(p =0.0224), time to reach maximum concentration (Tmax) was 1.73 and 3.02 h (p=0.0005) and AUC0-8 was 26.02 and 25.54 µg/h−1 mL−1 p = 0.672) under fasted and fed conditions respectively. Conclusion The test and the reference formulations were bioequivalent under both fasted and fed conditions. Although the Cmax was significantly lower and Tmax was significantly delayed under fed conditions, it did not affect the AUC. Therefore, being a time dependent antibiotic, clinically significant effect of food on efficacy of amoxicillin is unlikely. As the selected products were equivalent in vitro, these findings support scientific justification for conducting in vitro dissolution studies for solid oral amoxicillin products as a surrogate for in vivo bioequivalence studies.