Lowly-buffered biorelevant dissolution testing is not necessarily biopredictive of human bioequivalence study outcome: Relationship between dissolution and pharmacokinetics

It has been revealed that buffer capacity of aspirated human intraluminal fluid is much lower than that of in vitro compendial dissolution media. Since buffer capacity significantly alters the dissolution profile of certain drug products, dissolution testing in highly buffered media dictates poor predictability of in vivo drug performance. To mitigate this inconsistency, low buffer capacity medium was suggested as an in vivo representation (biorelevant dissolution testing). The purpose of this study was to characterize the dissolution profiles of enteric-coated drug products in different buffer capacity media in a flow through cell dissolution apparatus, and to evaluate the in vivo predictability of human bioequivalence study outcomes conducted in the fasted state. It was confirmed that the lower the buffer capacity of dissolution media, the higher the discriminatory power of esomeprazole magnesium hydrate enteric-coated pellets, reflecting human bioequivalence failure. In the meantime, two duloxetine hydrochloride enteric-coated pellets also exhibited distinct dissolution profiles in such a lowly buffered medium despite the fact that these two are bioequivalent in human. Biopharmaceutical and pharmacokinetic characteristics comparison suggested that low intestinal permeability and small systemic elimination rate of duloxetine hinders the clear impact of different dissolution profile on its in vivo performance. These data suggest that dissolution comparison in physiologically-relevant low buffer capacity media is not always indicative of human bioequivalence. Instead, biopharmaceutical and pharmacokinetic aspects must be taken into consideration to make biorelevant dissolution testing biopredictive.