Bioequivalence and food effect of heat-stressed and non–heat-stressed dapagliflozin 2.5- and 10-mg tablets

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作者：

LaCreta, Frank，Griffen, Steven C.，Liu, Xiaoni，Smith, Charles，Hines, Carey，Volk, Kevin，Tejwani, Ravindra，Boulton, David W.

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摘要：

Physical storage of formulations may result in physical composition changes that affect pharmacokinetics. Dapagliflozin, an oral sodium-glucose cotransporter 2 inhibitor used for type 2 diabetes mellitus, stored under prolonged exposure to heat converts crystalline dapagliflozin to an amorphous form. Bioequivalence of the amorphous to crystalline form and food effects of each form in the 2.5-mg formulation are unknown. Two open-label, crossover, single-dose studies in healthy participants assessed pharmacokinetics for heat-stressed (HS) and non–heat-stressed (NH) dapagliflozin 10-mg (study 1,N=29, fasted+HS food effect) and 2.5-mg (study 2,N=28, fasted+HS and NH food effect) tablets. The 90% confidence intervals for geometric mean ratios of area under the concentration–time curve (AUC) and peak concentration (Cmax) for HS 2.5- and 10-mg tablets were within 80–125%, indicating bioequivalence. In the fedvs.fasted state for 2.5-mg and 10-mg HS tablets, AUCs were similar, time to Cmaxwas prolonged by 1.25h, and Cmaxdecreased by approximately 50%. No serious adverse events were reported. Given that dapagliflozin's efficacy is dependent upon AUC, it was concluded that HS and NH dapagliflozin tablets are bioequivalent in 2.5- and 10-mg doses with no clinically meaningful food effect for either form.

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关键词：

Bioequivalence Dapagliflozin Pharmacokinetics Sodium-glucose cotransporter 2 inhibitor Drug stability Heat-stressed Amorphous form

DOI：

10.1016/j.ijpharm.2016.07.017

年份：

2016