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

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• 作者：Frank LaCreta^a ; ^{frank.lacreta@bms.com" class="auth_mail" title="E-mail the corresponding author} ; Steven C. Griffen^a ; ¹ ; ^{sgriffen@jdrf.org" class="auth_mail" title="E-mail the corresponding author} ; Xiaoni Liu^a ; ^{xiaoni.liu@bms.com" class="auth_mail" title="E-mail the corresponding author} ; Charles Smith^b ; ^{charles.smith@ppdi.com" class="auth_mail" title="E-mail the corresponding author} ; Carey Hines^b ; ^{carey.hines@ppdi.com" class="auth_mail" title="E-mail the corresponding author} ; Kevin Volk^c ; ^{kevin.volk@bms.com" class="auth_mail" title="E-mail the corresponding author} ; Ravindra Tejwani^c ; ² ; ^{tejwanir@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; David W. Boulton^d ; ^{david.boulton2@astrazeneca.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AUC0⿿t ; area under the plasma concentration⿿time curve from time 0 to the last quantifiable concentration ; AUC0⿿inf ; area under the plasma concentration⿿time curve from time 0 to infinity ; Cp ; plasma concentration ; Cmax ; maximum Cp ; Dapagliflozin ; [2S ; 3R ; 4R ; 5S ; 6R]-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3 ; 4 ; 5-triol ; compounded with (2S)-1 ; 2-propanediol ; hydrate (1 ; 1 ; 1) ; HS ; heat-stressed ; Kel ; terminal rate constant ; LS ; least squares ; NH ; non⿿heat-stressed ; tm
• 刊名：International Journal of Pharmaceutics
• 出版年：2016
• 出版时间：10 September 2016
• 年：2016
• 卷：511
• 期：1
• 页码：288-295
• 全文大小：699 K

文摘

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 (C_max) for HS 2.5- and 10-mg tablets were within 80⿿125%, indicating bioequivalence. In the fed vs. fasted state for 2.5-mg and 10-mg HS tablets, AUCs were similar, time to C_max was prolonged by 1.25 h, and C_max decreased 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.