Karim Aziz, Slater Margaret, Bradford Dawn, Schwartz Lisa, Laurent Aziz
Takeda Global Research & Development Center, Inc, 475 Half Day Road, Lincolnshire, IL 60069, USA.
J Clin Pharmacol. 2007 Jan;47(1):48-55. doi: 10.1177/0091270006293756.
An open-label, randomized, crossover study involving 28 healthy subjects was conducted to compare the peak (Cmax) and total (AUC(lqc), AUC(infinity)) exposures to pioglitazone and metformin after single-dose administration of a fixed-dose combination tablet containing 15 mg of pioglitazone plus 850 mg metformin when given under fasted versus fed states, with a washout period of 7 days between treatments. Two different fixed-dose combination formulations (bilayer and pioglitazone-micronized fixed-dose combination tablets) were tested. The pioglitazone-micronized fixed-dose combination formulation was selected for clinical development and regulatory approval; the present study describes food effect results with this formulation. For pioglitazone, least squares mean ratios (fed/fasted) and the 90% confidence intervals of these ratios were 1.05 (0.93-1.18) for Cmax, 1.13 (1.02-1.25) for AUC(lqc), and 1.11 (1.01-1.22) for AUC(infinity). For metformin, these values were 0.72 (0.65-0.79) for Cmax, 0.87 (0.81-0.94) for AUC(lqc), and 0.87 (0.81-0.94) for AUC(infinity). Dosing with food resulted in median prolongation of tmax values by 1.5 hours for metformin and 2.0 hours for pioglitazone. Because bioequivalency criteria were met (fed/fasted 90% confidence interval between 0.80 and 1.25) for both pioglitazone and metformin AUC, fixed-dose combination tablets can be taken with or without food, but to minimize gastrointestinal adverse effects of metformin, the fixed-dose combination tablets are recommended to be taken with food.
开展了一项开放标签、随机、交叉研究，纳入28名健康受试者，以比较在禁食和进食状态下单次服用含15毫克吡格列酮加850毫克二甲双胍的固定剂量复方片剂后，吡格列酮和二甲双胍的峰值（Cmax）和总暴露量（AUC(lqc)、AUC(infinity)），两次治疗之间的洗脱期为7天。测试了两种不同的固定剂量复方制剂（双层和吡格列酮微粉化固定剂量复方片剂）。吡格列酮微粉化固定剂量复方制剂被选用于临床开发和监管批准；本研究描述了该制剂的食物效应结果。对于吡格列酮，Cmax的最小二乘均值比（进食/禁食）及其90%置信区间为1.05（0.93 - 1.18），AUC(lqc)为1.13（1.02 - 1.25），AUC(infinity)为1.11（1.01 - 1.22）。对于二甲双胍，这些值Cmax为0.72（0.65 - 0.79），AUC(lqc)为0.87（0.81 - 0.94），AUC(infinity)为0.87（0.81 - 0.94）。进食时给药使二甲双胍的tmax值中位数延长1.5小时，吡格列酮延长2.0小时。由于吡格列酮和二甲双胍的AUC均符合生物等效性标准（进食/禁食90%置信区间在0.80至1.25之间），固定剂量复方片剂可以与食物同服或空腹服用，但为尽量减少二甲双胍的胃肠道不良反应，建议固定剂量复方片剂与食物同服。
