Comparison of Pharmacokinetic and Pharmacodynamic Effects of Two Hydrofluoroalkane Formulations of Salmeterol

Nazma Morde, J. Rebello, B. Brashier, M. Garg, Raghu K. Naidu, A. Birhade, K. Iyer, R. Jadhav
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Abstract

Introduction: To compare the Pharmacokinetic (PK) and Pharmacodynamic (PD) effects of two Hydrofluoroalkane (HFA) formulations of salmeterol xinafoate (Test HFA formulation, Cipla Ltd., India; Reference HFA formulation, Allen and Hanburys, UK) administered using pressurized metered dose inhalers. Methods: Three separate randomized, crossover, PK studies and one PD study comparing the efficacy and safety of the two HFA formulations of salmeterol xinafoate (25 μg per actuation) in healthy subjects were conducted. The PK assessments of the two formulations were done without charcoal blockade, with charcoal blockade, and with a Volumatic spacer device using a single dose. A PD study was also conducted to evaluate the systemic exposure of the two formulations using three different doses (50 μg, 150 μg and 300 μg). Results: In the PK study without charcoal, the 90% CI for the difference between the two formulations for AUC0-t was within the bioequivalence limits of 80-125%; however, Cmax marginally exceeded the upper bioequivalence limit to 136%. In the PK study with charcoal, the 90% CI for the difference between the two formulations for Cmax was within the bioequivalence limits of 80-125%; however, AUC0-t marginally exceeded the upper bioequivalence limit to 128%. The impact of marginally higher systemic exposure was therefore further evaluated in the PD study. The PD study confirmed there were no greater systemic safety effects of the test formulation on the primary PD endpoints such as heart rate and serum potassium as well as on other safety PD endpoints such as blood glucose and QTc interval. The PK study with spacer demonstrated bioequivalence between the test and reference formulations. Both formulations were safe and well tolerated. Conclusion: The test HFA formulation of salmeterol was therapeutically equivalent to the reference HFA formulation of salmeterol when used with and without a spacer.
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沙美特罗两种氢氟烷烃制剂的药动学和药效学效果比较
前言:比较沙美特罗两种氢氟烷烃制剂的药代动力学(PK)和药效学(PD)效果(Test HFA制剂,Cipla Ltd.,印度;参考HFA配方,Allen和Hanburys, UK)使用加压计量吸入器给药。方法:进行3个独立的随机、交叉、PK研究和1个PD研究,比较两种HFA制剂(25 μg /次)在健康受试者中的疗效和安全性。两种制剂的PK评估是在没有木炭阻断、木炭阻断和使用单剂量体积间隔装置的情况下进行的。研究人员还进行了PD研究,以评估两种制剂在三种不同剂量(50 μg、150 μg和300 μg)下的全身暴露。结果:在不加炭的PK研究中,AUC0-t两方差异的90% CI在80-125%的生物等效性范围内;Cmax略高于生物等效性上限136%。在用木炭进行的PK试验中,两种配方Cmax差异的90% CI在80-125%的生物等效性范围内;AUC0-t略高于生物等效性上限128%。因此,在PD研究中进一步评估了略高的全身暴露的影响。PD研究证实,试验配方对主要PD终点(如心率和血清钾)以及其他安全性PD终点(如血糖和QTc间期)没有更大的系统安全性影响。用间隔剂进行的PK研究表明,试验配方与参比配方具有生物等效性。两种制剂均安全且耐受性良好。结论:沙美特罗试验HFA制剂与沙美特罗参比HFA制剂在加或不加间隔剂时疗效相当。
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