Daley-Yates Peter T, Parkins David A, Thomas Marian J, Gillett Benjamin, House Karen W, Ortega Hector G
GlaxoSmithKline, Stockley Park, Middlesex, United Kingdom.
Clin Ther. 2009 Feb;31(2):370-85. doi: 10.1016/j.clinthera.2009.02.007.
The use of dry-powder inhalers (DPIs) to administer respiratory medicines is increasing, and new DPIs are likely to be developed because of expiring patents. However, there is considerable debate concerning the extent to which DPIs are interchangeable without altering disease control or the safety profile of the treatment.
This study was designed to compare the pharmacokinetic (PK), pharmacodynamic (PD), efficacy, and safety data for 2 DPIs delivering a combination of salmeterol 50 microg plus fluticasone propionate (FP) 250 microg (SFC 50/250) to investigate assumptions of bioequivalence.
Three studies compared SFC 50/250 delivery using a reservoir powder inhalation device (RPID) and a Diskus multiple-dose inhaler: an in vitro assessment of fine-particle-mass (FPM) profiles of the emitted doses; a PK/PD study of SFC 50/250 administered in two 14-day crossover treatment periods to 22 adults with moderate, persistent asthma to determine the equivalence of the RPID and Diskus inhaler in terms of drug delivery and systemic exposure; and a 12-week clinical efficacy and safety study of SFC 50/250 in 270 patients > or =12 years of age with moderate, persistent asthma to assess the equivalence of the RPID and Diskus inhaler based on peak expiratory flow (PEF) rates. FPM was summed from the quantity of active pharmaceutical ingredient deposited on stages 1 to 5 of a cascade impactor, representing an aerodynamic particle size range of 0.8 to 6.2 microm. Systemic exposure to SFC 50/250 was declared no greater with RPID than with the Diskus inhaler if the upper limit of the 90% CI for the ratio of FP AUC for the 2 devices was below the upper limit of the equivalence range (ie, <1.25). Adverse events, clinical laboratory test results, and vital signs were recorded throughout the 2 clinical studies.
In vitro, mean FPM values for the RPID and Diskus inhaler, respectively, were 13.1 and 12.8 microg/dose for salmeterol (P = NS) and 66.8 and 66.2 microg/dose for FP (P = NS). The only notable differences were mean FP for particle sizes 2.3 to 3.2 microm (21.4 microg/dose for RPID, 25.6 microg/dose for Diskus) and for sizes 4.0 to 6.2 microm (17.3 microg/dose for RPID, 11.7 microg/dose for Diskus). In the PK/PD study, there were 22 patients (16 men and 6 women), most (86%) of whom were white. Mean (SD) age was 26.0 (5.0) years (range, 19-35 years), and mean (SD) weight was 67.3 (8.9) kg. The 2 inhalers did not meet the criteria for declaring bioequivalence: estimated ratios (RPID:Diskus) were 2.00 (90% CI, 1.56 to 2.55) for FP AUC up to the time point of next dosing and 1.92 (90% CI, 1.64 to 2.25) for salmeterol maximum observed plasma concentration at the end of the dosing interval (at steady state). Urine cortisol (0-24 hours) was significantly lower for the RPID than for the Diskus inhaler (ratio, 0.74 [95% CI, 0.57 to 0.96]; P = 0.026); no significant difference in plasma cortisol was noted between the 2 inhalers (ratio, 0.85 [95% CI, 0.7 to 1.04]). A small but statistically significant increase in maximum heart rate (5 beats/min) was noted in the RPID group (ratio, 1.05 [95% CI, 1.01 to 1.10]; P = 0.029). No notable differences in other PD end points were observed. Drug-related adverse events occurred in both groups (2 [dysphagia and tremor] in the RPID group and 3 [2 cases of dysphonia, 1 case of mucous-membrane irritation] in the Diskus group). There were 270 patients (136 females, 134 males) in the clinical efficacy and safety study, most (94%) of whom were white; mean (SD) age was 37.2 (17.0) years (range, 11-77 years) in the RPID group and 35.4 (17.2) years (range, 12-77 years) in the Diskus group. The RPID and the Diskus inhaler met the predefined equivalence criteria (+/-15 L/min) in terms of mean change in morning PEF from baseline: 3.9 L/min (95% CI, -3.1 to 11.0). The 2 SFC 50/250 inhalers were well tolerated; the most frequently reported adverse event was bronchitis, reported by 12% of the patients in the RPID group and 9% of those in the Diskus group. The only serious adverse event, which occurred in the RPID group and was related to bronchial infection, was considered unrelated to treatment.
In vitro particle size distribution data were potentially superimposable for the RPID and the Diskus inhaler. The 2 devices were considered to be clinically equivalent in terms of mean morning PEF but were not considered equivalent in terms of PK systemic exposure. The 2 SFC 50/250 inhalers were well tolerated and had comparable safety profiles; no serious adverse events were attributed to the study product.
使用干粉吸入器(DPI)来施用呼吸药物的情况正在增加,并且由于专利到期,可能会开发新的DPI。然而,关于DPI在不改变疾病控制或治疗安全性的情况下可互换的程度存在相当大的争议。
本研究旨在比较两种递送50微克沙美特罗加250微克丙酸氟替卡松(SFC 50/250)组合的DPI的药代动力学(PK)、药效学(PD)、疗效和安全性数据,以研究生物等效性的假设。
三项研究比较了使用储库型干粉吸入装置(RPID)和都保多剂量吸入器递送SFC 50/250的情况:对发射剂量的细颗粒质量(FPM)分布进行体外评估;在两个为期14天的交叉治疗期内,对22名中度持续性哮喘成年患者施用SFC 50/250进行PK/PD研究,以确定RPID和都保吸入器在药物递送和全身暴露方面的等效性;以及对270名年龄≥12岁的中度持续性哮喘患者进行SFC 50/250的12周临床疗效和安全性研究,以基于呼气峰流速(PEF)评估RPID和都保吸入器的等效性。FPM是从沉积在级联撞击器第1至5阶段的活性药物成分数量求和得出的,代表空气动力学粒径范围为0.8至6.2微米。如果两种装置的丙酸氟替卡松AUC比值的90%CI上限低于等效范围上限(即<1.25),则宣称RPID对SFC 50/250的全身暴露不高于都保吸入器。在两项临床研究中记录不良事件、临床实验室检查结果和生命体征。
在体外,RPID和都保吸入器的沙美特罗平均FPM值分别为13.1和12.8微克/剂量(P = 无显著性差异),丙酸氟替卡松的平均FPM值分别为66.8和66.2微克/剂量(P = 无显著性差异)。唯一显著的差异是粒径为2.3至3.2微米的丙酸氟替卡松平均含量(RPID为21.4微克/剂量,都保为25.6微克/剂量)和粒径为4.0至6.2微米的含量(RPID为17.3微克/剂量,都保为11.7微克/剂量)。在PK/PD研究中,有22名患者(16名男性和6名女性),其中大多数(86%)为白人。平均(标准差)年龄为26.0(5.0)岁(范围19 - 35岁),平均(标准差)体重为67.3(8.9)千克。两种吸入器未达到宣称生物等效性的标准:直至下次给药时间点的丙酸氟替卡松AUC估计比值(RPID:都保)为2.00(90%CI,1.56至2.55),给药间隔结束时(稳态)沙美特罗最大观察血浆浓度的估计比值为1.92(90%CI,1.64至2.25)。RPID组0 - 24小时尿皮质醇显著低于都保吸入器(比值,0.74 [95%CI,0.57至0.96];P = 0.026);两种吸入器之间血浆皮质醇无显著差异(比值,0.85 [95%CI,0.7至1.04])。RPID组最大心率有小幅但具有统计学意义的增加(5次/分钟)(比值,1.05 [95%CI,1.01至1.10];P = 0.029)。在其他PD终点未观察到显著差异。两组均发生与药物相关的不良事件(RPID组2例[吞咽困难和震颤],都保组3例[2例发音困难,1例黏膜刺激])。临床疗效和安全性研究中有270名患者(136名女性,134名男性),其中大多数(94%)为白人;RPID组平均(标准差)年龄为37.2(17.0)岁(范围11 - 77岁),都保组为35.4(17.2)岁(范围12 - 77岁)。RPID和都保吸入器在早晨PEF较基线的平均变化方面符合预先定义的等效标准(±15升/分钟):3.9升/分钟(95%CI, - 3.1至11.0)。两种SFC 50/250吸入器耐受性良好;最常报告的不良事件是支气管炎,RPID组12%的患者和都保组9%的患者报告了该事件。唯一的严重不良事件发生在RPID组,与支气管感染有关,被认为与治疗无关。
RPID和都保吸入器的体外粒径分布数据可能具有叠加性。两种装置在早晨平均PEF方面被认为临床等效,但在PK全身暴露方面不被认为等效。两种SFC 50/250吸入器耐受性良好且具有可比的安全性;未将严重不良事件归因于研究产品。