METHODS: The studies were four-way crossover, single-dose, randomised, double-blind, in healthy volunteers. In Studies 1 and 2, subjects inhaled four puffs of BDP/FF/GB (Study 1: 100/6/12.5 μg [medium-strength BDP]; Study 2: 200/6/12.5 μg [high-strength]), ingesting activated charcoal in two of the periods (once per propellant). In Study 3, subjects inhaled medium- and high-strength BDP/FF/GB using a spacer. All three studies compared HFA-152a vs HFA-134a in terms of lung availability and total systemic exposure of beclometasone-17-monopropionate (B17MP; active metabolite of BDP), BDP, formoterol and GB. Bioequivalence was concluded if the 90 % confidence intervals (CIs) of the ratios between formulations of the geometric mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve between time zero and the last quantifiable timepoint (AUC0-t) for the analytes were between 80 and 125 %.
RESULTS: In Studies 1 and 2, systemic exposure bioequivalence (i.e., comparisons without charcoal block) was demonstrated, except for GB Cmax in Study 2 (upper 90 % CI 125.11 %). For lung availability (i.e., comparisons with charcoal block), B17MP and formoterol demonstrated bioequivalence in both studies, as did BDP in Study 2; in Study 1, BDP upper CIs were 126.96 % for Cmax and 127.34 % for AUC0-t). In Study 1, GB AUC0-t lower CI was 74.54 %; in Study 2 upper limits were 135.64 % for Cmax and 129.12 % for AUC0-t. In Study 3, the bioequivalence criteria were met for BDP, B17MP and formoterol with both BDP/FF/GB strengths, and were met for GB AUC0-t, although not for Cmax. Both formulations were similarly well tolerated in all three studies.
CONCLUSIONS: Overall, while formal bioequivalence cannot be concluded for all analytes, these data suggest therapeutic equivalence of the new formulation with the existing BDP/FF/GB pMDI formulation, therefore supporting reformulation using a propellant with low global warming potential.
方法:研究是四向交叉,单剂量,随机化,双盲,健康的志愿者在研究1和2中,受试者吸入了四个BDP/FF/GB(研究1:100/6/12.5μg[中等强度BDP];研究2:200/6/12.5μg[高强度]),在两个时期内摄取活性炭(每个推进剂一次)。在研究3中,受试者使用垫片吸入中高强度BDP/FF/GB。所有三项研究都比较了HFA-152a与HFA-134a的肺部可用性和倍氯米松-17-单丙酸酯(B17MP;BDP的活性代谢物)的全身总暴露量,BDP,福莫特罗和GB。如果分析物的几何平均最大血浆浓度(Cmax)和时间零点和最后可量化时间点(AUC0-t)之间的血浆浓度-时间曲线下面积的制剂之间的比率的90%置信区间(CI)在80-125%之间,则推断生物等效性。
结果:在研究1和2中,全身暴露生物等效性(即,没有木炭块的比较)被证明,除了研究2中的GBCmax(上限90%CI125.11%)。对于肺部可用性(即,与木炭块的比较),B17MP和福莫特罗在两项研究中证明了生物等效性,与研究2中的BDP一样;在研究1中,BDPupperCIs的Cmax为126.96%,AUC0-t为127.34%)。在研究1中,GBAUC0-t较低CI为74.54%;在研究2中,Cmax的上限为135.64%,AUC0-t的上限为129.12%。在研究3中,BDP符合生物等效性标准,B17MP和福莫特罗具有两种BDP/FF/GB强度,并满足GBAUC0-t,虽然不是Cmax。两种制剂在所有三项研究中都具有相似的良好耐受性。
结论:总体而言,虽然不能对所有分析物得出正式的生物等效性,这些数据表明新制剂与现有BDP/FF/GBpMDI制剂的治疗等效性,因此支持使用低全球变暖潜势的推进剂重新配制。