Abstract：
BACKGROUND: Use of propellants with high global warming potential (such as HFA-134a) for pressurised metered-dose inhalers (pMDIs) is being phased down. Switching to dry-powder inhalers may not be clinically feasible for all patients; an alternative is reformulation using propellants with low global warming potential. The combination of beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB) is available for asthma or chronic obstructive pulmonary disease via pMDI using HFA-134a as propellant. This is being reformulated using the low global warming potential propellant HFA-152a. This manuscript reports three studies comparing BDP/FF/GB pharmacokinetics delivered via pMDI using HFA-152a vs HFA-134a.
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.
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.
摘要：
背景：在加压计量吸入器（pMDI）中使用具有高全球变暖潜势的推进剂（如HFA-134a）正在逐步减少。对于所有患者来说，改用干粉吸入器在临床上可能并不可行；另一种选择是使用全球变暖潜势较低的推进剂重新配制。二丙酸倍氯米松/富马酸福莫特罗/格隆溴铵（BDP/FF/GB）的组合可通过使用HFA-134a作为推进剂的pMDI用于哮喘或慢性阻塞性肺疾病。正在使用低全球变暖潜能推进剂HFA-152a重新配制。该手稿报告了三项研究，比较了使用HFA-152a与HFA-134a通过pMDI递送的BDP/FF/GB药代动力学。
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。
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。
