Kunka R, Andrews S, Pimazzoni M, Callejas S, Ziviani L, Squassante L, Daley-Yates P T
Glaxo Wellcome Inc. Research Triangle Park, North Carolina, USA.
Respir Med. 2000 Jun;94 Suppl B:S10-6.
Fluticasone propionate pressurized metered dose inhalers (pMDIs) containing the hydrofluoroalkane (HFA) propellant, HFA 134a, are being developed to replace existing chlorofluorocarbon (CFC) pMDIs. This is part of the ongoing worldwide project to limit the damage to the earth's ozone layer. The in vivo performance and dose proportionality of fluticasone propionate HFA 134a pMDIs was examined for fluticasone propionate doses of 400, 1000 and 2000 microg using the 50, 125 and 250 microg strength pMDIs, respectively. The 125 and 250 microg strength HFA 134a pMDIs were compared with corresponding fluticasone propionate CFC pMDIs. Twenty-three healthy subjects participated in this single dose, randomized, five-way, cross-over study. Serial blood samples were collected 24 h post-dose to measure fluticasone propionate plasma concentrations. Twenty-four hour urinary-free cortisol was also measured before and after dosing. A dose-proportional increase in plasma fluticasone propionate concentrations was observed with increasing dose for the HFA 134a pMDIs. This was associated with a dose-related decrease in urinary cortisol excretion. Similar or lower fluticasone propionate systemic exposure was observed with the HFA 134a pMDIs compared to the corresponding CFC inhalers. The differences in systemic exposure observed for the HFA 134a and CFC pMDIs were too small to produce a differential effect on urinary cortisol excretion. Since fluticasone propionate has negligible oral bioavailability, the systemic exposure, which arises only from pulmonary absorption, is a measure of lung deposition. There was a good correlation between the in vitro fine particle mass produced by the different strengths and types of pMDI and the systemic exposure to fluticasone propionate. Therefore, the fluticasone propionate HFA 134a pMDI is an acceptable pharmaceutical alternative to the current CFC pMDI, producing similar lung deposition and no increase in systemic exposure at microgram equivalent doses.
正在研发含氢氟烷烃（HFA）推进剂HFA 134a的丙酸氟替卡松定量吸入气雾剂（pMDIs），以取代现有的氯氟烃（CFC）pMDIs。这是正在进行的全球项目的一部分，旨在限制对地球臭氧层的破坏。分别使用50、125和250微克规格的pMDIs，对400、1000和2000微克剂量的丙酸氟替卡松HFA 134a pMDIs的体内性能和剂量比例进行了研究。将125和250微克规格的HFA 134a pMDIs与相应的丙酸氟替卡松CFC pMDIs进行了比较。23名健康受试者参与了这项单剂量、随机、五交叉研究。给药后24小时采集系列血样，以测定丙酸氟替卡松血浆浓度。给药前后还测定了24小时尿游离皮质醇。对于HFA 134a pMDIs，随着剂量增加，血浆丙酸氟替卡松浓度呈剂量比例增加。这与尿皮质醇排泄的剂量相关减少有关。与相应的CFC吸入器相比，HFA 134a pMDIs观察到的丙酸氟替卡松全身暴露相似或更低。HFA 134a和CFC pMDIs观察到的全身暴露差异太小，无法对尿皮质醇排泄产生差异影响。由于丙酸氟替卡松的口服生物利用度可忽略不计，仅由肺部吸收引起的全身暴露是肺沉积的一种度量。不同规格和类型的pMDI产生的体外细颗粒质量与丙酸氟替卡松的全身暴露之间存在良好的相关性。因此，丙酸氟替卡松HFA 134a pMDI是当前CFC pMDI的一种可接受的药物替代品，在微克等效剂量下产生相似的肺沉积且全身暴露无增加。
