Ewing Pär, Oag Steven, Lundqvist Anders, Stomilovic Stina, Stellert Ida, Antonsson Malin, Nunes Sandro Filipe, Andersson Patrik U, Tehler Ulrika, Sjöberg Carl, Péterffy AnnaMaria, Gerde Per
Drug Metabolism and Pharmacokinetics, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
J Aerosol Med Pulm Drug Deliv. 2021 Aug;34(4):231-241. doi: 10.1089/jamp.2020.1637. Epub 2020 Nov 18.
The lower respiratory tract of the landrace pig has close anatomical and physiological similarities with that of the human, and hence, for inhalation studies this species is well suited for biopharmaceutical research. The objective of this study was to evaluate pharmacokinetics in pigs following one dose of Diskus™ Seretide™ forte device, labeled 500/50 fluticasone propionate (FP) and salmeterol xinafoate (SX), respectively. The PreciseInhale™ (PI) instrument was used to actuate the inhaler for testing and aerosol dosing to pigs. , the aerosol was characterized with a cascade impactor with respect to mass median aerodynamic diameter, geometric standard deviation, and fine particle dose. , dry powder inhalation exposure was delivered as a short bolus dose, to anesthetized and mechanically ventilated landrace pigs. In addition to plasma PK, PK assessment of airway epithelial lining fluid (ELF) was used in this study. ELF of the depth of three to fourth airway generation of the right lung was accessed using standard bronchoscopy and a synthetic absorptive matrix. Dry powder inhalation exposures with good consistency and well characterized aerosols to the pig lung were achieved by the use of the PreciseInhale™ instrument. Drug concentrations of ELF for both FP and SX were demonstrated to be four to five orders of magnitude higher than its corresponding systemic plasma drug concentrations. Clinical PK following inhalation of the same dose was used as benchmark, and the clinical study did demonstrate similar plasma PK profiles and drug exposures of both FP and SX as the current pig study. Two factors explain the close similarity of PK (1) similiar physiology between species and (2) the consistency of dosing to animals. To conclude, our study demonstrated the utility and translational potential of conducting PK studies in pigs in the development of inhaled pharmaceuticals.
长白猪的下呼吸道在解剖学和生理学上与人类有密切的相似性，因此，在吸入研究中，该物种非常适合生物制药研究。本研究的目的是评估猪在使用一次标注为500/50丙酸氟替卡松（FP）和昔萘酸沙美特罗（SX）的Diskus™ Seretide™ forte装置后的药代动力学。使用PreciseInhale™（PI）仪器驱动吸入器对猪进行测试和气溶胶给药。用串联冲击器对气溶胶的质量中值空气动力学直径、几何标准差和细颗粒剂量进行了表征。干粉吸入暴露以短脉冲剂量给予麻醉并机械通气的长白猪。除了血浆药代动力学外，本研究还使用了气道上皮衬液（ELF）的药代动力学评估。使用标准支气管镜和合成吸收基质获取右肺第三至第四级气道深度的ELF。通过使用PreciseInhale™仪器，实现了对猪肺的干粉吸入暴露，气溶胶具有良好的一致性和特征。FP和SX的ELF药物浓度被证明比其相应的全身血浆药物浓度高4至5个数量级。吸入相同剂量后的临床药代动力学用作基准，临床研究确实表明FP和SX的血浆药代动力学曲线和药物暴露与当前猪研究相似。有两个因素解释了药代动力学的密切相似性：（1）物种间相似的生理学；（2）给动物给药的一致性。总之，我们的研究证明了在猪身上进行药代动力学研究在吸入药物开发中的实用性和转化潜力。
