학술논문
Central and peripheral lung deposition of fluticasone propionate dry powder inhaler formulations in humans characterized by population pharmacokinetics
Original Research Article
Original Research Article
Document Type
Academic Journal
Author
Source
Pharmaceutical Research. May 2023, Vol. 40 Issue 5, p1177, 15 p.
Subject
Language
English
ISSN
0724-8741
Abstract
Author(s): Stefanie K. Drescher [sup.1], Yuanyuan Jiao [sup.2], Mong-Jen Chen [sup.1], Abhinav Kurumaddali [sup.1], Jie Shao [sup.1], Elham Amini [sup.1], Günther Hochhaus [sup.1], Jürgen B. Bulitta [sup.2] Author Affiliations: (1) [...]
This study aimed to gain an in-depth understanding of the pulmonary fate of three experimental fluticasone propionate (FP) dry powder inhaler formulations which differed in mass median aerodynamic diameters (MMAD; A-4.5 [micro]m, B-3.8 [micro]m and C-3.7 [micro]m; total single dose: 500 [micro]g). Systemic disposition parameter estimates were obtained from published pharmacokinetic data after intravenous dosing to improve robustness. A biphasic pulmonary absorption model, with mucociliary clearance from the slower absorption compartment, and three systemic disposition compartments was most suitable. Rapid absorption, presumably from peripheral lung, had half-lives of 6.9 to 14.6 min. The peripherally deposited dose (12.6 [micro]g) was significantly smaller for formulation A-4.5 [micro]m than for the other formulations (38.7 and 39.3 [micro]g for B-3.8 [micro]m and C-3.7 [micro]m). The slow absorption half-lives ranged from 6.86 to 9.13 h and were presumably associated with more central lung regions, where mucociliary clearance removed approximately half of the centrally deposited dose. Simulation-estimation studies showed that a biphasic absorption model could be reliably identified and that parameter estimates were unbiased and reasonably precise. Bioequivalence assessment of population pharmacokinetics derived central and peripheral lung doses suggested that formulation A-4.5 [micro]m lacked bioequivalence compared to the other formulations both for central and peripheral doses. In contrast, the other fomulations were bioequivalent. Overall, population pharmacokinetics holds promise to provide important insights into the pulmonary fate of inhalation drugs, which are not available from non-compartmental analysis. This supports the assessment of the pulmonary bioequivalence of fluticasone propionate inhaled formulations through pharmacokinetic approaches, and may be helpful for discussions on evaluating alternatives to clinical endpoint studies.
This study aimed to gain an in-depth understanding of the pulmonary fate of three experimental fluticasone propionate (FP) dry powder inhaler formulations which differed in mass median aerodynamic diameters (MMAD; A-4.5 [micro]m, B-3.8 [micro]m and C-3.7 [micro]m; total single dose: 500 [micro]g). Systemic disposition parameter estimates were obtained from published pharmacokinetic data after intravenous dosing to improve robustness. A biphasic pulmonary absorption model, with mucociliary clearance from the slower absorption compartment, and three systemic disposition compartments was most suitable. Rapid absorption, presumably from peripheral lung, had half-lives of 6.9 to 14.6 min. The peripherally deposited dose (12.6 [micro]g) was significantly smaller for formulation A-4.5 [micro]m than for the other formulations (38.7 and 39.3 [micro]g for B-3.8 [micro]m and C-3.7 [micro]m). The slow absorption half-lives ranged from 6.86 to 9.13 h and were presumably associated with more central lung regions, where mucociliary clearance removed approximately half of the centrally deposited dose. Simulation-estimation studies showed that a biphasic absorption model could be reliably identified and that parameter estimates were unbiased and reasonably precise. Bioequivalence assessment of population pharmacokinetics derived central and peripheral lung doses suggested that formulation A-4.5 [micro]m lacked bioequivalence compared to the other formulations both for central and peripheral doses. In contrast, the other fomulations were bioequivalent. Overall, population pharmacokinetics holds promise to provide important insights into the pulmonary fate of inhalation drugs, which are not available from non-compartmental analysis. This supports the assessment of the pulmonary bioequivalence of fluticasone propionate inhaled formulations through pharmacokinetic approaches, and may be helpful for discussions on evaluating alternatives to clinical endpoint studies.