Abstract
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 µm, B-3.8 µm and C-3.7 µm; total single dose: 500 µg). 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 µg) was significantly smaller for formulation A-4.5 µm than for the other formulations (38.7 and 39.3 µg for B-3.8 µm and C-3.7 µm). 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 µm 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.
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Data Availability
The raw data for the human PK study were published in AAPS J 2021; 23:48 supported by the US Food and Drug Administration through contracts HHSF223201110117A and HHSF223201610099C and grants 1U01FD004950 and 1U01FD005231. The present population PK analysis did not generate additional experimental data. The population PK modeling andMonte Carlo simulation code is provided in the supplementary materials of the present paper.
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Acknowledgements
We thank Drs. Denise Conti, Oluwamurewa (Murewa) Oguntimein, Renishkumar Delvadia, and other FDA colleagues for many fruitful discussions and their many contributions while executing the PK, bioanalytical, and NCA parts of this project. This work has been in part presented at the Drug Delivery to the Lungs conference, Edinburgh, UK in 2018 and the Respiratory Drug Delivery conference virtually in 2020. The DPI formulation development, dissolution testing and PK study, as described elsewhere [10], were supported by FDA contracts HHSF223201110117A and HHSF223201610099C, and by grants 1U01FD004950 and 1U01FD005231 (to GH and JBB). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the U.S. Food and Drug Administration (FDA).
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Drescher, S.K., Jiao, Y., Chen, MJ. et al. Central and peripheral lung deposition of fluticasone propionate dry powder inhaler formulations in humans characterized by population pharmacokinetics. Pharm Res 40, 1177–1191 (2023). https://doi.org/10.1007/s11095-023-03472-6
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DOI: https://doi.org/10.1007/s11095-023-03472-6