Assessing Central and Peripheral Pulmonary Deposition of Three Fluticasone Propionate (FP) Dry Powder Inhaler (DPI) Formulations with Different Aerodynamic Particle Size Distributions (APSD) in Healthy Subjects via Population Pharmacokinetics Modeling

Stefanie K Drescher¹, Mong-Jen Chen¹, Abhinav Kurumaddali¹, Uta Schilling¹, Yuanyuan Jiao¹, Jie Shao¹, Brandon Seay², Sandra M Baumstein³, Mutasim N. Abu-Hasan², Renishkumar Delvadia⁴, Lawrence Winner⁵, Christine Tabulov¹, Bavna Saluja⁴, Jag Shur⁶, Robert Price⁶, Michael Hindle⁷, Xiangyin Wei⁷, Murewa Oguntimein⁴, Denise S. Conti⁴, Juergen Bulitta¹ & Guenther Hochhaus¹

¹Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Orlando, FL, USA

²Division of Pediatric Pulmonary and Sleep Medicine, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, USA

³Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA

⁴Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA

⁵Department of Statistics, College of Liberal Arts & Sciences, University of Florida, Gainesville, FL, USA

⁶University of Bath, Bath, Great Britain

⁷Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, USA

Summary

This study aimed to evaluate whether pharmacokinetic (PK) data in healthy subjects can quantitatively compare the regional deposition of different fluticasone propionate (FP) dry powder inhaler (DPI) formulations. Three experimental FP formulations which differed in lactose fines, mass median aerodynamic diameter (MMAD) and fine particle dose (FPD), were assessed in a randomized, double-blind, four-period, four-way crossover study in 24 healthy subjects. Each of the three formulations was dosed as 5 capsules each containing a nominal dose of 100 µg of FP, with one formulation being replicated. Inhalation profiles during drug administration and FP plasma concentrations over 24 hours were quantified. The developed population PK model consisted of three body compartments. Absorption was described by two parallel first-order processes, i.e., a slow absorption presumably from central lung and fast absorption from peripheral lung. High peak inspiratory flow rate (PIFR) values significantly increased pulmonary absorbed doses. The three formulations were estimated to have a similar extent of bioavailability from central lung. However, formulations differed significantly in the extent of bioavailability from peripheral lung. This agreed well with in vitro Next Generation Cascade Impactor (NGI) data of these three DPI formulations. Therefore, human PK data in healthy subjects assessed via population PK modeling provided meaningful information on the rate and extent of drug deposition and absorption in the lungs for these three DPI formulations. The insights from this study may be leveraged to help the development of orally inhaled drug products.