Can Pharmacokinetic Studies Assess the Pulmonary Fate of Dry Powder Inhaler Formulations of Fluticasone Propionate?

Günther Hochhaus, Mong Jen Chen, Abhinav Kurumaddali, Uta Schilling, Yuanyuan Jiao, Stefanie K. Drescher, Elham Amini, Bhargava Kandala, Christine Tabulov, Jie Shao, Brandon Seay, Mutasim N. Abu-Hasan, Sandra M. Baumstein, Lawrence Winner, Jagdeep Shur, Robert Price, Michael Hindle, Xiangyin Wei, Cynthia Carrasco, Dennis SandellOluwamurewa Oguntimein, Minori Kinjo, Renishkumar Delvadia, Bhawana Saluja, Sau L. Lee, Denise S. Conti, Jürgen B. Bulitta

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11 Citations (SciVal)


In the context of streamlining generic approval, this study assessed whether pharmacokinetics (PK) could elucidate the pulmonary fate of orally inhaled drug products (OIDPs). Three fluticasone propionate (FP) dry powder inhaler (DPI) formulations (A-4.5, B-3.8, and C-3.7), differing only in type and composition of lactose fines, exhibited median mass aerodynamic diameter (MMAD) of 4.5 μm (A-4.5), 3.8 μm (B-3.8), and 3.7 μm (C-3.7) and varied in dissolution rates (A-4.5 slower than B-3.8 and C-3.7). In vitro total lung dose (TLDin vitro) was determined as the average dose passing through three anatomical mouth-throat (MT) models and yielded dose normalization factors (DNF) for each DPI formulation X (DNFx = TLDin vitro,x/TLDin vitro,A-4.5). The DNF was 1.00 for A-4.5, 1.32 for B-3.8, and 1.21 for C-3.7. Systemic PK after inhalation of 500 μg FP was assessed in a randomized, double-blind, four-way crossover study in 24 healthy volunteers. Peak concentrations (Cmax) of A-4.5 relative to those of B-3.8 or C-3.7 lacked bioequivalence without or with dose normalization. The area under the curve (AUC0–Inf) was bio-IN-equivalent before dose normalization and bioequivalent after dose normalization. Thus, PK could detect differences in pulmonary available dose (AUC0–Inf) and residence time (dose-normalized Cmax). The differences in dose-normalized Cmax could not be explained by differences in in vitro dissolution. This might suggest that Cmax differences may indicate differences in regional lung deposition. Overall this study supports the use of PK studies to provide relevant information on the pulmonary performance characteristics (i.e., available dose, residence time, and regional lung deposition).

Original languageEnglish
Article number48
JournalAAPS Journal
Issue number3
Early online date25 Mar 2021
Publication statusPublished - May 2021


  • bioequivalence of generic inhaled drugs
  • dry powder inhalers
  • fluticasone propionate
  • pharmacokinetics
  • regional lung deposition

ASJC Scopus subject areas

  • Pharmaceutical Science


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