TY - JOUR
T1 - Can Pharmacokinetic Studies Assess the Pulmonary Fate of Dry Powder Inhaler Formulations of Fluticasone Propionate?
AU - Hochhaus, Günther
AU - Chen, Mong Jen
AU - Kurumaddali, Abhinav
AU - Schilling, Uta
AU - Jiao, Yuanyuan
AU - Drescher, Stefanie K.
AU - Amini, Elham
AU - Kandala, Bhargava
AU - Tabulov, Christine
AU - Shao, Jie
AU - Seay, Brandon
AU - Abu-Hasan, Mutasim N.
AU - Baumstein, Sandra M.
AU - Winner, Lawrence
AU - Shur, Jagdeep
AU - Price, Robert
AU - Hindle, Michael
AU - Wei, Xiangyin
AU - Carrasco, Cynthia
AU - Sandell, Dennis
AU - Oguntimein, Oluwamurewa
AU - Kinjo, Minori
AU - Delvadia, Renishkumar
AU - Saluja, Bhawana
AU - Lee, Sau L.
AU - Conti, Denise S.
AU - Bulitta, Jürgen B.
N1 - Funding Information:
Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR001427.
Funding Information:
Funding for this work was made possible, in part, by the US Food and Drug Administration through contracts HHSF223201110117A and HHSF223201610099C and grants 1U01FD004950 and 1U01FD005231.
Publisher Copyright:
© 2021, American Association of Pharmaceutical Scientists.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/5
Y1 - 2021/5
N2 - 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).
AB - 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).
KW - bioequivalence of generic inhaled drugs
KW - dry powder inhalers
KW - fluticasone propionate
KW - pharmacokinetics
KW - regional lung deposition
UR - http://www.scopus.com/inward/record.url?scp=85103422961&partnerID=8YFLogxK
U2 - 10.1208/s12248-021-00569-x
DO - 10.1208/s12248-021-00569-x
M3 - Article
C2 - 33768368
AN - SCOPUS:85103422961
SN - 1550-7416
VL - 23
JO - AAPS Journal
JF - AAPS Journal
IS - 3
M1 - 48
ER -