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

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Abstract

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).

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Abbreviations

API:

Active pharmaceutical ingredient

APSD:

Aerodynamic particle size distribution

AUC0–Inf :

Area under the plasma concentration time curve from time zero until time infinity

AUC0–last :

Area under the plasma concentration time curve from time zero until the last observed plasma concentration

AIT:

Alberta Idealized Throat

BE:

Bioequivalence

BSV:

Between subject variability

Cmax :

Observed peak concentration in plasma

CV:

Coefficient of variation

D50:

Median particle diameter

DD:

Delivered dose

DNF:

Dose normalization factor

DPI:

Dry powder inhaler

ECG:

Electrocardiogram

EDTA:

Ethylene diamine tetra-acetic acid

FEV1:

Forced expiratory volume in one second

FP:

Fluticasone propionate

FPD<3 μm:

Fine particle dose less than 3 μm

FPD<5 μm:

Fine particle dose less than 5 μm

GSD:

Geometric standard deviation

HPLC/UV:

High performance liquid chromatography with ultraviolet detection

IND:

Investigational new drug

LC-MS/MS:

Liquid chromatography - tandem mass spectrometry

MMAD:

Median mass aerodynamic diameter

MAT:

Mean absorption time

MDT:

Mean dissolution time

MOC:

Micro-orifice collector

MRT:

Mean body residence time

MT:

Mouth-throat models

NGI:

Next generation impactor

PIFR:

Peak inspiratory flow rate

PK:

Pharmacokinetics

OPC:

Oropharyngeal consortium throat

OIDPs:

Orally inhaled drug products

RH:

Relative humidity

SAP:

Statistical analysis plan

TLDin vitro :

In vitro total lung dose

Tmax :

Time to peak concentrations

VCU:

Virginia Commonwealth University

WSV:

Within subject variability

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Funding

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.

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.

Author information

Author notes

  1. Mong-Jen Chen

    Present address: AbbVie Inc., North Chicago, Illinois, USA

  2. Renishkumar Delvadia

    Present address: Office of New Drug Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA

  3. Bhawana Saluja

    Present address: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA

Authors and Affiliations

  1. Department of Pharmaceutics, College of Pharmacy, University of Florida, 1345 Center Drive, Gainesville, Florida, 32610, USA

    Günther Hochhaus, Mong-Jen Chen, Abhinav Kurumaddali, Uta Schilling, Stefanie K. Drescher, Elham Amini, Simon M. Berger, Bhargava Kandala, Christine Tabulov & Jie Shao

  2. Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, 6550 Sanger Road, Gainesville, Florida, 32827-7445, USA

    Yuanyuan Jiao, Sandra M. Baumstein & Jürgen B. Bulitta

  3. Division of Pediatric Pulmonary and Sleep Medicine, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, Florida, USA

    Brandon Seay & Mutasim N. Abu-Hasan

  4. Department of Statistics, College of Liberal Arts & Sciences, University of Florida, Gainesville, Florida, USA

    Lawrence Winner

  5. Department of Pharmacy & Pharmacology, Centre for Therapeutic Innovation, University of Bath, Bath, UK

    Jagdeep Shur & Robert Price

  6. Department of Pharmaceutics, Virginia Commonwealth University, Richmond, Virginia, USA

    Michael Hindle & Xiangyin Wei

  7. Worldwide Clinical Trials, Austin, Texas, USA

    Cynthia Carrasco

  8. S5 Consulting, Blentarp, Sweden

    Dennis Sandell

  9. Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA

    Oluwamurewa Oguntimein, Minori Kinjo, Renishkumar Delvadia, Bhawana Saluja & Denise S. Conti

  10. Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA

    Sau L. Lee

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  1. Günther Hochhaus
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Correspondence to Günther Hochhaus or Jürgen B. Bulitta.

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"The original online version of this article was revised to add article Simon M. Berger at affiliation Department of Pharmaceutics, College of Pharmacy, University of Florida, 1345 Center Drive, Gainesville, Florida, 32610, USA" plus the same explanatory text of the problem as in the erratum/correction article.

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Hochhaus, G., Chen, MJ., Kurumaddali, A. et al. Can Pharmacokinetic Studies Assess the Pulmonary Fate of Dry Powder Inhaler Formulations of Fluticasone Propionate?. AAPS J 23, 48 (2021). https://doi.org/10.1208/s12248-021-00569-x

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