Research Articles
Pharmacokinetic and Pharmacodynamic Evaluation of the Suitability of Using Fluticasone and an Acute Rat Lung Inflammation Model to Differentiate Lung Versus Systemic Efficacy

https://doi.org/10.1002/jps.21714Get rights and content

Abstract

Inhaled corticosteroids (ICSs) are often prescribed as the first line therapy for pulmonary diseases such as asthma. The biggest concern of using steroid therapy is the systemic side effects at high dose. To reduce the side effects, the pharmaceutical industry has been putting effort to generate new drugs with maximized topical efficacy. One of the key challenges is to differentiate efficacy from local versus systemic contribution in preclinical animal models. Fluticasone with various formulations was used as a model compound to explore the possibilities to demonstrate lung targeted efficacy by intratracheally instillation in the lipopolysaccharide induced inflammation rat model. Fluticasone formulations contained various surfactant concentrations and particle sizes to achieve lung retention and lower systemic exposure. Neutrophil infiltration in broncoalveolar lavage fluid and cytokine production in whole blood were measured to assess pulmonary efficacy versus systemic efficacy. PK/PD characterization of fluticasone with various formulations in the rat inflammation model provided an integrated approach in preclinical to evaluate lung targeted efficacy for ICS. Our study concluded that the combination of the rat LPS model and fluticasone is not suitable to use for establishing potency and dose requirement for new drug candidate designed for topical only efficacy. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4354–4364, 2009

Section snippets

INTRODUCTION

Pulmonary diseases, such as chronic obstructive pulmonary disease (COPD) and asthma are complex human airway diseases which affect millions of people worldwide. For example, according to a report from the U.S. Centers for Disease Control and Prevention (CDC), greater than 6% of total American population suffers from asthma in 2004, up from a little over 3% in 1980. Despite the complexity, it is understood that human airway diseases often contain a strong local (lung) inflammatory component. For

Materials

LPS (E. coli O111: B4) was purchased from Sigma–Aldrich (St Louis, MO) and prepared in phosphate buffered saline solution (PBS). Fluticasone propionate was purchased from Seqoia Research Products (Oxford, UK). Microtainer tubes with lithium heparin for blood collection were purchased from Becton Dickinson Biosciences(Franklin Lakes, NJ). 96-well polypropylene plates were purchased from Corning Inc. (Corning, NY). Peri Proneb ultra compression nebulizer was purchased from Peri Co. (Midlothian,

RESULTS AND DISCUSSION

Micronization of fluticasone was successful. The particle size of the bulk material was reduced from a mean value (D50) of 1.6–0.2 µm. The solid form of the micronized material was examined by PXRD and TGA/SDTA without discernable change in crystal form postmicronization process which assured the quality of material used for further PK and PD studies (Fig. 1). Both nano and regular materials were dosed as suspension IT in rat for efficacy and PK studies. Control samples (milled vehicle) were

CONCLUSION

One of the most important qualifiers in searching for better drug candidates for inhalation is to reduce systemic side effects while maintaining efficacy. It is believed that a drug with durable, lung-targeted activity and low systemic exposure would have a theoretical advantage over currently used therapies with improved therapeutic index allowing for higher doses and a better safety profile.

In drug discovery, it is very important to demonstrate preclinical pulmonary targeted efficacy in an

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