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Pharmacokinetic and pharmacodynamic comparison of hydrofluoroalkane and chlorofluorocarbon formulations of budesonide
Author(s) -
Clearie Karine L.,
Williamson Peter. A.,
Meldrum Karen,
Gillen Michael,
Carlsson LarsGoran,
Carlholm Marie,
Ekelund Jan,
Lipworth Brian J.
Publication year - 2011
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2010.03857.x
Subject(s) - chlorofluorocarbon , inhaler , metered dose inhaler , crossover study , pharmacokinetics , budesonide , bioavailability , pharmacodynamics , pharmacology , medicine , anesthesia , chemistry , asthma , inhalation , alternative medicine , organic chemistry , pathology , placebo
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Chlorofluorocarbons (CFCs) have been implicated in damage to the ozone layer, and are due to be phased out in accordance with the Montreal Protocol. • Hydrofluoroalkane‐134a (HFA) has been found to act as an adequate propellant for pressurized metered‐dose inhaler delivery systems without the same deleterious environmental effects. WHAT THIS STUDY ADDS • This paper presents data from both steady‐state pharmacokinetic and pharmacodynamic assessments of HFA vs. CFC pressurized metered‐dose inhaler formulations of budesonide. It demonstrates that they are therapeutically equivalent in terms of relative lung bioavailability, airway efficacy and systemic effects. AIMS A hydrofluoroalkane formulation of budesonide pressurized metered‐dose inhaler has been developed to replace the existing chlorofluorocarbon one. The aim of this study was to evaluate the pharmacokinetic and pharmacodynamic characteristics of both formulations. METHODS Systemic bioavailability and bioactivity of both hydrofluoroalkane and chlorofluorocarbon pressurized metered‐dose inhaler formulations at 800 µg twice daily was determined during a randomized crossover systemic pharmacokinetic/pharmacodynamic study at steady state in healthy volunteers. Measurements included the following: plasma cortisol AUC 24h [area under the concentration‐time curve (0–24 h)], budesonide AUC 0–12h and C max . Clinical efficacy was determined during a randomized crossover pharmacodynamic study in asthmatic patients receiving 200 µg followed by 800 µg budesonide via chlorofluorocarbon or hydrofluoroalkane pressurized metered‐dose inhaler each for 4 weeks. Methacholine PC 20 (primary outcome), exhaled nitric oxide, spirometry, peak expiratory flow and symptoms were evaluated. RESULTS In the pharmacokinetic study, there were no differences in cortisol, AUC 0–12h [area under the concentration‐time curve (0–12 h)], T max (time to maximum concentration) or C max (peak serum concentration) between the hydrofluoroalkane and chlorofluorocarbon pressurized metered‐dose inhaler. The ratio of budesonide hydrofluoroalkane vs. chlorofluorocarbon pressurized metered‐dose inhaler for cortisol AUC 24h was 1.02 (95% confidence interval 0.93–1.11) and budesonide AUC 0–12h was 1.03 (90% confidence interval 0.9–1.18). In the asthma pharmacodynamic study, there was a significant dose response ( P < 0.0001) for methacholine PC 20 (provocative concentration of methacholine needed to produce a 20% fall in FEV 1 ) with a relative potency ratio of 1.10 (95% confidence interval 0.49–2.66), and no difference at either dose. No significant differences between formulations were seen with the secondary outcome variables. CONCLUSIONS Hydrofluoroalkane and chlorofluorocarbon formulations of budesonide were therapeutically equivalent in terms of relative lung bioavailability, airway efficacy and systemic effects.