Dose-response comparison of budesonide dry powder inhalers using adenosine monophosphate bronchial challenge

Lipworth, Brian J.; Sims, Erika J.; Das, Soumyajit; Buck, Helen; Paterson, Michelle

doi:10.1016/s1081-1206(10)61327-0

Cited by 15 publications

(12 citation statements)

References 29 publications

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“…The 95% CIs for the relative dose potency ratio of HFA vs. CFC were close to unity at 1.10; however, the 95% CI (0.49-2.66) was outside of the Ϯ50% limits of 0.5-2.0 [15]. Comparable results have been shown in a similar dose-response study published previously from our own laboratory [7].It could be argued that the change observed in the step up from 200 to 800 mg could be a time effect; however, we feel this is extremely unlikely. Sovijarvi et al found the doubling dilution difference between fluticasone and placebo to be 1.19, 1.33 and 1.27 after 72 h, 2 and 4 weeks, respectively, indicating that near-maximal response in methacholine PC20 is seen after 2 weeks of treatment.…”

Section: Discussionsupporting

confidence: 84%

Pharmacokinetic and pharmacodynamic comparison of hydrofluoroalkane and chlorofluorocarbon formulations of budesonide

Clearie

Williamson

Meldrum

et al. 2011

Brit J Clinical Pharma

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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. AIMSA 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. METHODSSystemic bioavailability and bioactivity of both hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler formulations at 800 mg twice daily was determined during a randomized crossover systemic pharmacokinetic/pharmacodynamic study at steady state in healthy volunteers. Measurements included the following: plasma cortisol AUC24h [area under the concentration-time curve (0-24 h)], budesonide AUC0-12h and Cmax. Clinical efficacy was determined during a randomized crossover pharmacodynamic study in asthmatic patients receiving 200 mg followed by 800 mg budesonide via chlorofluorocarbon or hydrofluoroalkane pressurized metered-dose inhaler each for 4 weeks. Methacholine PC20 (primary outcome), exhaled nitric oxide, spirometry, peak expiratory flow and symptoms were evaluated. RESULTSIn the pharmacokinetic study, there were no differences in cortisol, AUC0-12h [area under the concentration-time curve (0-12 h)], Tmax (time to maximum concentration) or Cmax (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 AUC24h was 1.02 (95% confidence interval 0.93-1.11) and budesonide AUC0-12h 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 PC20 (provocative concentration of methacholine needed to produce a 20% fall in FEV1) 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. CONCLUSIONSHydrofluoroalkane and chlorofluorocarbon formulations of budesonide were therapeutically equivalent in terms of relative lung bioavailability, airway efficacy and systemic effects.

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Section: Discussionsupporting

confidence: 84%

Pharmacokinetic and pharmacodynamic comparison of hydrofluoroalkane and chlorofluorocarbon formulations of budesonide

Clearie

Williamson

Meldrum

et al. 2011

Brit J Clinical Pharma

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“…However, control of underlying inflammation and remodeling was not assessed and individual patients with more severe asthma may require higher doses to achieve the corresponding maximal effects. Previously published evidence suggests that AHR, which is loosely related to inflammation, may be more likely to show ICS dose-dependence than FEV1, PEF or symptoms [9,12,31,61] and a dose-dependent rate of reduction of eNO and asthma symptoms has been observed [7,16,17]. In a meta-analysis of sixteen trials using multiple drug formulations (FP, triamcinolone, BUD and mometasone), a statistically significant inhaled corticosteroid dose-response relationship was found for morning PEF and a dose-response relation for FEV1 was found for BUD [2].…”

Section: Discussionmentioning

confidence: 99%

Is low dose inhaled corticosteroid therapy as effective for inflammation and remodeling in asthma? A randomized, parallel group study

Baraket¹,

Oliver²,

Burgess³

et al. 2012

Respiratory Research

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BackgroundWhile most of the clinical benefits of inhaled corticosteroid (ICS) therapy may occur at low doses, results of dose-ranging studies are inconsistent. Although symptom/lung function response to low and high dose ICS medication is comparable, it is uncertain whether low dose ICSs are as effective as high dose in the treatment of inflammation and remodeling.Methods22 mild or moderate asthmatic adult subjects (corticosteroid free for > 2 months) participated in a randomized, parallel group study to compare effects of fluticasone propionate (FP) 200 mcg/day and 1000 mcg/day. Alveolar macrophage (AM)-derived cytokines and basement membrane thickness (BMT) were measured at baseline and after 7 weeks treatment while symptoms, spirometry, exhaled nitric oxide (eNO) and airway hyperresponsiveness (AHR) to mannitol at baseline and 6 weeks.ResultsFP improved spirometry, eNO, symptoms and AHR with no difference between low and high dose FP. Both high and low dose FP reduced GM-CSF, TNF-alpha and IL-1ra, with no change in BMT and with no differences between low and high dose FP.Conclusions200 μg/day of FP was as effective as 1000 μg/day in improving asthma control, airway inflammation, lung function and AHR in adults in the short term. Future studies should examine potential differential effects between low and high dose combination therapy (ICS/long acting beta agonist) on inflammation and airway remodeling over longer treatment periods.

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“…The coefficient of variance for bronchial challenge is approximately a 1.7 doubling dilution shift [8]. This is in the context of a 1-2 dd shift only following introduction of an ICS, though subsequent treatment effects are diminished [5]. Our study attempted to elucidate the utility of inflammatory surrogates in 'real life' during ICS dose reduction and alternative step-down therapy.…”

Section: Discussionmentioning

confidence: 99%

Proof of concept study to evaluate step‐down therapy with inhaled corticosteroid alone or additive therapy on surrogate inflammatory markers in asthma

McKinlay

Williamson

Short

et al. 2010

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Much of the focus of inflammatory surrogates and airway challenges in asthma has been directed towards success of therapy and diagnosis. Few have considered them in the context of guiding dose reduction once sufficient control has been achieved. WHAT THIS STUDY ADDS • Adenosine monophosphate (AMP) as an indirect bronchial airway challenge, together with non invasive inflammatory surrogate measures were not found to be clinically useful when guiding therapy in a group of asthmatic patients through step 3–4 in British Thoracic Society asthma guidelines. However, they may still play a role in predicting failure of individual step‐down. AIM The aim of the study was to evaluate the usefulness of inflammatory surrogates in determining step‐down therapy in asthma. METHODS AMP challenge, serum eosinophil cationic protein (ECP), exhaled nitric oxide (eNO) and pulmonary function tests were recorded. Subjects were divided into two groups following high dose inhaled corticosteroids (ICS): Group A fixed dose ICS vs. Group B ICS alone and in combination with add on therapies. RESULTS No differences were seen in inflammatory measures between fixed dose ICS and reduced dose ICS alone or with combination therapies. CONCLUSIONS AMP challenge conferred no additional benefit in guiding step‐down therapy. The role of inflammatory surrogates may still play a role in predicting failed step‐down on an individual basis.

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Dose-response comparison of budesonide dry powder inhalers using adenosine monophosphate bronchial challenge

Cited by 15 publications

References 29 publications

Pharmacokinetic and pharmacodynamic comparison of hydrofluoroalkane and chlorofluorocarbon formulations of budesonide

Pharmacokinetic and pharmacodynamic comparison of hydrofluoroalkane and chlorofluorocarbon formulations of budesonide

Is low dose inhaled corticosteroid therapy as effective for inflammation and remodeling in asthma? A randomized, parallel group study

Proof of concept study to evaluate step‐down therapy with inhaled corticosteroid alone or additive therapy on surrogate inflammatory markers in asthma

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