Anders Källén

Increasing Doses of Inhaled Corticosteroids Compared to Adding Long-Acting Inhaled β2-Agonists in Achieving Asthma Control

BACKGROUND Combination therapy with inhaled corticosteroids (ICSs) and long-acting beta(2)-agonists (LABAs), or treatment with high doses of ICSs alone improves asthma control when therapy with low-dose ICSs is not sufficient. However, it is not known which of these treatment options is more effective in sustaining asthma control. OBJECTIVES To evaluate the effect of increasing the ICS dosage vs adding LABAs on the time spent with well-controlled asthma or poorly controlled asthma. METHODS Post hoc analysis of the Formoterol and Corticosteroid Establishing Therapy study, which compared a fourfold increase in the budesonide dose with and without formoterol. RESULTS Time with well-controlled asthma was improved by 19% (95% confidence interval [CI], 3 to 35%; p = 0.017) by adding formoterol, 24 microg/d, to therapy with budesonide, 200 microg/d, compared to 2% (95% CI, -9 to 12%; p = 0.76) with therapy with budesonide, 800 microg/d, alone. Time with well-controlled asthma was further improved by 29% (95% CI, 13 to 47%; p < 0.001) by adding formoterol to therapy with budesonide, 800 microg/d. Time with poorly controlled asthma was significantly reduced using the same interventions by 43% (95% CI, 25 to 57%), 22% (95% CI, 7 to 44%), and 50% (95% CI, 30 to 64%), respectively. Adding formoterol to budesonide was significantly more effective in increasing time with well-controlled asthma when compared to increasing the budesonide dose fourfold (increase, 16%; 95% CI, 1 to 33%; p = 0.035), with a trend for a greater reduction in time with poor control (decrease, 21%; 95% CI, -5 to 42%). CONCLUSION The addition of formoterol to therapy with low-dose budesonide increases the probability of well-controlled asthma compared to a substantial increase in the dose of an ICS.

Differences in bronchodilating potency of salbutamol in Turbuhaler as compared with a pressurized metered-dose inhaler formulation in patients with reversible airway obstruction

Two studies are presented, with the aim of establishing the dose potency ratio for salbutamol given via Turbuhaler and via a pressurized metered-dose inhaler (pMDI). Both studies were of a double-blind, randomized design. Outpatients with mild-to-moderate chronic reversible airway obstruction were given single doses of salbutamol administered via Turbuhaler and via pMDI. Efficacy and safety variables were measured before and during 6 h after each dose. The first study was a four-way crossover study including 12 patients. The salbutamol doses given were: 50, 100 and 2x100 microg via Turbuhaler and 2x100 microg via pMDI (Ventolin). The study showed that 2x100 microg of salbutamol inhaled via Turbuhaler is more potent than 2x100 microg salbutamol inhaled via a pMDI, and that 100 microg salbutamol via Turbuhaler is at least as potent as 2x100 microg salbutamol inhaled via a pMDI. The second study including 50 patients was a placebo-controlled five-way crossover, study. Two doses of salbutamol via Turbuhaler, 50 and 2x100 microg, and via pMDI, 100 and 2x200 microg, were given. There was a dose-dependent response in forced expiratory volume in one second (FEV1) for both inhalers. Adjusted for differences in baseline FEV1 values, the estimated relative dose potency for Turbuhaler versus pMDI was 1.98:1 (95% confidence interval 12-3.2). These studies showed that the same bronchodilating effect can be achieved when half the dose of salbutamol given via a conventional pressurized metered-dose inhaler is given via Turbuhaler.

Effects of budesonide by means of the Turbuhaler on the hypothalmic-pituitary-adrenal axis in asthmatic subjects: A dose-response study

BACKGROUND As a general phenomenon, corticosteroids may suppress the activity in the hypothalamic-pituitary-adrenal (HPA) axis. The adrenal stimulation test is a commonly used method to assess the relative risk of exogenous corticosteroids to induce systemic side effects. OBJECTIVES This clinical trial was performed to assess the effects of budesonide on the HPA axis (at 800, 1600, or 3200 microg/day, given as a twice daily regimen, administered by means of the Turbuhaler) in adult patients with mild, non-steroid-dependent asthma. METHODS Sixty-four asthmatic patients received budesonide or placebo by inhalation or 10 mg/day oral prednisone once daily as a positive control in a double-blind, double-dummy, randomized, placebo-controlled, parallel-group, multicenter study. Plasma cortisol concentration was measured to assess the effect on the HPA axis before and during a 6-hour infusion of synthetic adrenocorticotropic hormone (ACTH), cosyntropin. RESULTS After 6 weeks of treatment, plasma cortisol concentrations after adrenal stimulation by cosyntropin infusion had fallen by 4% in the placebo group; by 13%, 11%, and 27% in the budesonide groups (800, 1600, and 3200 microg/day, respectively); and by 35% in the prednisone group. The decrease was significant only in the 3200 microg/day budesonide (p = 0.03) and prednisone (p = 0.005) groups. Over the same time period, decreases in basal plasma cortisol concentrations were 1% in the placebo group; 19%, 19%, and 34% in the three budesonide groups; and 37% in the prednisone group. Only in the prednisone group was the decrease significant (p = 0.03 vs placebo). CONCLUSIONS In this study budesonide inhaled by means of the Turbuhaler, at doses recommended for clinical use (800 or 1600 microg/day), did not produce any statistically significant suppression of the HPA axis compared with placebo.

Repeated intranasal TLR7 stimulation reduces allergen responsiveness in allergic rhinitis

BackgroundInteractions between Th1 and Th2 immune responses are of importance to the onset and development of allergic disorders. A Toll-like receptor 7 agonist such as AZD8848 may have potential as a treatment for allergic airway disease by skewing the immune system away from a Th2 profile.ObjectiveTo evaluate the efficacy and safety of intranasal AZD8848.MethodsIn a placebo-controlled single ascending dose study, AZD8848 (0.3-600 μg) was given intranasally to 48 healthy subjects and 12 patients with allergic rhinitis (NCT00688779). In a placebo-controlled repeat challenge/treatment study, AZD8848 (30 and 60 μg) was given once weekly for five weeks to 74 patients with allergic rhinitis out of season: starting 24 hours after the final dose, daily allergen challenges were given for seven days (NCT00770003). Safety, tolerability, pharmacokinetics, and biomarkers were monitored. During the allergen challenge series, nasal symptoms and lavage fluid levels of tryptase and α2-macroglobulin, reflecting mast cell activity and plasma exudation, were monitored.ResultsAZD8848 produced reversible blood lymphocyte reductions and dose-dependent flu-like symptoms: 30–100 μg produced consistent yet tolerable effects. Plasma interleukin-1 receptor antagonist was elevated after administration of AZD8848, reflecting interferon production secondary to TLR7 stimulation. At repeat challenge/treatment, AZD8848 reduced nasal symptoms recorded ten minutes after allergen challenge up to eight days after the final dose. Tryptase and α2-macroglobulin were also reduced by AZD8848.ConclusionsRepeated intranasal stimulation of Toll-like receptor 7 by AZD8848 was safe and produced a sustained reduction in the responsiveness to allergen in allergic rhinitis.Trial registrationNCT00688779 and NCT00770003 as indicated above.

On the Definition of Therapeutic Equivalence

What do we mean by therapeutic equivalence and how do we prove that two drugs are therapeutically equivalent? We suggest that therapeutic equivalence should be defined and demonstrated using predefined limits on the dose scale rather than on the effect scale. A simple design of an equivalence study is discussed, including statistical analysis and the power calculation.

Drug disposition analysis: a comparison between budesonide and fluticasone.

The characterisation of distribution and elimination properties of a drug is usually done using parameters like clearance and distributional volumes. To refine this characterisation, in this paper, we use drug disposition analysis to compare the distribution and elimination of the two glucocorticosteroids budesonide and fluticasone propionate, known to differ in this respect. This gives a more detailed description of the well known differences in distributional volumes using concepts like mean residence time and fraction of dose outside the central compartment. It clearly shows that fluticasone, although having lower plasma concentrations, still resides in the body in appreciable quantities.

A Note on Therapeutic Equivalence and Therapeutic Ratio with Application to Studies in Respiratory Diseases

This paper argues that the concepts of therapeutic equivalence and noninferiority trials have some unclear logic and give results that might not be in accordance with clinical experience. They are also totally unnecessary. The discussion focuses on therapeutic equivalence trials, but carries over directly to noninferiority trials. Therapeutic equivalence proves to be a flexible tool for delusion and should be abandoned. Statistics should end where it can claim to be correct and useful, in this case, with estimates and confidence limits of clinically relevant parameters such as relative dose potency. If therapeutic equivalence is still needed for special purposes, the testing and definition should be done on the dose scale. SUMMARY AND CONCLUSION

A Simple Absorption Model for Dose-escalating Studies

A simple model for absorption that generalizes zero and first order absorption processes is discussed. We show how traditional methods can be used to investigate how reasonable this model is, and discuss the effects of the absorption model on classical PK parameters. The methods are illustrated with two real-life data sets from dose-escalating studies.