Repeated intranasal TLR7 stimulation reduces allergen responsiveness in allergic rhinitis.

BACKGROUND: Interactions 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. OBJECTIVE: To evaluate the efficacy and safety of intranasal AZD8848. METHODS: In 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. RESULTS: AZD8848 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. CONCLUSIONS: Repeated 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 REGISTRATION: NCT00688779 and NCT00770003 as indicated above.

Increasing doses of inhaled corticosteroids compared to adding long-acting inhaled beta2-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.

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.

Multivariate estimation of the relative dose potency.

As a follow-up to a previous publication we illustrate how multivariate analysis of dose-response trials can be done, providing single number, relative dose potency, results for the comparison between two treatments, also when a number of variables are measured.

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.