Budesonide/formoterol and formoterol provide similar rapid relief in patients with acute asthma showing refractoriness to salbutamol

BACKGROUND: To compare the efficacy and safety of budesonide/formoterol (Symbicort(®)) with formoterol (Oxis(®)) in the treatment of patients with acute asthma who showed evidence of refractoriness to short-acting β(2)-agonist therapy. METHODS: In a 3 hour, randomized, double-blind study, a total of 115 patients with acute asthma (mean FEV(1 )40% of predicted normal) and a refractory response to salbutamol (mean reversibility 2% of predicted normal after inhalation of 400 μg), were randomized to receive either budesonide/formoterol (320/9 μg, 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes [total dose 1280/36 μg]) or formoterol (9 μg, 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes [total dose 36 μg]). The primary efficacy variable was the average FEV(1 )from the first intake of study medication to the measurement at 90 minutes. Secondary endpoints included changes in FEV(1 )at other timepoints and change in respiratory rate at 180 minutes. Treatment success, treatment failure and patient assessment of the effectiveness of the study medication were also measured. RESULTS: FEV(1 )increased after administration of the study medication in both treatment groups. No statistically significant difference between the treatment groups was apparent for the primary outcome variable, or for any of the other efficacy endpoints. There were no statistically significant between-group differences for treatment success, treatment failure or patient assessment of medication effectiveness. Both treatments were well tolerated. CONCLUSION: Budesonide/formoterol and formoterol provided similarly rapid relief of acute bronchoconstriction in patients with asthma who showed evidence of refractoriness to a short-acting β(2)-agonist

Clinical pharmacokinetics of AZD3199, an inhaled ultra-long-acting β2-adrenoreceptor agonist (uLABA)

Leif Bjermer,1 Piotr Kuna,2 Carin Jorup,3 Thomas Bengtsson,4 Johan Rosenborg4 1Department of Respiratory Medicine and Allergology, University Hospital, Lund, Sweden; 2Department of Internal Medicine, Asthma and Allergy, Barlicki University Hospital, Medical University of Lodz, Lodz, Poland; 3AstraZeneca R&D, Mölndal, Sweden; 4StatMind, Lund, Sweden Objective: The clinical pharmacokinetics of AZD3199, an ultra-long-acting β2-agonist, were investigated in healthy volunteers and patients with asthma or chronic obstructive pulmonary disease (COPD). Materials and methods: Five studies are presented: one single ascending dose study in healthy Caucasian males; two multiple ascending dose studies in healthy males, one in Caucasians and one in Japanese; a Phase IIA asthma study; and a Phase IIB COPD study. Subjects received AZD3199 via a Spira nebulizer (Turbuhaler; equivalent delivered doses 5–3200 µg) or Turbuhaler (single delivered doses of 120–1920 µg or repeated delivered once-daily doses 240–1,680 µg). AZD3199 pharmacokinetics were assessed using total plasma concentration and urinary excretion, and tolerability using adverse events, clinical laboratory tests, and physical examinations. Results: AZD3199 appeared rapidly in the systemic circulation following single and multiple dosing in healthy volunteers and patients (maximum plasma concentration within 30 minutes), with dose-proportional time-independent pharmacokinetics. Plasma exposure to unmetabolized drug was similar in healthy volunteers and patients with asthma, but relatively lower in patients with COPD. Estimated terminal half-life was up to 142 hours in healthy Caucasian males. AZD3199 was well tolerated and showed no or at most mild systemic effects. Conclusion: AZD3199 plasma exposure in healthy volunteers and patients suggested linear pharmacokinetics and a long half-life. Systemic availability was similar in healthy subjects and patients with asthma, but was lower in patients with COPD. These clinical trials suggest that AZD3199 is well-tolerated in healthy male volunteers and patients, with no safety concerns identified to preclude further evaluation. Keywords: AZD3199, uLABA, COPD, asthma, pharmacokinetics, tolerabilit

The effect of formoterol over 24 h in patients with asthma: the role of enantiomers

The single-dose effect of formoterol racemate and enantiomers on bronchodilatation up to 24 h was determined. Forty-six reversible asthmatic patients were randomised to this double blind, crossover study. Formoterol was inhaled by nebulizer (HaloLite(R)); 4.5 and 36 mug of the racemate (rac-formoterol), 2.25 and 18 mug of (R;R)-formoterol, 18 mug of (S;S)-formoterol, or placebo. Airway and systemic effects were assessed by serial measurements of forced expiratory volume during the first second, FEV1 (24 h), and heart rate (4 h). Rac- and (R;R)formoterol significantly and dose-dependently increased FEV1, with similar mean maximal effect. (S;S)-formoterol was without significant effects on FEV1 and heart rate. (R;R)- and rac-formoterol were still effective 22-24 h after single high doses, but this was associated with some systemic side effect (increased heart rate) initially. Average 22-24 h FEV1 was 8% (rac-formoterol 36 mug) and 11% ((R-R)-formoterol 18 mug) over placebo, respectively. No significant differences in effects were observed between rac- and (R;R)-formoterol. Thus, the single dose bronchodilatating effect of formoterol resides in (R;R)-formoterol. This study does not indicate a clinically important advantage of (R;R)-formoterol as acute bronchodilator compared to the racemate