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

Contraction-related factors affect the concentration of a kallidin-like peptide in rat muscle tissue

In order to study the effects of the manipulation of various factors related to muscular activity on the concentration of kinins in muscular tissue, a microdialysis probe was implanted in the adductor muscle of the hindlimb in anaesthetized rats. After collection of baseline samples, the perfusion fluid was changed to a Ringer solution containing sodium lactate (10 or 20 mm), adenosine (50 or 100 μM) or a lower pH (7.0 or 6.6). Whereas perfusion with lactate did not have any significant effect on the concentration of kinins in the dialysate, the perfusion with a lower pH or with adenosine dose-dependently increased the kinin content in the samples. In a second microdialysis experiment, by using specific radioimmunoassays (RIA) for bradykinin and kallidin, we observed that about 70 % of the total kinins dialysed from rat muscle are a kallidin-like peptide. Also, the simultaneous perfusion with 100 μM caffeine totally abolished the increase in kinin levels induced by the perfusion at pH 6.6. In a third experiment, soleus muscles from rat were stimulated in vitro during 30 min in the presence or absence of 77 μM caffeine. Electrically stimulated contraction, but not the addition of 10 mU ml−1 insulin, induced an increase in the concentration of the kallidin-like peptide in the buffer. This effect was totally prevented by the addition of the adenosine antagonist caffeine. These results show that a kallidin-like peptide is released from rat muscle, and that its production is enhanced by muscle activity. Furthermore, the increase in kinin peptides during muscle contraction may be mediated by an increase in adenosine levels