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

Abstract

ObjectiveThe 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 methodsFive 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.ResultsAZD3199 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.ConclusionAZD3199 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.

<p>Pharmacokinetics and safety of revefenacin in subjects with impaired renal or hepatic function</p>

“…7,8 This finding of lower revefenacin exposure in COPD patients is consistent with observations for other inhaled LAMAs (umeclidinium, tiotropium), the corticosteroids budesonide and fluticasone propionate, and the LABAs olodaterol and AZD3199. [23][24][25][26] The observed increased exposure to the metabolite THRX-195518 in COPD patients relative to healthy subjects may be due to a difference in elimination and/or possibly the formation of THRX-195518. 7,8 Mean t 1/2 for revefenacin was approximately 30 hrs across groups in these studies, within the range of values reported in COPD patients.…”

<p>Ultra Long-Acting β-Agonists in Chronic Obstructive Pulmonary Disease</p>

“…Single ascending dose studies using nebulizer delivery and multidose studies using dry powder delivery in healthy participants with either mild-to-moderate persistent asthma or moderate-to-severe COPD showed AZD3199 was rapidly absorbed and had a prolonged half-life of up to 142 h. 79 It was well tolerated with mild dose-dependent reductions in serum potassium levels and increases in heart rate. In a double-blind, placebo-controlled, randomized, cross-over, single-dose study in mild-to-moderate asthma, the bronchodilating effects of inhaled AZD3199 delivered by dry-powder inhaler augmented peak FEV 1 and maintained bronchodilation at 24 h with 480 and 1920 mcg doses when compared with placebo.…”

Progress and Prospects for Long-Acting Β 2 -Agonists in the Treatment of Chronic Obstructive Pulmonary Disease

“…Он был отобран из новой серии двухосновных С-1-дез-гидрокси-7-гидрокси бензтиазолона агонистов β 2 -адренорецепторов и обладает высокой селек-тивностью (более чем в 1500 раз) в отношении человеческих β 2 -адренорецепторов [pEC 50 7,9 ± 0,12 (n = 8)] по сравнению с человеческими β 1 -и β 3 -адренорецепторами [57]. У здоровых добровольцев концентрация AZD3199 в плазме имела линейную фармакокинетику и длительный период полувыве-дения [58]. Системная биодоступность у здоровых и больных БА была сходной и более низкой -у боль-ных с ХОБЛ.…”