Predicted heart rate effect of inhaled PF‐00610355, a long acting β‐adrenoceptor agonist, in volunteers and patients with chronic obstructive pulmonary disease

Abstract

Aim To assess the cardiovascular effects of a new inhaled long‐acting β‐adrenoceptor agonist PF‐00610355 in COPD patients. Methods Thirteen thousand and sixty‐two heart rate measurements collected in 10 clinical studies from 579 healthy volunteers, asthma and COPD patients were analyzed. The relationship between heart rate profiles and predicted plasma concentration profiles, patient status, demographics and concomitant medication was evaluated using non‐linear mixed‐effects models. The median heart rate increase in COPD patients for doses of PF‐00610355 up to 280 μg once daily was simulated with the final pharmacokinetic/pharmacodynamic (PKPD) model. Results An Emax model accounting for delayed on‐and off‐set of the PF‐00610355‐induced change in heart rate was developed. The predicted potency in COPD patients was three‐fold lower compared with healthy volunteers, while no difference in maximum drug effect was identified. Simulations suggested a maximum placebo‐corrected increase of 2.7 (0.90–4.82) beats min−1 in COPD patients for a PF‐00610355 dose of 280 μg once daily, with 19% subjects experiencing a heart rate increase of more than 20 beats min−1 compared with 8% in the placebo group. Conclusions This PKPD analysis supports the clinical observation that no relevant effects of PF‐00610355 on heart rate in COPD patients should be expected for doses up to 280 μg once daily.

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

“… 74 , 76 An analysis of 10 clinical studies enrolling 579 healthy volunteers and individuals with asthma and COPD using pharmacokinetic/pharmacodynamic modeling suggested that 19% of individuals with COPD treated with 280 mcg of PF-610355 would increase heart rate by 20 or more beats/minute compared with 8% of those receiving placebo. 77 Further development of this agent has been discontinued.…”

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

“…Фармакокинетический/фармакодинамический анализ позволил предположить, что суточная одно-кратная доза в 280 мкг PF-610355 не обладает значи-мым влиянием на частоту сердечных сокращений у больных с ХОБЛ [56]. Хотя профиль препарата был интересен, в 2011 г. разработка этот вещества для лечения БА и ХОБЛ была прекращена, вероятно, по стратегическим и регуляторным соображениям.…”

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

“…A preliminary trial documented that PF-610355 induced a clear 24 h bronchodilator effect in asthmatic patients [54].In patients with COPD, it has been estimated that once daily fine-particle dose of 28.1 μg versus placebo has a moderate probability of providing an average improvement above 100 mL at trough [55]. The 50 μg fine-particle dose, on the other hand, has a greater than 0.78 probability of achieving a 120 mL improvement versus placebo at trough.A pharmacokinetic/pharmacodynamic analysis suggested ОБЗОРЫ that no relevant effects of PF-610355 on heart rate in COPD patients should be expected for doses up to 280 μg once daily [56]. Although this interesting profile, in 2011 the development of the compound for the treatment of asthma and COPD was discontinuedlikely for strategic and regulatory reasons.…”

“…The 50 μg fine-particle dose, on the other hand, has a greater than 0.78 probability of achieving a 120 mL improvement versus placebo at trough.A pharmacokinetic/pharmacodynamic analysis suggested ВЕСТНИК СОВРЕМЕННОЙ КЛИНИЧЕСКОЙ МЕДИЦИНЫ 2017 Том 10, вып. 1 11 ОБЗОРЫ that no relevant effects of PF-610355 on heart rate in COPD patients should be expected for doses up to 280 μg once daily [56]. Although this interesting profile, in 2011 the development of the compound for the treatment of asthma and COPD was discontinuedlikely for strategic and regulatory reasons.…”