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Ultralow Dose Pharmacokinetic and Pharmacodynamic Study of Abediterol in Asthmatic Patients in Two Devices
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A1390 - Ultralow Dose Pharmacokinetic and Pharmacodynamic Study of Abediterol in Asthmatic Patients in Two Devices
Author Block: C. Astbury1, J. Beier2, H. Pujol3, L. Jimenez4, B. Seoane5, A. Aggarwal6; 1Respiratory, Inflammation and Autoimmunity IMED Biotech Unit, AstraZeneca, Barcelona, Spain, 2Insaf Respiratory Research, Wiesbaden, Germany, 3RIA TMU, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Barcelona, Spain, 4Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Barcelona, Spain, 5Biometrics and Information Sciences, Global Medicines Development, AstraZeneca, Barcelona, Spain, 6RIA TMU, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Boston, MA, United States.
Background:
Abediterol (AZD0548) is a novel, potent long-acting β2-agonist, in development for once-daily maintenance treatment of asthma, in combination with a glucocorticoid receptor agonist or other anti-inflammatory agent.
Methods:
This was a Phase IIa, single-dose, randomised, double-blind, double-dummy, placebo-controlled, six‑way crossover study. Thirty asthmatic patients (32-71 years) received single doses of abediterol (0.05, 0.156 and 2.5μg in pMDI and 0.156 and 2.5µg in DPI) and placebo, on top of ongoing maintenance therapy. The primary efficacy endpoint was change from baseline in trough forced expiratory volume in 1 s (FEV1). Relative bioavailability assessed as pharmacokinetic endpoint.
Results:
All 5 abediterol treatments showed a dose-ordered, clinically meaningful bronchodilation sustained for at least 24h. Mean improvement in trough FEV1 (LS means vs placebo) at various dose levels with both devices were statistically significant and ranged from 106 to 406mL. Comparisons between devices within the same dose level showed no differences in bronchodilation nor on the safety endpoints. No plasma levels were detected at the two lower doses. At 2.5 µg, systemic exposure was similar in the two devices. At this dose level, ratios of geometric means (pMDI/DPI) were 1.11 for Cmax (90%CI 0.840-1.47) and 0.979 for AUC (90%CI 0.781-1.23). All treatments were safe and well tolerated.
Conclusions:
This study confirmed the potent, rapid and long-acting bronchodilatory effect of abediterol and showed a very consistent dose ordered response compared with previous data in patients with asthma. Further studies will be conducted to establish the optimal dose of abediterol.
Author Block: C. Astbury1, J. Beier2, H. Pujol3, L. Jimenez4, B. Seoane5, A. Aggarwal6; 1Respiratory, Inflammation and Autoimmunity IMED Biotech Unit, AstraZeneca, Barcelona, Spain, 2Insaf Respiratory Research, Wiesbaden, Germany, 3RIA TMU, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Barcelona, Spain, 4Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Barcelona, Spain, 5Biometrics and Information Sciences, Global Medicines Development, AstraZeneca, Barcelona, Spain, 6RIA TMU, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Boston, MA, United States.
Background:
Abediterol (AZD0548) is a novel, potent long-acting β2-agonist, in development for once-daily maintenance treatment of asthma, in combination with a glucocorticoid receptor agonist or other anti-inflammatory agent.
Methods:
This was a Phase IIa, single-dose, randomised, double-blind, double-dummy, placebo-controlled, six‑way crossover study. Thirty asthmatic patients (32-71 years) received single doses of abediterol (0.05, 0.156 and 2.5μg in pMDI and 0.156 and 2.5µg in DPI) and placebo, on top of ongoing maintenance therapy. The primary efficacy endpoint was change from baseline in trough forced expiratory volume in 1 s (FEV1). Relative bioavailability assessed as pharmacokinetic endpoint.
Results:
All 5 abediterol treatments showed a dose-ordered, clinically meaningful bronchodilation sustained for at least 24h. Mean improvement in trough FEV1 (LS means vs placebo) at various dose levels with both devices were statistically significant and ranged from 106 to 406mL. Comparisons between devices within the same dose level showed no differences in bronchodilation nor on the safety endpoints. No plasma levels were detected at the two lower doses. At 2.5 µg, systemic exposure was similar in the two devices. At this dose level, ratios of geometric means (pMDI/DPI) were 1.11 for Cmax (90%CI 0.840-1.47) and 0.979 for AUC (90%CI 0.781-1.23). All treatments were safe and well tolerated.
Conclusions:
This study confirmed the potent, rapid and long-acting bronchodilatory effect of abediterol and showed a very consistent dose ordered response compared with previous data in patients with asthma. Further studies will be conducted to establish the optimal dose of abediterol.
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