Cees Korstanje1, Masanori Suzuki2, Koichiro Yuno3, Shuichi Sato4, Masashi Ukai5, Marlowe J Schneidkraut6, Gan X Yan7. 1. Drug Discovery Sciences and Management - EU, Astellas Pharma B.V., Leiden, Netherlands. Electronic address: cees.korstanje@astellas.com. 2. Research Quality Assurance, Astellas Pharma Inc., Ibaraki, Japan. Electronic address: masanori-suzuki@astellas.com. 3. Drug Safety Research Laboratories, Astellas Pharma Inc., Ibaraki, Japan. Electronic address: koichiro.yuno@astellas.com. 4. Drug Repurposing and Application Management, Astellas Pharma Inc., Ibaraki, Japan. Electronic address: shuichi.sato@astellas.com. 5. Translational Science Research Labs, Astellas Pharma Inc., Ibaraki, Japan. Electronic address: masashi.ukai@astellas.com. 6. Drug Discovery Sciences and Management - US, Astellas Research Institute of America Northbrook, IL 60062, USA. Electronic address: marlowe.schneidkraut@astellas.com. 7. Lankenau Medical Center and Lankenau Institute for Medical Research, Wynnewood, PA, USA. Electronic address: yanganxin@comcast.net.
Abstract
INTRODUCTION: Translational assessment of cardiac safety parameters is a challenge in clinical development of beta-3 adrenoceptor agonists. The preclinical tools are presented that were used for assessing human safety for mirabegron. METHODS: Studies were performed on electrical conductance at ion channels responsible for cardiac repolarization (IKr, IKs, Ito, INa, and ICa,L), on QT-interval, subendocardial APD90, Tpeak-end interval, and arrhythmia's in ventricular dog wedge tissue in vitro and on cardiovascular function (BP, HR, and QTc) in conscious dogs. RESULTS: In conscious dogs, mirabegron (0.01-10mg/kg, p.o.) dose-dependently increased HR, reduced SBP but DBP was unchanged. Propranolol blocked the decrease in SBP and attenuated HR increase at 100mg/kg mirabegron. Mirabegron, at 30, 60, or 100mg/kg, p.o., had no significant effect on the QTc interval. In paced dog ventricular wedge, neither mirabegron nor metabolites M5, M11, M12, M14, and M16 prolonged QT, altered transmural dispersion of repolarization, induced premature ventricular contractions, or induced ventricular tachycardia. Mirabegron nor its metabolites inhibited IKr, IKs, Ito INa, or ICa,L at clinically relevant concentrations. DISCUSSION: Up to exposure levels well exceeding human clinical exposure no discernible effects on ion channel conductance or on arrhythmogenic parameters in ventricular wedge resulted for mirabegron, or its main metabolites, confirming human cardiac safety findings. In vivo, dose-related increases in HR with effects markedly higher than seen clinically, was mediated in part by cross-activation of beta-1 adrenoceptors. This non-clinical cardiac safety test program therefore proved predictive for human cardiac safety for mirabegron.
INTRODUCTION: Translational assessment of cardiac safety parameters is a challenge in clinical development of beta-3 adrenoceptor agonists. The preclinical tools are presented that were used for assessing human safety for mirabegron. METHODS: Studies were performed on electrical conductance at ion channels responsible for cardiac repolarization (IKr, IKs, Ito, INa, and ICa,L), on QT-interval, subendocardial APD90, Tpeak-end interval, and arrhythmia's in ventricular dog wedge tissue in vitro and on cardiovascular function (BP, HR, and QTc) in conscious dogs. RESULTS: In conscious dogs, mirabegron (0.01-10mg/kg, p.o.) dose-dependently increased HR, reduced SBP but DBP was unchanged. Propranolol blocked the decrease in SBP and attenuated HR increase at 100mg/kg mirabegron. Mirabegron, at 30, 60, or 100mg/kg, p.o., had no significant effect on the QTc interval. In paced dog ventricular wedge, neither mirabegron nor metabolites M5, M11, M12, M14, and M16 prolonged QT, altered transmural dispersion of repolarization, induced premature ventricular contractions, or induced ventricular tachycardia. Mirabegron nor its metabolites inhibited IKr, IKs, Ito INa, or ICa,L at clinically relevant concentrations. DISCUSSION: Up to exposure levels well exceeding human clinical exposure no discernible effects on ion channel conductance or on arrhythmogenic parameters in ventricular wedge resulted for mirabegron, or its main metabolites, confirming human cardiac safety findings. In vivo, dose-related increases in HR with effects markedly higher than seen clinically, was mediated in part by cross-activation of beta-1 adrenoceptors. This non-clinical cardiac safety test program therefore proved predictive for human cardiac safety for mirabegron.
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