QT Interval Shortening With Isavuconazole: In Vitro and In Vivo Effects on Cardiac Repolarization
| Autor: | Peter R. Kowey, Takao Yamazaki, Mark Yen, Salim Mujais, Christopher Lademacher, Amit Desai, Tomasz Wojtkowski, B Parker, Robert Townsend, Donna Kowalski, James Keirns, Marlowe J. Schneidkraut |
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| Rok vydání: | 2017 |
| Předmět: |
Adult
Male 0301 basic medicine Tachycardia medicine.medical_specialty Antifungal Agents Time Factors Calcium Channels L-Type Pyridines 030106 microbiology Action Potentials Transfection Placebo Models Biological Risk Assessment QT interval Loading dose Cell Line Electrocardiography Young Adult 03 medical and health sciences 0302 clinical medicine Double-Blind Method Heart Conduction System Heart Rate Moxifloxacin Internal medicine Nitriles medicine Humans Pharmacology (medical) 030212 general & internal medicine Adverse effect Pharmacology Dose-Response Relationship Drug medicine.diagnostic_test business.industry Research Arrhythmias Cardiac Articles Triazoles Calcium Channel Blockers Isavuconazonium Cardiology Female medicine.symptom business medicine.drug |
| Zdroj: | Clinical Pharmacology and Therapeutics |
| ISSN: | 0009-9236 |
| DOI: | 10.1002/cpt.620 |
| Popis: | The effects of isavuconazole (active moiety of isavuconazonium sulfate) on cardiac ion channels in vitro and cardiac repolarization clinically were assessed in a phase I, randomized, double‐blind study in healthy individuals who received isavuconazole (after 2‐day loading dose), at therapeutic or supratherapeutic doses daily for 11 days, moxifloxacin (400 mg q.d.), or placebo. A post‐hoc analysis of the phase III SECURE trial assessed effects on cardiac safety. L‐type Ca2+ channels were most sensitive to inhibition by isavuconazole. The 50% inhibitory concentrations for ion channels were higher than maximum serum concentrations of nonprotein‐bound isavuconazole in vivo. In the phase I study (n = 161), isavuconazole shortened the QT interval in a dose‐ and plasma concentration‐related manner. There were no serious treatment‐emergent adverse events; palpitations and tachycardia were observed in placebo and supratherapeutic isavuconazole groups; no cardiac safety signals were detected in the SECURE study (n = 257). Isavuconazole was associated with a shortened cardiac QT interval. |
| Databáze: | OpenAIRE |
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