Utilization of the chronic atrioventricular block cynomolgus monkey as an in vivo model to evaluate drug interaction-associated torsade de pointes.

Abstract

It has been difficult to experimentally reproduce synergistic effects of ketoconazole on terfenadine-induced torsade de pointes. We assessed proarrhythmic effects of terfenadine (30 mg/kg, p.o.) with/without ketoconazole (100 mg/kg, p.o.) pretreatment using the chronic atrioventricular block cynomolgus monkeys with repeated-measured design (n = 4). Terfenadine with ketoconazole pretreatment repeatedly induced non-sustained torsade de pointes in each animal, although terfenadine alone did not induce it at all. Thus, the chronic atrioventricular block cynomolgus monkeys can be used for studying drug interaction-associated torsade de pointes, providing a non-clinical strategy to circumvent untoward drug interactions in patients specially under polypharmacy.

• Authors: Ai Goto, Kengo Sakamoto, Mihoko Hagiwara-Nagasawa, Ryuichi Kambayashi, Koki Chiba, Yoshio Nunoi, Hiroko Izumi-Nakaseko, Akio Matsumoto, Atsushi Sugiyama
• Journal: Journal of pharmacological sciences (J Pharmacol Sci) Vol. 142 Issue 4 Pg. 172-175 (Apr 2020) ISSN: 1347-8648 [Electronic] Japan
• PMID: 31982331 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Chemical References

• Terfenadine
• Ketoconazole

Topics

• Animals
• Atrioventricular Block
• Chronic Disease
• Disease Models, Animal
• Drug Synergism
• Ketoconazole (administration & dosage, adverse effects)
• Macaca fascicularis
• Polypharmacy
• Terfenadine (administration & dosage, adverse effects)
• Torsades de Pointes (chemically induced)