tetano
Editor, Senior Moderator
J Pharmacol Sci
. 2024 Mar;154(3):218-224.
doi: 10.1016/j.jphs.2024.02.002. Epub 2024 Feb 2. Characterization of cardiovascular profile of anti-influenza drug peramivir: A reverse-translational study using the isoflurane-anesthetized dog
Ryuichi Kambayashi[SUP] 1 [/SUP], Ai Goto[SUP] 1 [/SUP], Hiroko Izumi-Nakaseko[SUP] 1 [/SUP], Yoshinori Takei[SUP] 1 [/SUP], Atsushi Sugiyama[SUP] 2 [/SUP]
Affiliations
An injectable anti-influenza drug peramivir has been reported to induce QT-interval prolongation in some phase III studies, although its thorough QT/QTc study was negative. We investigated the discrepancy among those clinical studies using isoflurane-anesthetized beagle dogs (n = 4). Peramivir in doses of 1 mg/kg/10 min (sub-therapeutic dose) followed by 10 mg/kg/10 min (clinically-relevant dose) was intravenously administered. Peramivir prolonged QT interval/QTcV and T[SUB]peak[/SUB]-T[SUB]end[/SUB], and tended to delay ventricular repolarization in a reverse-frequency dependent manner, indicating I[SUB]Kr[/SUB] inhibition in vivo. Meanwhile, peramivir did not alter P-wave duration, PR interval or QRS width, indicating a lack of impact on cardiac conduction via Na[SUP]+[/SUP] or Ca[SUP]2+[/SUP] channel inhibition in vivo. Peramivir prolonged T[SUB]peak[/SUB]-T[SUB]end[/SUB] and tended to prolong terminal repolarization period, which would develop substrates for initiating and maintaining spiral reentry, respectively. Meanwhile, peramivir did not prolong J-T[SUB]peak[/SUB]c, which could not induce early afterdepolarization, a trigger inducing torsade de pointes. Thus, our results support that clinical dose exposure of peramivir can delay the ventricular repolarization in influenza patients. Peramivir has only a small potential to induce torsade de pointes in patients with the intact hearts, but caution should be paid on its use for patients formerly having the trigger for torsade de pointes.
Keywords: Atrial effective refractory period; In vivo animal model; Peramivir; Proarrhythmic surrogate marker; QT prolongation.
. 2024 Mar;154(3):218-224.
doi: 10.1016/j.jphs.2024.02.002. Epub 2024 Feb 2. Characterization of cardiovascular profile of anti-influenza drug peramivir: A reverse-translational study using the isoflurane-anesthetized dog
Ryuichi Kambayashi[SUP] 1 [/SUP], Ai Goto[SUP] 1 [/SUP], Hiroko Izumi-Nakaseko[SUP] 1 [/SUP], Yoshinori Takei[SUP] 1 [/SUP], Atsushi Sugiyama[SUP] 2 [/SUP]
Affiliations
- PMID: 38395523
- DOI: 10.1016/j.jphs.2024.02.002
An injectable anti-influenza drug peramivir has been reported to induce QT-interval prolongation in some phase III studies, although its thorough QT/QTc study was negative. We investigated the discrepancy among those clinical studies using isoflurane-anesthetized beagle dogs (n = 4). Peramivir in doses of 1 mg/kg/10 min (sub-therapeutic dose) followed by 10 mg/kg/10 min (clinically-relevant dose) was intravenously administered. Peramivir prolonged QT interval/QTcV and T[SUB]peak[/SUB]-T[SUB]end[/SUB], and tended to delay ventricular repolarization in a reverse-frequency dependent manner, indicating I[SUB]Kr[/SUB] inhibition in vivo. Meanwhile, peramivir did not alter P-wave duration, PR interval or QRS width, indicating a lack of impact on cardiac conduction via Na[SUP]+[/SUP] or Ca[SUP]2+[/SUP] channel inhibition in vivo. Peramivir prolonged T[SUB]peak[/SUB]-T[SUB]end[/SUB] and tended to prolong terminal repolarization period, which would develop substrates for initiating and maintaining spiral reentry, respectively. Meanwhile, peramivir did not prolong J-T[SUB]peak[/SUB]c, which could not induce early afterdepolarization, a trigger inducing torsade de pointes. Thus, our results support that clinical dose exposure of peramivir can delay the ventricular repolarization in influenza patients. Peramivir has only a small potential to induce torsade de pointes in patients with the intact hearts, but caution should be paid on its use for patients formerly having the trigger for torsade de pointes.
Keywords: Atrial effective refractory period; In vivo animal model; Peramivir; Proarrhythmic surrogate marker; QT prolongation.