Clinical impact of fluvoxamine-mediated long QTU syndrome

Nia, Amir M.; Dahlem, Kristina M.; Gassanov, Natig; Hungerbühler, H; Fuhr, Uwe; Er, Fikret

doi:10.1007/s00228-011-1091-7

Cited by 5 publications

(5 citation statements)

References 18 publications

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“…In contrast to previous studies [3, 4] in which fluvoxamine did not seem to be a QTc-prolonging drug, we obtained evidence, consistently with Nia et al [5], of a patient on fluvoxamine therapy with a prolonged QTc of 0.51 s, which shortened after drug withdrawal.…”

supporting

confidence: 80%

An unusual etiology of torsade de pointes-induced syncope

Morosin¹,

Dametto²,

Bianco³

et al. 2017

aoms

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supporting

confidence: 80%

An unusual etiology of torsade de pointes-induced syncope

Morosin¹,

Dametto²,

Bianco³

et al. 2017

aoms

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“…44 Fluvoxamine has been classified as a class 3 compound by CredibleMeds, so here it was considered as TdP−. However, some clinical studies 45,46 reported that fluvoxamine, at therapeutic doses, increases the risk of TdP induction. These authors recommend that patients on fluvoxamine treatment should be monitored closely for QT/QTc interval prolongation with serial ECG.…”

Section: Discussionmentioning

confidence: 99%

In Silico Classifiers for the Assessment of Drug Proarrhythmicity

Llopis-Lorente

Gomis-Tena

Cano

et al. 2020

J. Chem. Inf. Model.

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Drug-induced torsade de pointes (TdP) is a life-threatening ventricular arrhythmia responsible for the withdrawal of many drugs from the market. Although currently used TdP risk-assessment methods are effective, they are expensive and prone to produce false positives. In recent years, in silico cardiac simulations have proven to be a valuable tool for the prediction of drug effects. The objective of this work is to evaluate different biomarkers of drug-induced proarrhythmic risk and to develop an in silico risk classifier. Cellular simulations were performed using a modified version of the O’Hara et al. ventricular action potential model and existing pharmacological data (IC50 and effective free therapeutic plasma concentration, EFTPC) for 109 drugs of known torsadogenic risk (51 positive). For each compound, four biomarkers were tested: T x (drug concentration leading to a 10% prolongation of the action potential over the EFTPC), T qNet (net charge carried by ionic currents when exposed to 10 times the EFTPC with respect to the net charge in control), T triang (triangulation for a drug concentration of 10 times the EFTPC over triangulation in control), and T EAD (drug concentration originating early afterdepolarizations over EFTPC). Receiver operating characteristic (ROC) curves were built for each biomarker to evaluate their individual predictive quality. At the optimal cutoff point, accuracies for T x, T qNet, T triang, and T EAD were 89.9, 91.7, 90.8, and 78.9% respectively. The resulting accuracy of the hERG IC50 test (current biomarker) was 78.9%. When combining T x, T qNet and T triang into a classifier based on decision trees, the prediction improves, achieving an accuracy of 94.5%. The sensitivity analysis revealed that most of the effects on the action potential are mainly due to changes in I Kr, I CaL, I NaL and I Ks. In fact, considering that drugs affect only these four currents, TdP risk classification can be as accurate as when considering effects on the seven main currents proposed by the CiPA initiative. Finally, we built a ready-to-use tool (based on more than 450 000 simulations), which can be used to quickly assess the proarrhythmic risk of a compound. In conclusion, our in silico tool can be useful for the preclinical assessment of TdP-risk and to reduce costs related with new drug development. The TdP risk-assessment tool and the software used in this work are available at .

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“…While only one clinical case of fluvoxamine-induced torsade de pointes has been reported (Manet et al, 1993), bradycardic action (de Wilde et al, 1983;Granfors et al, 2004;Pacher and Kecskemeti, 2004;Saletu et al, 1977), QT-interval prolongation (Klok et al, 1981;Nia et al, …”

Section: Discussionmentioning

confidence: 99%

“…in guinea pigs (Ohtani et al, 2001). It should be noted that in some previous clinical studies (Klok et al, 1981;Nia et al, 2012), the QT interval was prolonged by clinical doses of fluvoxamine; however, such prolongation was not observed in the other clinical reports (Beach et al, 2014;Okayasu et al, 2012). Since fluvoxamine prolonged the QT interval in a dose-related manner in this study, one can speculate that the discrepancy among the previous reports might in part depend on the difference of the plasma free drug concentration and/or concomitant use of other drugs.…”

Section: Electrophysiological Effectsmentioning

confidence: 95%

“…Moreover, fluvoxamine by itself was reported to inhibit human ether-a-go-go-related gene (hERG) channels (Milnes et al, 2003). Indeed, in some previous clinical studies (Klok et al, 1981;Nia et al, 2012), the QT interval was prolonged by clinical doses of fluvoxamine; however, such prolongation was not observed in the other clinical reports (Beach et al, 2014;Okayasu et al, 2012). Furthermore, specific data are very limited regarding the proarrhythmic effects of fluvoxamine (Claassen, 1983;Manet et al, 1993;Wouters and Deiman, 1983).…”

Section: Introductionmentioning

confidence: 99%

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Fluvoxamine by itself has potential to directly induce long QT syndrome at supra-therapeutic concentrations

et al. 2015

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-Fluvoxamine is one of the typical selective serotonin-reuptake inhibitors. While its combined use with QT-prolonging drugs has been contraindicated because of the increase in plasma concentrations of such drugs, information is still limited whether fluvoxamine by itself may directly prolong the QT interval. We examined electropharmacological effects of fluvoxamine together with its pharmacokinetic profile by using the halothane-anesthetized dogs (n = 4). Fluvoxamine was intravenously administered in three escalating doses of 0.1, 1 and 10 mg/kg over 10 min with a pause of 20 min between the doses. The low dose provided therapeutic plasma drug concentration, whereas the middle and high doses attained approximately 10 and 100 times of the therapeutic ones, respectively. Supra-therapeutic concentration of fluvoxamine exerted the negative chronotropic, inotropic and hypotensive effects; and suppressed the atrioventricular nodal and intraventricular conductions, indicating inhibitory actions on Ca 2+ and Na + channels, whereas it delayed the repolarization in a reverse use-dependent manner, reflecting characteristics of rapidly activating delayed rectifier K + current channel-blocking property. Fluvoxamine prolonged the terminal repolarization phase at 100 times higher concentration than the therapeutic, indicating its proarrhythmic potential. Thus, fluvoxamine by itself has potential to directly induce long QT syndrome at supra-therapeutic concentrations.

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Clinical impact of fluvoxamine-mediated long QTU syndrome

Cited by 5 publications

References 18 publications

An unusual etiology of torsade de pointes-induced syncope

An unusual etiology of torsade de pointes-induced syncope

In Silico Classifiers for the Assessment of Drug Proarrhythmicity

Fluvoxamine by itself has potential to directly induce long QT syndrome at supra-therapeutic concentrations

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