Prolongation of Cardiac Ventricular Repolarization Under Paliperidone: How and How Much?

Vigneault, Patrick; Kaddar, Nisrin; Bourgault, Sarah; Caillier, Bertrand; Pilote, Sylvie; Patoine, Dany; Simard, Chantale; Drolet, Benoît

doi:10.1097/fjc.0b013e318217d941

Cited by 21 publications

(8 citation statements)

References 15 publications

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“…The QT interval corrected for heart rate (HR; QTc) is a measure of ventricular repolarization on a 12‐lead surface electrocardiogram (ECG). Drug‐induced inhibition of human ether‐a‐go‐go‐related‐gene (hERG) potassium channels has been associated with QT/QTc interval prolongation . QT/QTc prolongation can lead to an increased susceptibility to cardiac arrhythmias, in particular torsades de pointes , that can degenerate into ventricular fibrillation and sudden death .…”

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confidence: 99%

Lenalidomide at Therapeutic and Supratherapeutic Doses Does Not Prolong QTc Intervals in the Thorough QTc Study Conducted in Healthy Men

Chen¹,

Ye²,

Liu³

et al. 2013

Basic Clin Pharma Tox

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The effect of lenalidomide on the corrected QT (QTc) interval was evaluated in healthy men and extended to patients based on the lenalidomide concentration–QTc (C–QTc) relationship. A rigorous assessment of the effect of lenalidomide on QTc intervals was conducted in healthy volunteers who each received, in randomized order, a single oral dose of 10 mg lenalidomide, 50 mg lenalidomide, 400 mg moxifloxacin (positive control) and placebo. Plasma lenalidomide exposure was compared between healthy volunteers and patients with multiple myeloma or myelodysplastic syndromes. In healthy volunteers, moxifloxacin produced the expected significant prolongation in QTcI (individual correction). For lenalidomide 10 mg and 50 mg, the time-matched changes from placebo in the baseline-adjusted least-squares mean QTcI were <3 ms with the upper limit of the two-sided 90% confidence interval for the change <10 ms at all time-points. No subjects experienced QTcI >450 ms or change from baseline >60 ms after lenalidomide administration. Similar results were seen with QT interval data corrected by Fridericia and Bazett methods. The C–QTc analysis yielded no significant association between lenalidomide concentrations and QTcI changes up to 1522 ng/mL; this range was close to that observed in patients receiving lenalidomide doses up to 50 mg, including those with reduced drug clearance due to renal impairment. In conclusion, single doses of lenalidomide up to 50 mg were not associated with prolonged QTc intervals in healthy males. The C–QTc analysis further assured that lenalidomide doses up to 50 mg are not expected to prolong QTc intervals in patients.

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mentioning

confidence: 99%

Lenalidomide at Therapeutic and Supratherapeutic Doses Does Not Prolong QTc Intervals in the Thorough QTc Study Conducted in Healthy Men

Chen¹,

Ye²,

Liu³

et al. 2013

Basic Clin Pharma Tox

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“…Risperidone also has the ability to inhibit the human ether‐a‐go‐go‐related gene ( hERG ) channel current, a recombinant channel encoded by an I Kr ‐cloned equivalent. Vigneault et al 6. showed in animal models that 9OH‐RIS also inhibits the hERG channel current, prolonging QT intervals.…”

Section: Discussionmentioning

confidence: 99%

Two cases of life‐threatening arrhythmia induced by risperidone: evaluation of risperidone and 9‐hydroxy‐risperidone concentrations

Ito

Enokiya

Kawamoto

et al. 2017

Acute Medicine & Surgery

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CasesCase 1: A 20‐year‐old woman suffering a suspected overdose was transported to the hospital. She presented bradycardia with wide QRS waves and QT prolongation, followed by cardiac arrest. Extracorporeal cardiopulmonary resuscitation was implemented, improving circulation. Risperidone and 9OH‐RIS levels were 9.6 ng/mL and 127.6 ng/mL, respectively. Case 2: A 54‐year‐old woman was hospitalized for femoral fracture and underwent surgery. Her electrocardiogram showed bradycardia and complete AV block. Risperidone and 9OH‐RIS levels were 3.2 ng/mL and 61.4 ng/mL, respectively.OutcomeIn both cases, only serum concentration of 90H‐RIS were elevated.ConclusionArrhythmia related to risperidone has proven rare but sometimes fatal. Serum concentrations of risperidone and the metabolite 9‐hydroxy‐risperidone (9OH‐RIS) during these events are seldom documented. As 9OH‐RIS shows pharmacological activity equivalent to risperidone, it may induce life‐threatening arrhythmia (regardless of the intake dosage). It is critical to evaluate the serum concentration of 9OH‐RIS in suspected risperidone toxicity.

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“…Our automated high-throughput approach is a powerful qualitative and quantitative method to rank order compounds according to their predictive cardiac risk and aims to bridge the gap between assay throughput and clinical relevance. (Aarons et al, 1998;Zhou et al, 1998;Teschemacher et al, 1999;Tie et al, 2000;Paul et al, 2002;Kirsch et al, 2004;Guo et al, 2005;Tarantino et al, 2005;Scholz et al, 2007;Luo et al, 2008;Huang et al, 2010;Zhang et al, 2010;Gintant, 2011;Lee et al, 2011;Vigneault et al, 2011;El Harchi et al, 2012;Crumb, 2014;Gualdani et al, 2015;Yun et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Assessment of drug-induced arrhythmic risk using limit cycle and autocorrelation analysis of human iPSC-cardiomyocyte contractility

Kirby

Phatak

et al. 2016

Toxicology and Applied Pharmacology

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Cardiac safety assays incorporating label-free detection of human stem-cell derived cardiomyocyte contractility provide human relevance and medium throughput screening to assess compound-induced cardiotoxicity. In an effort to provide quantitative analysis of the large kinetic datasets resulting from these real-time studies, we applied bioinformatic approaches based on nonlinear dynamical system analysis, including limit cycle analysis and autocorrelation function, to systematically assess beat irregularity. The algorithms were integrated into a software program to seamlessly generate results for 96-well impedance-based data. Our approach was validated by analyzing dose- and time-dependent changes in beat patterns induced by known proarrhythmic compounds and screening a cardiotoxicity library to rank order compounds based on their proarrhythmic potential. We demonstrate a strong correlation for dose-dependent beat irregularity monitored by electrical impedance and quantified by autocorrelation analysis to traditional manual patch clamp potency values for hERG blockers. In addition, our platform identifies non-hERG blockers known to cause clinical arrhythmia. Our method provides a novel suite of medium-throughput quantitative tools for assessing compound effects on cardiac contractility and predicting compounds with potential proarrhythmia and may be applied to in vitro paradigms for pre-clinical cardiac safety evaluation.

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Prolongation of Cardiac Ventricular Repolarization Under Paliperidone: How and How Much?

Abstract: Paliperidone prolongs the QT interval by blocking HERG current at clinically relevant concentrations and is potentially unsafe.

Cited by 21 publications

References 15 publications

Lenalidomide at Therapeutic and Supratherapeutic Doses Does Not Prolong QTc Intervals in the Thorough QTc Study Conducted in Healthy Men

Lenalidomide at Therapeutic and Supratherapeutic Doses Does Not Prolong QTc Intervals in the Thorough QTc Study Conducted in Healthy Men

Two cases of life‐threatening arrhythmia induced by risperidone: evaluation of risperidone and 9‐hydroxy‐risperidone concentrations

Assessment of drug-induced arrhythmic risk using limit cycle and autocorrelation analysis of human iPSC-cardiomyocyte contractility

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