Drug‐induced Proarrhythmia and Torsade de Pointes: A Primer for Students and Practitioners of Medicine and Pharmacy

Abstract

Multiple marketing withdrawals due to proarrhythmic concerns occurred in the United States, Canada, and the United Kingdom in the late 1980s to early 2000s. This primer reviews the clinical implications of a drug's identified proarrhythmic liability, the issues associated with these safety-related withdrawals, and the actions taken by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and by regulatory agencies in terms of changing drug development practices and introducing new nonclinical and clinical tests to asses proarrhythmic liability. ICH Guidelines S7B and E14 were released in 2005. Since then, they have been adopted by many regional regulatory authorities and have guided nonclinical and clinical proarrhythmic cardiac safety assessments during drug development. While this regulatory paradigm has been successful in preventing drugs with unanticipated potential for inducing the rare but potentially fatal polymorphic ventricular arrhythmia torsade de pointes from entering the market, it has led to the termination of drug development programs for other potentially useful medicines because of isolated results from studies with limited predictive value. Research efforts are now exploring alternative approaches to better predict potential proarrhythmic liabilities. For example, in the domain of human electrocardiographic assessments, concentration-response modeling conducted during phase 1 clinical development has recently become an accepted alternate primary methodology to the ICH E14 "thorough QT/QTc" study for defining a drug's corrected QT interval prolongation liability under certain conditions. When a drug's therapeutic benefit is considered important at a public health level but there is also an identified proarrhythmic liability that may result from administration of the single drug in certain individuals and/or drug-drug interactions, marketing approval will be accompanied by appropriate directions in the drug's prescribing information. Health-care professionals in the fields of medicine and pharmacy need to consider the prescribing information in conjunction with individual patients' clinical characteristics and concomitant medications when prescribing and dispensing such drugs.

A Phase 1 Study of Intravenous Plazomicin in Healthy Adults to Assess Potential Effects on the QT/QTc Interval, Safety, and Pharmacokinetics

“…As part of the safety assessments of new drugs, thorough QT studies are routinely performed to characterize the potential for prolongation of the QT interval, and alternative approaches, such as concentration-response modeling, have also recently become acceptable. 14,15 Drug-induced prolongation of the QT interval can be proarrhythmic and degenerate into torsade de pointes, a potentially fatal ventricular arrhythmia. 16 A number of compounds across various therapeutic classes have proarrhythmic potential, including fluoroquinolone antibiotics, which are used for the treatment of cUTI.…”

Comparative Cardiac Safety of Selective Serotonin Reuptake Inhibitors among Individuals Receiving Maintenance Hemodialysis

“…Concurrent use of two or more QT-prolonging medications and the use of a QT-prolonging medication in combination with a metabolic inhibitor may result in QT interval lengthening. 35,36 Future studies are needed to fully elucidate the cardiac safety profiles of SSRIs in the hemodialysis population, including the frequency and magnitude of SSRI-induced QT prolongation measured via serial ECG monitoring or implantable loop recorders. However, in the interim, our results suggest that SSRI therapy selection should be individualized and clinicians should consider the differential QT-prolonging properties of SSRIs, among other factors, in their prescribing choices.…”

“…A lower QT-prolonging-potential SSRI may be a better option for patients at high risk for drug-induced QT prolongation, such as women, the elderly, individuals with cardiac conduction abnormalities, and those treated with other non-SSRI QT-prolonging medications. 35,36 However, if citalopram or escitalopram therapy is unavoidable in a high-risk patient, clinicians should look to the drug safety warnings issued by pharmaceutic regulatory agencies for guidance on therapeutic monitoring. 19224 Regulatory agencies, including the FDA, recommend serial ECG monitoring throughout the course of therapy in high-risk patients.…”

“…Subgroups of interest included individuals with and without known risk factors for druginduced QT prolongation: advanced age, female sex, cardiac conduction disorder, heart failure, liver disease, and use of other non-SSRI QT-prolonging medications. 35,36 Across all analyses, we used inverse probability of treatment (IPT) weighting to control for confounding. Briefly, we calculated the predicted probability (i.e., propensity score) of receiving an SSRI with higher versus lower QT-prolonging potential as a function of baseline covariates using multivariable logistic regression.…”

The Potential Role of the J‐Tpeak Interval in Proarrhythmic Cardiac Safety: Current State of the Science From the American College of Clinical Pharmacology and the Cardiac Safety Research Consortium

“…A third prospective study was conducted 18,22 to (1) confirm that concentration-response analysis using QTc and J-T peak c ECG data from small-sample clinical pharmacology studies can be used to confirm that balanced ion channel-blocking drugs do not cause J-T peak c prolongation; and (2) to test the hypothesis that calcium channel block can reduce QTc prolongation from hERG block by shortening the J-T peak c interval. Overall, results suggest that the absence of druginduced J-T peak c prolongation seems consistent with balanced ion channel block.…”