The impact of drug-induced QT interval prolongation on drug discovery and development

• Published in: Nature reviews. Drug discovery Vol. 2; no. 6; pp. 439 - 447
• Main Authors: Fermini, Bernard, Fossa, Anthony A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2003; Nature Publishing Group
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cancer Research; Cardiovascular Agents - adverse effects; Cardiovascular Agents - therapeutic use; Electrocardiogram; Electrocardiography; Heart conduction system; Humans; Long QT Syndrome - chemically induced; Long QT Syndrome - physiopathology; Management; Medicinal Chemistry; Molecular Medicine; Pharmaceutical research; Pharmacology/Toxicology; Physiological aspects; Potassium channels; review-article; Technology, Pharmaceutical - economics; Technology, Pharmaceutical - legislation & jurisprudence; Technology, Pharmaceutical - methods; United States
• ISSN: 1474-1776; 1474-1784; 1474-1784
• DOI: 10.1038/nrd1108

Key Points During the past decade, a number of non-cardiovascular drugs have had their label revised or have been withdrawn from the market because of unexpected post-marketing reports of sudden cardiac death associated with a prolongation of the QT interval on the surface electrocardiogram, and an increased propensity to develop a ventricular tachyarrhythmia called Torsades de Pointes (TdP). When corrected for individual heart rate, the QT interval is defined as 'corrected' QT, or QTc. Although a direct link between QT interval prolongation and arrhythmogenesis is still unclear, QT prolongation is now the subject of increased regulatory review and is considered a significant risk factor for predicting human safety of new chemical entities (NCEs). Any evidence that a new drug prolongs the QTc interval is a significant development concern for pharmaceutical companies, as it raises the apprehension of TdP, and its subsequent regulatory approvability. Furthermore, the focus of interpretation of QTc prolongation by non-cardiovascular drugs by worldwide regulatory agencies has changed from one of noted side effect to that of life-threatening fatal outcome. There is at present no conclusive evidence to show that drug-induced prolongation of the QT interval inevitably leads to TdP. The link between QT interval prolongation and TdP is seemingly very complex and affected by a host of influential factors including age, electrolyte imbalance (for example, hypokalemia, hypomagnesemia and hypocalcemia), gender, disease states (for example, cardiomyopathy, myocardial ischaemia and infarction, hypertension, hypothyroidism, diabetes, renal or hepatic dysfunction) and concomitant medications. Not all drugs that prolong the QT interval carry the same potential to induce TdP. Regulatory agencies are concerned that, for the majority of QT prolonging drugs, their arrhythmogenic potential was only recognized during post-marketing surveillance and/or often many months/years after they were approved and used in the clinic. As a result, regulatory agencies will continue to rely on QT interval prolongation as a surrogate indication for TdP. In 1997, the European Agency for the Evaluation of Medicinal Products (EMEA) was the first to issue a 'points to consider' document from the Committee for Proprietary Medicinal Products. This document outlined a series of experimental non-clinical and clinical models for assessing the potential for QT prolongation by non-cardiovascular agents. During the past two years, regulatory scrutiny has continued to increase with Health Canada issuing a detailed draft guidance entitled 'Assessment of the QT Prolongation Potential of Non-anti-arrhythmic Drugs'. A preliminary concept paper for clinical testing entitled 'The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs' was recently issued by the Food and Drug Administration's Center for Drug Evaluation and Research, and Health Canada's Therapeutic Products Directorate. A similar preclinical draft counterpart described as the S7B document and entitled 'Note for guidance on safety pharmacology studies for assessing the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals' is under review at present, and should be finalized by the end of this year. This document provides guidelines on suitable levels and methods of preclinical testing in order to further determine the potential for a drug to produce QT prolongation. Developing a compound with a preclinical QT signal is not inconceivable, provided a carefully planned clinical development programme is adopted. However, millions of dollars in added research and development costs are at stake for such NCEs. These costs eventually compel sponsors to carefully assess which diseases can be targeted and/or medications can ultimately be developed despite the need for therapies. Once it is established that a drug has the potential to prolong the QTc interval at clinically relevant concentrations, a company must evaluate the approvability, labelling implications and consequent commercial fallout of such a NCE against the benefit of continuing development. Given these high hurdles, it is not inconceivable that several NCEs will not be developed. Ultimately, careful planning of clinical studies and making an integrated assessment of the risk/benefit ratio of a drug that prolongs the QT interval will weigh heavily upon its approvability, especially when the competitive landscape has compounds available with a better cardiac safety profile. Pharmaceutical companies are striving to improve the drug discovery/development process to identify, as early as possible, the risk of novel agents, or their metabolites, to cause QT interval prolongation and make appropriate go/no-go decisions or to modify their development programme accordingly. During the past decade, a number of non-cardiovascular drugs have had their label revised or have been withdrawn from the market because of unexpected post-marketing reports of sudden cardiac death associated with a prolongation of the QT interval, and an increased propensity to develop a ventricular tachyarrhythmia called Torsades de Pointes. Although a direct link between QT interval prolongation and arrhythmogenesis is still unclear, QT prolongation is now the subject of increased regulatory review and is considered a significant risk factor for predicting human safety of New Chemical Entities. Consequently, pharmaceutical companies are striving to improve the drug discovery and development process to identify, as early as possible, the risk of novel agents, or their metabolites, of causing QT interval prolongation and to make appropriate go/no-go decisions or modify their development programme accordingly.