Drug-Induced QT Interval Prolongation and Regulatory Guidance

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Chapter: Pharmacovigilance: Withdrawal of Terodiline: A Tale of Two Toxicities

A number of drugs such as terfenadine, astemizole, pimozide and cisapride were found to induce torsade de pointes and other proarrhythmias following drug interactions.


DRUG-INDUCED QT INTERVAL PROLONGATION AND REGULATORY GUIDANCE

In view of the numerous high-profile, non-antiarrhythmic drugs which attracted considerable regulatory attention during the period 1990–96 due to their potential to prolong the QT interval and induce torsade de pointes, the Committee for Proprietary Medicinal Products (CPMP) adopted two significant documents in December 1997. One of these was the CPMP document ‘Points to Consider: The Assess-ment of the Potential for QT Interval Prolongation by Non-cardiovascular Medicinal Products’ (Anon, 1997a). The recommendations contained therein were not mandatory, but they represented preclinical and clinical strategies that the EU regulators advocated for the investigation of any new chemical entity (NCE) for its capability to prolong the QT interval and induce proarrhythmia. Following the regulatory concerns and the CPMP document, the European Society of Cardi-ology organized a Policy Conference on drug-induced QT interval prolongation under the auspices of its Committee for Scientific and Clinical Initiatives. This conference endorsed a more rigorous investigation of the preclinical electrophysiologic and clinical electro-cardiographic effects of new drugs (Haverkamp et al., 2000). A similar Expert Meeting in the United States, sponsored by the Duke Clinical Research Institute and American Heart Journal, also advocated a proactive approach to identifying this important risk (Anderson et al., 2002).

A number of drugs such as terfenadine, astemizole, pimozide and cisapride were found to induce torsade de pointes and other proarrhythmias following drug interactions. Therefore, the other strategic document adopted by the CPMP was its ‘Note for Guidance on the Investigation of Drug Interactions’ (Anon, 1997b).

Such is the regulatory concern on drug-induced QT interval prolongation that there has now evolved two internationally harmonized regulatory guidelines on strategies by which to evaluate new drugs for this liability. In May 2005, the ICH adopted two guide-lines that deal with this safety concern – one deal-ing with preclinical strategy (ICH S7B) and the other dealing with clinical strategy (ICH E14). While the focus of ICH S7B is on detecting delayed ventricular repolarization and QT interval prolongation, ICH E14 focusses on detecting QT/QT interval prolongation. At the time of writing this chapter, the Committee for Medicinal Products for Human Use (CHMP) of the EU had adopted (Step 5 of ICH) these guide-lines (ICH E14 as CHMP/ICH/2/04 and ICH S7B as CHMP/ICH/423/02) during their meeting in May 2005, with an operational implementation date of November 2005 (Anon, 2005a,b). Both the US Food and Drug Administration and the Japanese Ministry of Health, Labour and Welfare will notify later the dates for implementation of these guidelines within their jurisdictions. Both ICH S7B (preclinical) and ICH E14 (clinical) provide state-of-the-art recommen-dations on strategies for investigating a new drug for its potential to delay ventricular repolarization and induce QT interval prolongation.

Both the CPMP document ‘Points to Consider: The Assessment of the Potential for QT Interval Prolonga-tion by Non-cardiovascular Medicinal Products’ and the ICH guideline S7B provide recommendations on preclinical strategies by which to investigate a drug for its QT-liability. The core studies recommended by the ICH S7B guideline are in vitro IKr or hERG chan-nel studies, and in vivo investigations in dog or other laboratory animals such as monkey, swine, rabbit, ferret and guinea pig.

Both the CPMP document ‘Points to Consider: The Assessment of the Potential for QT Interval Prolonga-tion by Non-cardiovascular Medicinal Products’ and the ICH guideline E14 also provide recommendations on clinical strategies by which to investigate a drug for its potential to prolong the QT interval. Of special current interest is the call by ICH E14 for a single clinical trial, termed the ‘thorough QT/QTc study’, specifically dedicated to investigating the effect of an NCE on ECG parameters, with a special focus on QT interval (Anon, 2005b). This clinical guideline raises a number of important issues and will present signif-icant challenges during drug development.

The conduct of the ‘thorough QT/QTc study’, typi-cally in healthy volunteers, requires prior knowledge of the full pharmacology of the drug, as well as its potential therapeutic doses in man. Unfortunately, even today, the CYP isoform(s) responsible for the metabolism of terodiline has not been adequately identified, and the role of CYP2D6-mediated genetic factors remains a matter of informed speculation. It is also obvious that the pharmacokinetics and pharmacodynamics of each individual enantiomer of chirally active drugs should be fully investigated. Despite the known stereoselectivity in primary phar-macodynamics of terodiline enantiomers, little was investigated with respect to their cardiac effects, most particularly their electrophysiological effects at ion channels, and yet the techniques were available at the outset. In the absence of these vital data, it is impossible to predict special patient populations at risk, and the hazards from potential drug interac-tions. It is ironic that terodiline should have been withdrawn from the market in the year in which the CPMP adopted its guideline on ‘Clinical Investigation of Chiral Active Substances’ (Anon, 1993b; Shah, Midgley and Branch, 1998).

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