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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