Despite the fact that QT interval is not a very reliable surrogate of torsade de pointes, it is neverthe-less true that drugs that prolong QT interval are considered more likely to cause torsade de pointes in susceptible patients than drugs that do not.
RISK–BENEFIT ASSESSMENT
Despite
the fact that QT interval is not a very reliable surrogate of torsade de
pointes, it is neverthe-less true that drugs that prolong QT interval are
considered more likely to cause torsade de pointes in susceptible patients than
drugs that do not. There-fore, QT interval prolongation has been used in
distin-guishing safer drugs from those that are less safe within the same
class. Not surprisingly, regulatory authorities are reluctant to approve drugs
that prolong the QT interval when the potential benefits are very modest, and
especially when alternatives without the QT-liability are already available.
For example, ebas-tine (a non-sedating H1-antihistamine) has not
been approved in the United States because of its abil-ity to prolong the QT
interval, although there are no documented reports of torsade de pointes
associated with its extensive use elsewhere. The reason is almost certainly the
availability of alternatives without such a liability. However, it should not
be assumed that just because a drug prolongs the QT interval, it might not be
approvable.
A
number of factors determine whether drugs that prolong the QT interval can be
approved, particularly because the QT-liability of a drug does not neces-sarily
translate into a proarrhythmic activity (Shah, 2002; 2004). In contrast to ebastine,
drugs such as ziprasidone or arsenic trioxide that prolong the QT interval to a
much greater extent have nevertheless been approved, because they were
considered to have an acceptable risk–benefit profile. Arsenic trioxide
illustrates particularly well how even a drug with very marked potential to
prolong the QT interval, and actu-ally induce torsade de pointes, may be
approved with specific guidelines associated with its clinical use, if it is
shown to fulfil an unmet need. Arsenic triox-ide (‘Trisenox’) was approved in
September 2000 in the United States and in October 2001 in the EU for its
remarkable efficacy in induction of remission and consolidation in patients
with a specific form of acute promyelocytic leukaemia who are refractory to, or
have relapsed from, retinoid and anthracycline chemotherapy. Protease
inhibitors are another class of drugs that block hERG, prolong the QT interval
and induce torsade de pointes (Anson et
al., 2005). However, their clinical benefits far outweigh their very small
proarrhythmic risk.
With
respect to risk–benefit analysis of a drug that actually induces torsade de
pointes and other ventric-ular tachyarrhythmias, the benefit offered by the new
drug merits very careful assessment. Furthermore, the risk of torsade de
pointes is not an ‘all-or-none’ effect. Depending on the benefit offered by the
drug, an inci-dence of 1 in 3000 might be unacceptable whereas an incidence of
1 in 500 000 may be considered acceptable with a whole range of risk–benefit in
between. As stated earlier, risk–benefit analysis in drug development and the
regulatory approval process includes not only the alternatives already
available, but also the seriousness of the condition under treat-ment. For
relatively benign indications such as hay fever or gastroparesis, a risk of
proarrhythmias even as low as 1 in 100 000 recipients is unlikely to be
acceptable.
Related Topics
TH 2019 - 2024 pharmacy180.com; Developed by Therithal info.