The marketing authorization holder of terodiline has to be commended for the speed and the willingness with which the drug was withdrawn as soon as it became evident that the risk is unlikely to be immediately manageable.
DEVELOPMENT OF SINGLE
ENANTIOMERS OR METABOLITES OF MARKETED RACEMIC DRUGS
The
comparison between prenylamine and terodiline described in this chapter shows
the strengths of a scientific synthesis of all the available information when
evaluating the significance of even a handful of spontaneous reports of an
adverse event, and formu-lating the most appropriate regulatory strategies for risk
management. This is especially relevant when another member of the same
chemical, pharmacologic or therapeutic class is associated with the same low
frequency adverse event.
The
marketing authorization holder of terodiline has to be commended for the speed
and the willingness with which the drug was withdrawn as soon as it became
evident that the risk is unlikely to be immediately manageable. Unfortunately,
they did not follow up the recommendation from the regulatory assessor to
investigate separately the two enantiomers system-atically for their
pharmacology, and possibly develop one of these if it can be shown to be devoid
of potassium-channel-blocking activity while retaining a beneficial therapeutic
effect. In the light of subsequent investigations showing that − -(S)-terodiline does not affect the
QTc interval (Hartigan-Go et al.,
1996) and does indeed have some anticholinergic proper-ties, the possibility
that − -(S)-terodiline
might have a much superior risk–benefit profile compared to the racemic mixture
is a real one. At the time of its with-drawal in 1991, the development of a
single enan-tiomer may have appeared an arduous and potentially unrewarding
activity, but paradoxically this has been one of the striking features of new
drug develop-ment in the period 1994–2002. This trend has resulted in the
development of (S)-ketoprofen, (S)-ofloxacin, (S)-omeprazole, (R)-salbutamol,
(S)-citalopram and (S)-ketamine among many others that are still in the
pipeline (Shah, 2000).
It
is interesting that astemizole has two metabo-lites – desmethylastemizole and
norastemizole. Preclinical data show that desmethylastemizole is as cardiotoxic
as the parent drug. Since desmethylastem-izole has a very long half-life
relative to astemizole, plasma levels of desmethylastemizole are generally
about 30-fold higher than that of astemizole, and the clinically observed
cardiotoxicity appears to be mainly due to desmethylastemizole. In one patient
with astemizole-induced torsade de pointes, plasma desmethylastemizole and
astemizole concentrations were 7.7–17.3 ng/mL and < 0 5 ng/mL, respectively
(Volperian et al., 1996). Not
surprisingly, cardiotox-icity of astemizole is the highest following an
over-dose, or when a high loading dose is administered to quickly achieve the
steady-state therapeutic concen-trations (Anon, 1987). In both these
situations, there is rapid accumulation of desmethylastemizole. Findings such
as these not only preclude the development of some metabolites, but also
illustrate the strengths of simple observations that should guide the drug
devel-opment programme and evaluation of post-marketing case reports of adverse
drug reactions.
Development
of active but safer metabolites which are devoid of the unwanted secondary
cardiotoxic pharmacology, or unwanted metabolic profile and drug interaction
potential, has been another trend in drug development (Shah, 2005a).
Preclinical data have suggested that the risk–benefit ratio might be superior
for the metabolite compared to the corre-sponding parent drug for fexofenadine
(a metabo-lite of terfenadine), norcisapride (a metabolite of cisapride),
norastemizole (a metabolite of astemizole), desmethylloratadine (a metabolite
of loratadine) or norlevacetylmethadol (a metabolite of levacetyl-methadol).
These preclinical leads have already been followed up for some of these
metabolites, and fexofe nadine and desmethylloratadine are now already on the
market.
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