Both terodiline and prenylamine bear an uncanny resemblance in their pharmacokinetics.
PHARMACOKINETICS AND RECOMMENDED
DOSE SCHEDULES
Both
terodiline and prenylamine bear an uncanny resemblance in their
pharmacokinetics. Therefore, the dose schedules of the two drugs should be
scruti-nized in the context of wide inter-individual variability, their long
elimination half-lives and the potential to accumulate.
Prenylamine
is extensively metabolized in man by ring hydroxylation and further methylation
of the subsequent phenolic metabolites – its absolute bioavailability is
estimated to be 15% (Paar et al.,
1990). This metabolism displays wide inter-individual variation, with a
terminal elimination half-life of 14 1 ± 6 9 hours. Generally, the
steady-state plasma level was reached after 5–7 days, indicating that the terminal
half-lives of both the enantiomers of preny-lamine were in the region of 24
hours (Gietl et al., 1990). The time
to steady-state concentrations may be much longer in those who cannot eliminate
the drug effectively (see later). However, when first marketed, the standard
recommended dose of prenylamine for the majority of patients was 60 mg
three-times daily, which could be increased to 60 mg four- or five-times daily
in those patients who did not respond within 7 days of starting treatment.
Thus,
another area of concern in the re-development of terodiline should have been
its metabolic dispo-sition and its impact on dosing recommendations. Terodiline
is also extensively (85%) metabolized to a phenol, p-hydroxy-terodiline, and
there is wide inter-individual variation in its metabolism (Karlen et al., 1982; Hallen et al., 1994). Although p-hydroxy-terodiline
has a profile of pharmacological activity similar to that of racemic
terodiline, its potency is low. Even at steady state, this metabolite
constitutes only 10%–20% (about 0 05 μg/mL) of the terodiline steady-state
plasma level in man. These observations indicate that in man the contribution
of this metabo-lite to the anticholinergic effect observed in clinical studies
is minor (Hallen et al., 1990).
Following
their studies on the pharmacokinetics of terodiline in nine healthy volunteers
who were given (i) 12.5 mg intravenously and orally and (ii) 20 mg
intravenously and 25 mg orally, on two differ-ent occasions, Karlen et al. (1982) had concluded that the
long serum half-life of terodiline should permit its once-daily administration.
Side effects were often encountered at concentrations exceeding 0 6 μg/mL
(Andersson, 1984). The mean half-life of terodiline in the elderly is 131
(range 63–237) hours, in contrast to 57 (range 35–72) hours in young adults
(Hallen et al., 1989). Therefore, the
corresponding times to steady-state plasma levels would be 7–15 days in young
adults but 2–7 weeks in the elderly.
The
average steady-state serum concentrations on a 12.5 mg twice-daily dose are 0
238g/mL in healthy volunteers, and 0 518
μg/mL in geriatric patients. This concentration in the elderly, the main target
population for the use of terodiline, is close to the toxic concentration, and
yet the dose recommended for the elderly was 25 mg twice daily.
The
similarity to the inappropriate dosing recom-mendation for prenylamine is
self-evident. The dosing recommendations for prenylamine and terodiline have to
be seen in the context of their CYP2D6-mediated polymorphic metabolism, and the
potential for accu-mulation in those unable to effectively eliminate the
cardiotoxic enantiomers.
When
announcing its withdrawal, the marketing authorization holder of terodiline
advised prescribers to identify immediately all their patients being treated
with it, and to stop the drug as soon as practicable. They also cautioned
prescribers to bear in mind the long half-life of terodiline if alternative
anticholin-ergic treatment was considered, and recommended a washout period
that on average would be 2–3 weeks (but in some cases as long as 6 weeks).
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