Pharmacokinetics and Recommended Dose Schedules

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).