Pharmacokinetic Similarity To Prenylamine And Recommended Dose Schedules

Both terodiline and prenylamine bear an uncanny resemblance in their pharmacokinetics and the dose schedules of the two drugs should be scrutinised in the context of their elimination half-lives.

Prenylamine is extensively metabolised in man by ring hydroxylation and further methylation of the phenolic metabolites—its absolute bioavailability is estimated to be 15%. This metabolism displays wide inter-individual variation. The pharmaco-kinetics are enantioselective, favouring the elimination of the (+)-(S)-enantiomer (Geitl et al., 1990; Paar et al., 1990). The mean plasma half-lives after a single dose were 8.2 hours for the (—)-(R)-enantiomer and 24 hours for the (+)-(S)-enantio-mer. With chronic dosing, however, the mean half-lives for the (—)-(R)- and (+)-(S)-prenylamine in 8 volunteers were 13.7 and 17.4 hours respectively. The maximum plasma concentration and AUC (area under curve of plasma concentration vs. time) of the (—)-(R)-enantiomer were shown to exceed those of the ( + )-(S)-enantiomer by 4- to 5-fold— the apparent oral clearance of the (+)-(S)-form was 4.6-fold and the renal clearance 2.4-fold higher than that of the (—)-(R)-form.

Thus, another area of concern in the re-development of terodiline should have been its metabolic disposition. Terodiline is also extensively (85%) metabolised to a phenol, p-hydroxy-terodiline, which is as active as the parent compound. There is wide inter-individual variation in its metabolism (Karlen et al., 1982; Hallen et al., 1994).

The effects of racemic terodiline on isolated detrusor preparations from rabbit and man were compared with those of its (+)-(R)- and (—)-(S)-isomers, and with those of its main metabolite, p-hydroxy-terodiline (Andersson et al., 1988). It was concluded that (+)-(R)-terodiline is the main contributor of the detrusor effects of the racemate, and that a component of this activity is antic-holinergic in nature. p-Hydroxy-terodiline had a profile of pharmacological activity similar to that of racemic terodiline, but its potency was low. Since this metabolite is present in the plasma in low concentrations even at steady state (about 0.05 mg/mL), its contribution to the clinical effects of terodiline is probably small. The estimated potencies of the parent drug and the main metabolite and the fact that p-hydroxyterodiline constitutes only 10%-20% of the terodiline steady-state plasma level in man indicate that the contribution of this metabolite to the chronotropic effect observed in clinical studies is minor (Hallen et al., 1990).

In studies using human liver microsomes, the metabolism of terodiline at high concentrations has been shown to be stereoselective for the (+)-(R)-enantiomer (Noren et al., 1989) although, at steady state, the ratio of the concentrations of the two enantiomers at clinical doses is close to unity (Hallen et al., 1995).

The average steady-state serum concentrations on a 12.5 mg twice daily dose are 0.518 mg/mL in geriatric patients and 0.238 mg/mL in healthy volunteers. The mean half-lives of the drug are 57 (range 35-72) hours in young adults and 131 (range 63-237) hours in the elderly (Hallen et al., 1989). Therefore, the corresponding times to steady-state plasma levels would be 7-15 days in young adults and 2-7 weeks in the elderly.

Following their studies on the pharmacokinetics of terodiline in 9 healthy volunteers who were given (i) 12.5 mg intravenously and orally and (ii) 20 mg intravenously and 25 mg orally on two different occasions, Karlen et al. (1982) had concluded that the long serum half-life of terodi-line should permit its once daily administration. Side-effects were often encountered at concentrations exceeding 0.6 mg/mL (Andersson, 1984).

When announcing its withdrawal, the marketing authorisation holder of terodiline advised prescri-bers to identify immediately all their patients being treated with it and stop the drug as soon as practicable. They also cautioned the prescribers to bear in mind the long half-life of terodiline if alternative anticholinergic treatment was considered and recommended a washout period, which on average would be 2-3 weeks but in some cases as long as 6 weeks.

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