Tolterodine

Abstract

Tolterodine is a competitive muscarinic receptor antagonist that shows in vivo selectivity for the bladder over the salivary glands compared with oxybutinin. Results of randomised double-blind placebo-controlled studies indicate that tolterodine 4 mg/day (administered as immediate-release tablets 2mg twice daily or extended-release capsules 4mg daily) is superior to placebo in improving micturition diary variables in patients with overactive bladder. Moreover, tolterodine 2mg twice daily is as effective as oxybutynin 5mg 3 times daily. Maximum treatment effects with both drugs occurred after 5 to 8 weeks of treatment and improvements were maintained during long term treatment for up to 24 months. In a pooled analysis of four 12-week studies, equivalent and significant reductions in micturition frequency (−2.3 and −2.0 vs −1.4, p < 0.001) and the incidence of urge incontinence episodes (−1.6 and −1.8 vs −1.1, p < 0.05) were reported for tolterodine 2mg twice daily and oxybutynin 5mg 3 times daily compared with placebo. Functional bladder capacity was also significantly increased. Improvements in patient perceptions of their urgency symptoms and of problems caused by their bladder condition were significantly greater during treatment with tolterodine than with placebo. Tolterodine was generally well tolerated in clinical trials of up to 24 months’ duration. Dry mouth was the most frequent adverse event. The incidence (40 vs 78%, p < 0.001) and intensity of this event was lower with tolterodine 2mg twice daily than oxybutynin 5mg 3 times daily. Additionally, a 23% lower incidence of dry mouth was reported with once daily extended-release tolterodine capsules than with twice daily immediate-release tablets (p < 0.02). The incidence of adverse CNS events with tolterodine was low and similar to that of placebo. Tolterodine was well tolerated in elderly patients and no serious tolerability concerns were identified. Conclusions: Tolterodine is the first antimuscarinic agent to be specifically developed for the treatment of overactive bladder. The functional selectivity of tolterodine for the bladder translates into good efficacy and tolerability in patients, including the elderly, with overactive bladder. Tolterodine is as effective as oxybutynin in improving micturition diary variables but is associated with a significantly lower incidence and intensity of dry mouth. This favourable tolerability profile, together with sustained clinical efficacy during long term treatment, places tolterodine as a valuable treatment for the symptoms of overactive bladder. Tolterodine and its active 5-hydroxymethyl metabolite (5-HM) are potent and competitive muscarinic receptor antagonists and share a similar pharmacological profile. Neither compound showed specificity for any particular muscarinic receptor subtype in radioligand-binding studies. Tolterodine and oxybutynin are equipotent muscarinic receptor antagonists in vitro. Carbachol-induced contractions of guinea-pig urinary bladder strips and nerve-mediated contractions of isolated human detrusor preparations were inhibited to a similar extent by tolterodine and oxybutynin. Tolterodine and 5-HM show functional selectivity for the bladder over the salivary glands in vivo compared with oxybutinin. In the anaesthetised cat, intravenous tolterodine and 5-HM produced more effective inhibition of acetylcholine-induced bladder contraction than of electrically-evoked salivation. In contrast, oxybutynin showed the opposite selectivity profile. In clinical studies involving healthy volunteers, tolterodine inhibited urodynamic bladder function, had a longer duration of effect on the bladder than on the salivary glands and a greater magnitude of effect on bladder function than on visual accommodation. The pharmacodynamic effects of tolterodine were not generally influenced by metabolic phenotype. The pharmacokinetic properties of tolterodine are influenced by cytochrome P450 (CYP) 2D6 polymorphism. In individuals lacking this enzyme, described as poor metabolisers, the active metabolite 5-HM cannot be formed and pharmacological effects are mediated by tolterodine alone. In contrast, the pharmacologically active moiety is represented by the sum of unbound tolterodine and 5-HM in extensive metabolisers. Nevertheless, the same dosage can be used irrespective of CYP2D6 phenotype as exposure to pharmacologically active moiety is comparable for the two subgroups. Tolterodine is rapidly absorbed after oral administration of the immediate-release tablet formulation, reaching peak serum levels (C_max) within 1 to 2 hours (t_max) in healthy volunteers. The effective exposure to tolterodine is unaffected by the presence of food. Tolterodine is extensively bound to plasma proteins (3.7% remaining unbound), whereas 36% of 5-HM exists as free drug. Pharmacokinetic equivalence was demonstrated between a once daily extended-release capsule formulation of tolterodine 4mg and (immediate-release) tolterodine tablets 2mg twice daily. However, serum drug levels fluctuated less with the former preparation as evinced by median C_max values of the active moiety that were around 75% of that observed with the twice-daily tablet formulation whereas minimum serum concentrations were 1.5-fold higher. The extended-release capsule formulation shows no evidence of ‘dose-dumping’ when administered with meals. Tolterodine undergoes extensive first-pass hepatic metabolism, predominantly via CYP2D6-mediated oxidation and CYP 3A4-mediated N-dealkylation. With the exception of 5-HM, metabolites of tolterodine are not considered to contribute to the therapeutic effect. Tolterodine (immediate-release tablets) has a mean systemic clearance of 44 L/h and an elimination half-life of 1.9 to 3.6 hours in extensive metabolisers. In poor metabolisers,...