Trospium Chloride in the Treatment of Overactive Bladder: PHARMACOLOGY

In: Main

7 May 2010

Trospium chloride is a quaternary amine that antagonizes the effect of acetylcholine on muscarinic receptors in cholinergically innervated organs. It exhibits parasympatholytic action by reducing the detrusor tone of smooth muscle in the bladder as well as uncontrolled detrusor contractions that can cause OAB with incontinence.

Although the anticholinergic drugs that are currently used to treat OAB have antimuscarinic activity, their affinity to bind to muscarinic subreceptors is variable. Muscarinic receptor subtypes include M1, M2, M3, M4 M5; M2 and M3 are associated primarily with bladder activity in a ratio of 80 to 20, respectively. When compared with other agents, tro-spium exhibits a higher relative binding to all receptors and is the most equi-potent molecule at a ratio of M2:M3. Whereas anticholinergics inhibit M2 and M3 receptors associated with micturition, they also inhibit other muscarinic receptors associated with smooth muscle, secretory glands, bowel motility, ocular function, and the brain, producing unpleasant side effects.
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EFFICACY3 The Zinner Study

Patients who were 18 years of age or older and who had symptoms of OAB urge incontinence for at least six months were randomly assigned, in a ratio of 1:1, to receive 20 mg twice daily or matching placebo in a 12-week, multicenter, parallel, double-blind, placebo-controlled trial that was conducted at 51 sites. The outcome parameters in this study consisted of two primary efficacy variables: (1) the change in average number of toilet voids per 24 hours and (2) the change in the average number of urge incontinence episodes per 24 hours. The secondary efficacy variables included (1) the time from the baseline evaluation to the onset of the drug’s efficacy, (2) the average volume per void, (3) the average urgency (degree and frequency), and (4) the average number of diurnal and nocturnal voids (Table 2).

Table 2   Mean (SE) Change from Baseline to Week 12 for Study 1

Efficacy Endpoint Placebo (n = 256) Trospium Chloride (n = 253)

P Value

Urinary frequency per 24 hours Mean baseline Mean change from baseline 12.9-1.3 (0.2) 12.7-2.4 (0.2)

<.00l

Urge incontinence episodes per week Mean baseline Mean change from baseline 30.1 -13.9 (1.2) 27.3-15.4 (1.1)

<.0l2

Urinary void volume/toilet void (ml)* Mean baseline Mean change from baseline 154.6 9.4 (2.8) 154.8 35.6 (2.8)

<.00l

SE = standard error.* Placebo, n = 253; trospium chloride, n = 248.

Data from Sanctura™ prescribing information. Lexington, MA: Indevus Pharmaceuticals, Inc.3

The Indevus Urgency Severity Scale (IUSS) was used to measure urgency severity. This four-point validation scale allows patients to rate their urgency severity at each void. The scale ranged from 0 to 3, with 0 representing no urgency and 3 representing extreme urgency discomfort that abruptly stops all activity or tasks. Investigators concluded that patients taking 20 mg of tro-spium twice daily exhibited statistically significant improvements, compared with the placebo group, for the two primary efficacy variables as well as all secondary efficacy variables.

Another study that examined the effects of twice-daily trospium 20 mg used a similar design. The only difference between the two studies was the number of subjects enrolled in each. The results of this study are summarized in Table 3.

The Todorova Study

Todorova and colleagues conducted a phase 1, single-blind, randomized, placebo-controlled, four-arm, parallel-group clinical trial in 64 healthy, young male volunteers (18 to 35 years of age) to compare the potential CNS adverse effects of the three antimuscarinic drugs, oxybutynin, and trospium—with placebo. Subjects with clinically relevant acute or chronic diseases, a quantitative electroencephalogram (qEEG) outside of the normal range during screening, a history of headaches with qEEG abnormalities, poor EEG quality, laboratory values outside the normal range, positive drug tests, high blood pressure, or abnormal weight were excluded from the study.

Sixteen participants were assigned to receive one of the four trial medications administered in three successive doses every 5 hours:

  • placebo given three times a day
  • tolterodine 2 mg twice a day plus one placebo tablet
  • three times a day
  • trospium 15 mg three times a day

The objective measures used to assess the effects of each treatment group on the CNS included drug-induced changes in the qEEG of the participants during two different resting conditions and under mental demand. The study results showed that tolterodine and trospium did not induce changes of the qEEG power in five of six frequency bands, compared with placebo (10% confidence interval). Oxybutynin produced signifi cant power reductions in four frequency bands (P < .01) with a maximum effect one to two hours after administration, indicating that oxybutynin, which is a highly lipophilic tertiary amine, exerted distinct CNS effects.

Table 3 Mean (SE) Change from Baseline to Week 12 for Study 2

Efficacy Endpoint Placebo (n = 325) Trospium Chloride(n = 323)

P Value

Urinary frequency per 24 hours Mean baseline Mean change from baseline 13.2-1.8 (0.2) 12.9-2.7 (0.2)

<.00l

Urge incontinence episodes per week Mean baseline Mean change from baseline 27.3 -12.1 (1.0) 26.9-16.1 (1.0)

<.0l2

Urinary void volume/toilet void (ml)* Mean baseline Mean change from baseline 154.6 9.4 (2.8) 154.8 35.6 (2.8)

<.00l

SE = standard error.* Placebo, n = 320; trospium chloride, n = 319.

Data from Sanctura™ prescribing information. Lexington, MA: Indevus Pharmaceuticals, Inc.3

Although tolterodine is a tertiary amine, its lipophilicity is 30 times less than that of oxybutynin; therefore, its penetration into the blood-brain barrier is low. The effects of tolterodine on the CNS did not differ significantly from those of trospium, which has a minimal ability to cross the blood-brain barrier. The findings thus suggest that both of these drugs act primarily in the periphery. Therefore, because oxybutynin has more pronounced CNS effects, its use in geriatric patients may be inappropriate.

The Madersbacher Study

Madersbacher et al. conducted a randomized, double-blind, multicenter trial to compare the efficacy, tolerability, and ADEs of trospium with those of canadian oxybutynin HCl (Oxy). Ninety-five patients with spinal cord injuries and detrusor hyperreflexia were evaluated in this study. Individuals weighing more than 90 kg or who were younger than 18 years of age were excluded from the study. The study design consisted of a week without drugs and then two weeks of treatment with either trospium (20 mg twice daily) or Oxy (5 mg three times daily).

There were no statistically significant differences between the trospium and Oxy groups in terms of increasing maximum bladder capacity, compliance, and residual volume and decreasing maximum voiding detrusor pressure. However, the number of withdrawals from treatment and the number of reports of severe dry mouth were fewer for patients taking trospium than for those taking Oxy. Consequently, elderly patients who are more prone to dry mouth may benefit from taking tro-spium.


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