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Antimuscarinic Efficacy and Predictability in Overactive Bladder

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

MEDICAL FRONTIERS - International Continence Society / International Urogynecological Association (ICS/IUGA)

Toronto, Ontario / August 23-27, 2010

As discussed here at the scientific sessions by Dr. Pamela Ellsworth, Associate Professor of Urology and Surgery, Brown University, Providence, Rhode Island, symptoms of overactive bladder (OAB) disrupt an individual’s activities of daily living throughout the day until they go to bed and then on throughout the night. “From a physical standpoint, OAB symptoms limit physical activities and in the workplace, there is no question that symptoms limit productivity and are associated with absences from work,” she added.

Frequent nighttime micturitions have been associated with poor sleep quality and OAB symptoms have also been linked with depression. Indeed, in one survey, two-thirds of patients with OAB reported that symptoms had a negative impact on health-related quality of life, including mobility and self-care, “so there is no question that this condition has a significant impact not only on the patient but also on family and significant others,” Dr. Ellsworth told delegates.

Exploring the Persistence/Efficacy Relationship

Although clinical studies have demonstrated that the antimuscarinics (AMs) are reasonably effective, safe and well-tolerated, the day-to-day clinical experience suggests that patients are frequently dissatisfied with their medication and switching to an alternative AM is not uncommon.

In a study conducted by Dr. Ramandeep Basra, Guy’s and St Thomas’ NHS Foundation Trust, London, UK, and colleagues, persistence rates with AM therapy drop with each successive switch of therapy. With 133 patients completing the first year of follow-up and 68 the second year, persistence with the first-, second- and third-line drugs was 17.2 weeks, 13.2 weeks and 7.6 weeks, respectively.

The first-line agents used in the two centres taking part in the study were solifenacin and tolterodine ER; alternatively, tolterodine IR, oxybutynin transdermal IR and ER, and darifenacin were prescribed. “Drug-related side effects accounted for <50% of the discontinuation of the first-line agent,” Dr. Basra reported, “and changes in medication may be associated with loss of faith in the validity of treatment, less willingness to try an alternative and dissatisfaction with treatment overall. [Since] most patients [in this study] used only a single agent for OAB, the first medication may be the most important in patients’ adherence in medical treatment of OAB.”

With efficacy influenced by persistency, Dr. David Castro-Díaz, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain, and multicentre colleagues sought to determine reasons motivating treatment switch. Some 2038 patients reporting OAB symptom scores of =8 on the 8-item validated OAB questionnaire who had changed their OAB treatment within 3 to 4 months prior to study entry were surveyed. Reasons for the last treatment change included lack of efficacy (60%); adverse effects (AEs) (24%); patient request (8%); lack of adherence (6%); and other (2%). Overall, treatment change was mostly initiated by physicians (69% of the time), especially specialists (96%), while 31% of the time patients requested the change in treatment.

Dr. Scott MacDiarmid, Director, Bladder Control and Pelvic Pain Center, Wake Forest University, Winston-Salem, North Carolina, concurred with these results and stated, “The number 1 reason that patients stop taking AMs as a drug class is because they didn’t work well enough.” In one survey of OAB patients (Figure 1), for example, almost half (46%) reported they stopped taking their medication because “it didn’t work as expected.” However, it appears physicians are undertreating OAB. “Even among patients who are currently on an OAB drug, if we took the ones who are not 100% better and switched them to a new medication or added behavioural therapy or dose-escalated, we would make them better but we are not actually doing this,” Dr. MacDiarmid added. Noting that efficacy is the most important attribute of any AM because efficacy is what matters most to patients, a more effective treatment strategy may represent a significant step forward in the treatment of OAB.

Figure 1.


Efficacy, Dosing and Formulation

In clinical practice, determining and initiating the optimal dose to control OAB symptoms may be difficult. While titrating may be the proper strategy in many circumstances, delay in a significant response while AEs emerge might reduce compliance as patients expect rapid and effective treatment.

A retrospective analysis of 1059 patients with symptoms of OAB for =6 months demonstrated that treatment with darifenacin 7.5 mg or 15 mg reduced bothersome OAB symptoms as early as week 2. However, greater improvement was observed in the higher dose. For example, on days 6 to 8, the absolute median difference in incontinence episodes, micturitions/day and urgency episodes/day was -0.5, -0.5 and -0.9 for the higher dose vs. -0.2, -0.3 and -0.5 for the lower dose, respectively (Abstract 620). From this study, it appears that initial dosage can affect the extent and depth of efficacy.

Another AM that has proven to be effective in OAB patients is tolterodine, available in IR and ER formulations of 2- and 4-mg doses. The ER formulation was developed with an improved tolerability profile over the IR formulation. In an analysis of a regional managed care plan, D’Souza et al. demonstrated that adherence was significantly better for ER than IR agents (J Manag Care Pharm 2008;14(3):291-301). In a naturalistic setting, Peeker et al. reported that tolterodine ER provided clinically significant improvement in OAB symptoms and self-perceived health-related quality of life over the 6 months of their observational study (Scand J Urol Nephrol 2010;44(3):138-46).

Building on Predictability

Tolterodine is a well-studied and widely-used AM. Upon oral administration, it is converted to 5-HMT primarily via cytochrome P450 (CYP) 2D6. A significant fraction of unconverted drug is found in plasma; thus, the ratio of tolterodine to 5-HMT varies, depending on the CYP 2D6 metabolizer status of the patient, which is genetically determined. Both tolterodine and 5-HMT have potent AM activity.

An emerging option in OAB treatment is fesoterodine, a prodrug to 5-HMT which undergoes a simple and extensive conversion into its active metabolite. Following oral dosing, the prodrug is undetectable in plasma, suggesting full conversion into 5-HMT, making its pharmacokinetic/pharmacodynamic profile highly predictable. According to speakers here, from a clinical standpoint, this subsequently translates into more predictable efficacy for OAB patients. It has been developed as a 4- and 8-mg modified-release formulation and has been evaluated in a phase III randomized, double-blind, placebo-controlled trial and compared to tolterodine ER 4 mg in 2 other trials.

A Review of Results

Dr. MacDiarmid reminded delegates that the primary end point of the European registration study of fesoterodine by Chapple et al. (Eur Urol 2007;52:1204-12) was reduction in urgency urinary incontinence (UUI). It was given at 4 and 8 mg and was compared with placebo. At baseline, patients were experiencing a mean of 4 UUI episodes/day.

At the end of 12 weeks, the median per cent reduction in UUI was 87.5% in the 8-mg arm, 80% in the 4-mg arm and 50% among placebo controls (Figure 2). “[The] 4-mg and 8-mg [arms] statistically outperformed placebo at all time points as well as at 2, 8 and 12 weeks,” Dr. MacDiarmid reported. He told delegates that US trial data “were essentially superimposable on data from the European trial, where the median per cent reduction in UUI was 82% with fesoterodine 8 mg in the US trial.”

As expected with AMs, the pooled analysis of the phase III studies showed that dry mouth was more common at 35% with 8 mg compared with 19% for the 4-mg dose. Constipation rates were not much higher at 6% for the higher dose compared with 4% for the 4-mg dose and 2% for placebo. No central nervous system (CNS) side effects were observed in either of these studies.

All patients who finished the phase III trials were asked to enter into open-label extensions where they received the 8-mg dose only. At a mean duration of 23 months, “71% of patients who started on 8 mg remained on 8 mg,” observed Dr. MacDiarmid, “and… there were no outliers in terms of tolerability or safety.”

Two comparative studies were then initiated in which fesoterodine 4 mg escalated to 8 mg after 1 week was compared to tolterodine ER 4 mg. Treatment continued for a total of 12 weeks. The primary end point was change from baseline to week 12 in UUI episodes; a number of other end
red.

Figure 2.

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In both studies, fesoterodine 8 mg was significantly more efficacious than tolterodine ER 4 mg. In both studies, about two-thirds of patients taking fesoterodine reported they were dry over a 3-day diary period (Figure 3)—“and if you can get a 63% dry rate in patients with 2 leaks a day at baseline, I find that is good data,” Dr. MacDiarmid remarked.

A summary of all bladder diary variables in both studies also indicated greater efficacy on the majority of end points, including quality of life based on OAB questionnaire scores. Dry mouth rates with tolterodine were lower at roughly 15% in both studies vs. about 27% for fesoterodine but rates of severe dry mouth were similar, ranging from 0.1 to 1% for tolterodine vs. 1 to 2% for fesoterodine 8 mg.

“I think the efficacy of fesoterodine is very robust, especially for the 8-mg dose, and I think this data will allow us to better individualize treatment for pa
sensitivity to the drug,” Dr. MacDiarmid concluded.

Figure 3.

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Summary

Symptoms of OAB are distressing for most patients and diminish quality of life. AMs have long been the pharmacological mainstay in OAB but patients often discontinue treatment because of lack of efficacy and side effects. Selecting an AM that is most likely to lead to symptom control the first time is an important component of OAB strategy as patients are more likely to persist with treatment. While tolterodine ER is an established effective treatment in OAB, the prodrug fesoterodine exhibits a highly predictable pharmacokinetic/pharmacodynamic profile. This, combined with the availability of a more efficacious 8-mg dose, will make it a welcome complement to better tailor treatment and optimize the likelihood of a promising outcome.

Questions and Answers

The following section is based on discussions during the scientific sessions with Dr. Pamela Ellsworth, Associate Professor of Urology and Surgery, Brown University, Providence, Rhode Island; and Prof. Martin Michel, Professor of Pharmacology and Pharmacotherapy, University of Amsterdam, The Netherlands.

Q: In the fesoterodine flexible-dose studies, how did outcomes compare between those who chose to go up to the 8-mg dose and those who stayed on the 4-mg dose?

Dr. Ellsworth: Those who chose to dose-escalate [to 8 mg after 1 week] had a lower response at week 2 than those who did not but at 12 weeks, we saw a dramatic improvement in the former group and outcomes were comparable to those who chose to stay on the 4-mg dose. So this highlights the fact that this is a diverse patient population and some patients truly require more drug.

Q: What is the rationale for uptitrating rather than downtitrating from the more effective dose?

Prof. Michel: First of all, you do not expose patients who do not need the higher dose to unnecessary [AEs]. In addition, the body is amazingly able to compensate in response to drug therapy, which means that if we start at a lower dose, these compensations may kick in and the higher dose may be better tolerated [later] than if you give the high dose right away.

Q: What is the impact of fesoterodine on cognitive function, particularly if elderly patients have to be on long-term therapy?

Dr. Ellsworth: No data are available for cognitive function and for CNS effects, there are no red flags with this drug compared with placebo.

Note: At time of printing, fesoterodine is not available in Canada.

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