Sanctura (Trospium Chloride) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

Sanctura is an antispasmodic, antimuscarinic agent.

Trospium chloride antagonizes the effect of acetylcholine on muscarinic receptors in cholinergically innervated organs. Its parasympatholytic action reduces the tonus of smooth muscle in the bladder. Receptor assays showed that trospium chloride has negligible affinity for nicotinic receptors as compared to muscarinic receptors at concentrations obtained from therapeutic doses.

PHARMACODYNAMICS

Placebo-controlled studies employing urodynamic variables were conducted in patients with conditions characterized by involuntary detrusor contractions. The results demonstrate that Sanctura increases maximum cystometric bladder capacity and volume at first detrusor contraction.

PHARMACOKINETICS

Absorption:    After oral administration, less than 10% of the dose is absorbed. Mean absolute bioavailability of a 20 mg dose is 9.6% (range: 4.0-16.1%). Peak plasma concentrations (C_max) occur between 5 to 6 hours post-dose. Mean C_max increases greater than dose-proportionally; a 3-fold and 4-fold increase in C_max was observed for dose increases from 20 mg to 40 mg and from 20 mg to 60 mg, respectively. AUC exhibits dose linearity for single doses up to 60 mg. Sanctura exhibits diurnal variability in exposure with a decrease in C_max and AUC of up to 59% and 33%, respectively, for evening relative to morning doses.

Effect of Food:    Administration with a high fat meal resulted in reduced absorption, with AUC and C_max values 70-80% lower than those obtained when Sanctura was administered while fasting. Therefore, it is recommended that Sanctura should be taken at least one hour prior to meals or on an empty stomach. (See DOSAGE AND ADMINISTRATION and PRECAUTIONS: Information for Patients).

Distribution:    Protein binding ranged from 50 to 85% when therapeutic concentration levels (0.5 - 50 ng/mL) were incubated with human serum in vitro.

The³ H-trospium chloride ratio of plasma to whole blood was 1.6:1. This ratio indicates that the majority of³ H-trospium chloride is distributed in plasma. The apparent volume of distribution for a 20 mg oral dose is 395 (± 140) liters.

Metabolism:    The metabolic pathway of trospium in humans has not been fully defined. Of the 10% of the dose absorbed, metabolites account for approximately 40% of the excreted dose following oral administration. The major metabolic pathway is hypothesized as ester hydrolysis with subsequent conjugation of benzylic acid to form azoniaspironortropanol with glucuronic acid. Cytochrome P450 is not expected to contribute significantly to the elimination of trospium. In vitro data from human liver microsomes investigating the inhibitory effect of trospium on seven cytochrome P450 isoenzyme substrates (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4) suggest a lack of inhibition at clinically relevant concentrations of trospium.

Excretion:    The plasma half-life for Sanctura following oral administration is approximately 20 hours. After administration of oral¹⁴ C-trospium chloride, the majority of the dose (85.2%) was recovered in feces and a smaller amount (5.8% of the dose) was recovered in urine; 60% of the radioactivity excreted in urine was unchanged trospium.

The mean renal clearance for trospium (29.07 L/hour) is 4-fold higher than average glomerular filtration rate, indicating that active tubular secretion is a major route of elimination for trospium. There may be competition for elimination with other compounds that are also renally eliminated (See PRECAUTIONS: Drug Interactions).

A summary of mean (± standard deviation) pharmacokinetic parameters for a single 20 mg dose of Sanctura is provided in Table 1.

The mean plasma concentration-time (+ SD) profile for Sanctura is shown in Figure 1.

PHARMACOKINETICS IN SPECIAL POPULATIONS

Age:    Age did not appear to significantly affect the pharmacokinetics of Sanctura, however, increased anticholinergic side effects unrelated to drug exposure were observed in patients >/=75 years of age. (See PRECAUTIONS: Geriatric Use and DOSAGE AND ADMINISTRATION).

Pediatric:   

The pharmacokinetics of Sanctura were not evaluated in pediatric patients.

Gender:    Studies comparing the pharmacokinetics in different genders had conflicting results. When a single 40 mg Sanctura dose was administered to 16 elderly subjects, exposure was 45% lower in elderly females compared to elderly males. When 20 mg Sanctura was dosed BID for 4 days to 6 elderly males and 6 elderly females (60 to 75 years), AUC and C_max were 26% and 68% higher, respectively, in females without hormone replacement therapy than in males.

Race:    Pharmacokinetic differences due to race have not been studied.

Renal Insufficiency:    Severe renal impairment significantly altered the disposition of Sanctura. A 4.5-fold and 2-fold increase in mean AUC_0-(infinity) and C_max, respectively, and the appearance of an additional elimination phase with a long half-life (~33 hr) was detected in patients with severe renal insufficiency (CLcr < 30 mL/min) compared with healthy, nearly age-matched subjects. The different pharmacokinetic behavior of Sanctura in patients with severe renal insufficiency necessitates adjustment of dosage frequency. The pharmacokinetics of Sanctura have not been studied in people with moderate or mild renal impairment (CLcr ranging from 30-80 mL/min).(See PRECAUTIONS: General and DOSAGE AND ADMINISTRATION).

Hepatic Insufficiency:    There is no information regarding the effect of severe hepatic impairment on exposure to Sanctura. Maximum trospium concentration (C_max) increased 12% and 63% in subjects with mild and moderate hepatic impairment, respectively, compared to healthy subjects. Mean area under the plasma concentration-time curve (AUC) was similar. Caution should be used when administering Sanctura to patients with moderate and severe hepatic dysfunction. (See PRECAUTIONS: General).

DRUG-DRUG INTERACTIONS

No in vivo drug-drug interaction studies have been performed to assess the effect of concomitant medications on the pharmacokinetics of Sanctura or to assess the effect of Sanctura on the pharmacokinetics of other drugs. Sanctura is metabolized by esterases and excreted by the kidneys by a combination of tubular secretion and glomerular filtration. Based on in vitro data, no clinically relevant interactions with the metabolism of trospium are expected. However, drugs which are actively secreted may interact with trospium by competing for renal tubular secretion. (See PRECAUTIONS: Drug Interactions).

ELECTROPHYSIOLOGY

The effect of 20 mg BID and up to 100 mg BID Sanctura on QT interval was evaluated in a single-blind, randomized, placebo and active (moxifloxacin 400 mg QD) controlled 5 day parallel trial in 170 male and female healthy volunteer subjects aged 18 to 45 years. The QT interval was measured over a 24 hour period at steady state. The 100 mg BID dose of Sanctura was chosen because this achieves the C_max expected in severe renal impairment. Sanctura was not associated with an increase in individual corrected (QTcI) or Fridericia corrected (QTcF) QT interval at any time during steady state measurement, while moxifloxacin was associated with a 6.4 msec increase in QTcF.

In this study, asymptomatic, non-specific T wave inversions were observed more often in subjects receiving Sanctura than in subjects receiving moxifloxacin or placebo following five days of treatment. This finding was not observed during routine safety monitoring in 2 other placebo-controlled clinical trials in 591 Sanctura-treated overactive bladder patients (See CLINICAL STUDIES). The clinical significance of T wave inversion in this study is unknown. Sanctura is associated with an increase in heart rate that correlates with increasing plasma concentrations. In the study described above, Sanctura demonstrated a mean increase in heart rate compared to placebo of 9.1 bpm for the 20 mg dose and of 18.0 bpm for the 100 mg dose. In the two U.S. placebo-controlled trials in patients with overactive bladder, the mean increase in heart rate compared to placebo in Study 1 was observed to be 3.0 bpm and in Study 2 was 4.0 bpm.

CLINICAL STUDIES

Sanctura was evaluated for the treatment of patients with overactive bladder who had symptoms of urinary frequency, urgency, and urge incontinence in two U.S. 12-week, placebo-controlled studies and one 9-month open label extension.

Study 1 was a randomized, double-blind, placebo-controlled, parallel-group study in 523 patients. A total of 262 patients received Sanctura 20 mg twice daily and 261 patients received placebo. The majority of patients were Caucasian (85%) and female (74%) with a mean age of 61 years (range 21 to 90 years). Entry criteria required that patients have urge or mixed incontinence (with a predominance of urge), urge incontinence episodes of at least 7 per week, and greater than 70 micturitions per week. The patient's medical history and urinary diary during the treatment-free baseline confirmed the diagnosis. Reductions in urinary frequency, urge incontinence episodes and urinary void volume for placebo and Sanctura treatment groups are summarized in Table 2 and Figures 2 and 3.

Study 2 was nearly identical in design to Study 1. A total of 329 patients received Sanctura 20 mg twice daily and 329 patients received placebo. The majority of patients were Caucasian (88%) and female (82%) with a mean age of 61 years (range 19 to 94 years). Entry criteria were identical to Study 1. Reductions in urinary frequency, urge incontinence episodes, and urinary void volume for placebo and Sanctura treatment groups are summarized in Table 3 and Figures 4 and 5.