Trosec
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Trosec - Scientific Information

Manufacture: Sunovion Pharmaceuticals Inc.
Country: Canada
Condition: Overactive Bladder, Urinary Incontinence
Class: Urinary antispasmodics
Form: Tablets
Ingredients: trospium chloride, calcium carbonate, carboxymethylcellulose sodium, carnauba wax, colloidal silicon dioxide, croscarmellose sodium, ferric oxide, lactose monohydrate, microcrystalline cellulose, polyethylene glycol 8000, povidone, stearic acid, sucrose, talc, titanium dioxide, wheat starch, white wax.

Pharmaceutical Information

Drug Substance

Proper name:Trospium chloride
Chemical name:Spiro[8-azoniabicyclo[3,2,1]octane-8,1'-pyrrolidinium]-3-[(hydroxydiphenyl-acetyl)-
oxy]-chloride(1α, 3β, 5α)-(9Cl)
Molecular formula and molecular mass:
Molecular formula:C25H30ClNO3Molecular mass:427.97
Structural formula:



Physicochemical properties:Trospium chloride is a white to almost white crystalline
powder
The compound=s solubility in water is approximately
1 g/2 mL.
n-Octanol/phosphate buffer (pH 7.4) = 0.038.
The molecule is hydrophilic and highly charged.4

Clinical Trials

Study demographics and trial design

TROSEC was evaluated for the treatment of patients with overactive bladder who had symptoms of urinary frequency, urgency, and urge incontinence in two US 12-week, placebo-controlled studies and one 9-month open label extension1, 2.

Study 11 was a randomized, double-blind, placebo-controlled, parallel-group study in 523 patients. A total of 262 patients received TROSEC 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.

Study 22 was nearly identical in design to Study 1. A total of 329 patients received TROSEC 20 mg twice daily and 329 patient 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.

Table 3 - Summary of patient demographics: Studies 1 and 2
Trial design Dosage (route) and
duration
Study subjects
(n=number)
Mean age
(Range)
Gender
Study 1Randomized, double-
blind, placebo-
controlled, parallel-
group plus open-label
treatment phase
TROSEC
20 mg bid (oral)



Placebo bid (oral)

12-week double-blind
treatment phase plus
9-month open-label
treatment phase
TROSEC: N =
262




Placebo: N = 261
61 yrs
(21-90 yrs)
134M/389F
Study 2Randomized, double-
blind, placebo-
controlled, parallel-
group
TROSEC
20 mg bid (oral)



Placebo bid (oral)

12-week double-blind
treatment phase
TROSEC: N =
329





Placebo: N = 329
61 yrs
(19-94 yrs)
122M/536F

M = male, F = female, yrs = years

Study results

Study 1

Reductions in urinary frequency, urge incontinence episodes and urinary void volume for placebo and TROSEC treatment groups are summarized in Table 4 and Figures 2 and 3.

Table 4: Mean (SE) change from baseline to end of treatment (Week 12 or last observation carried forward) for urinary frequency, urge incontinence episodes, and void volume in Study 1
Efficacy endpoint Placebo
N=256
TROSEC
N=253
P-value
Urinary frequency/24 hours a,*
Mean baseline12.912.7<0.001
Mean change from baseline-1.3 (0.2)-2.4 (0.2)
Urge incontinence episodes/week b,*
Mean baseline30.127.30.012
Mean change from baseline-13.9 (1.2)-15.4 (1.1)
Urinary void volume/toilet void
(mL) a, c
Mean baseline156.6155.1<0.001
Mean change from baseline7.7 (3.1)32.1 (3.1)

a Treatment differences assessed by analysis of variance for ITT:LOCF data set.

b Treatment differences assessed by ranked analysis of variance for ITT:LOCF data set.

c Placebo N=253, TROSEC N=248.

* Denotes co-primary endpoint.

ITT=intent-to-treat, LOCF=last observation carried forward.



Figure 2 - Mean Change from Baseline in Urinary Frequency/24 Hours, by Visit: Study 1



Figure 3 - Mean Change from Baseline in Urge Incontinence/Week, by Visit: Study 1

Study 2

Reductions in urinary frequency, urge incontinence episodes, and urinary void volume for placebo and TROSEC treatment groups are summarized in Table 5 and Figures 4 and 5.

Table 5: Mean (SE) change from baseline to end of treatment (Week 12 or last observation carried forward) for urinary frequency, urge incontinence episodes, and void volume in Study 2
Efficacy endpoint Placebo
N=325
TROSEC
N=323
P-value
Urinary frequency/24 hours a,*
Mean baseline13.212.9<0.001
Mean change from baseline-1.8 (0.2)-2.7 (0.2)
Urge incontinence episodes/week b
Mean baseline27.326.9<0.001
Mean change from baseline-12.1 (1.0)-16.1 (1.0)
Urinary void volume/toilet void
(mL) a, c
Mean baseline154.6154.8<0.001
Mean change from baseline9.4 (2.8)35.6 (2.8)

a Treatment differences assessed by analysis of variance for ITT:LOCF data set.

b Treatment differences assessed by ranked analysis of variance for ITT:LOCF data set.

c Placebo N=253, TROSEC N=248.

* Denotes co-primary endpoint.

ITT=intent-to-treat, LOCF=last observation carried forward.



Figure 4 - Mean Change from Baseline in Urinary Frequency/24 Hours, by Visit: Study 2



Figure 5 - Mean Change from Baseline in Urge Incontinence/Week, by Visit: Study 2

In addition to the placebo-controlled studies, active-controlled, randomized, double-blind, multicentre trials, ranging from 2 to 52 weeks in duration, compared trospium chloride to oxybutynin hydrochloride, in patients with detrusor instability or detrusor hyperreflexia. Trospium chloride had comparable efficacy to oxybutynin, but better tolerability5, 6.

Detailed Pharmacology

ANIMAL

Pharmacodynamics

Intravenous administration of trospium chloride to female rats produced marked inhibition of cholinergic spasms when acetylcholine was dripped onto the exteriorised bladder. Effects of trospium chloride have also been demonstrated on lower urinary tract functions in the dog.

Trospium chloride demonstrates high affinity for muscarinic receptors, with equipotent binding to M2 and M3 receptors (pKi values: 9.2 and 9.3)4.

Pharmacokinetics

Placental transfer and distribution in milk

Gestating rats were given 50 μg/kg 3H-trospium chloride by i.v. injection on the 10th, 16th and 20th day of gestation. Only small amounts of the hydrophilic trospium chloride crossed into the placenta. Trospium chloride concentrations in the placenta were similar to those in blood but lower than in the liver, kidneys and heart. The highest radioactivity concentrations in the fetal organs occurred in the livers.

The transfer of 3H-trospium chloride and its metabolites into the milk of lactating rats after oral and i.v. administration was determined between the 7th and 9th day postpartum. The percentage of i.v. injected trospium chloride activity excreted into the milk within 24 hours was 4.36 x 10-2. Generally, trospium chloride and azoniaspironortropanol (as the only metabolite) were present. After oral administration, the milk levels never exceeded the blood levels.

HUMAN

Pharmacokinetics

Absorption and bioavailability

Linear dependence of dose was established for PK parameters. Mean absolute bioavailabilities for oral doses of 20, 40, and 60 mg were 9.6%, 10.8%, and 12%, respectively, with an overall absolute bioavailability of 10.8%. Mean absorption rates for oral doses of 20, 40, and 60 mg were 14.6%, 13.2%, and 14.3%, respectively, with an overall absorption rate of 14% of dose. Cmax occurred approximately 5 hours post-dose, showing slow drug absorption.

Following 20 mg bid dosing for 6 days, trospium chloride plasma concentrations at steady-state on Day 6 were 1.56 ng/mL vs. 1.2 ng/mL following a single dose of 20 mg.

AUC and Cmax values were 70-80% lower under fed versus fasted conditions. 90% CIs for the PK parameters of AUC0-4 and Cmax fell outside the CI limits of acceptance. The CI for half value duration (HVD) slightly overlapped the CI limits of acceptance. Thus, the absorption of trospium chloride from the GI tract may be altered by concomitant food intake. Due to the food effects observed, it is recommended that TROSEC be taken on an empty stomach (see “DOSAGE AND ADMINISTRATION”).

Cmax and AUC values decreased up to 59% and 33%, respectively, when TROSEC was administered in the evening compared to in the morning. (See “ACTION AND CLINICAL PHARMACOLOGY”).

Distribution and protein binding

In plasma protein binding studies with human serum, binding rates between the range of approximately 48 to 78% over various concentration ranges were observed. These rates do not suggest any likely interference with other drugs. Competitive plasma protein binding is also unlikely due to low plasma concentration exposure at the therapeutic dose (<10 ng/mL after a single 40 mg dose).

The plasma to whole blood ratio of non-volatile 3H-trospium chloride was 1:6:1 at 0.75 hours post-dose (single i.v. target dose of 1 mg in healthy male subjects). Given that the normal hematocrit is approximately 45% in healthy men, the 1:6:1 ratio translates to a 12% distribution of 3H-trospium chloride in blood cells.

Metabolism and excretion

Trospium chloride has negligible inhibitory effects on seven cytochrome P450 isoenzymes, including CYP3A4 and CYPD26 based on in vitro data3.

After oral administration, 60% of the radioactivity excreted in urine was unchanged trospium, demonstrating first pass metabolism. The mean renal clearance rate observed (29.07 L/hour) indicates that trospium is actively secreted into the urine.

Following intravenously administered radio-labelled trospium chloride, more than 90% of the dose was recovered; approximately 70% in urine and 20% in faeces. Greater than 80% of the radioactivity excreted in urine was [3H]-trospium. The major metabolite, azoniaspironortropanol, represented approximately 10% of the excreted dose in urine. In addition, 2 unknown metabolites combined to represent less than 10% of the excreted dose.

Toxicology

Single-Dose Toxicity

In mice and rats, oral and i.v. dosing of trospium chloride produced similar effects.

The calculated LD50 for mice is 425 mg/kg oral and 7.5 mg/kg i.v. for males and 365 mg/kg oral and 8.4 mg/kg i.v. for females.

In rats, high oral doses (630 - 1260 mg/kg) produced clinical signs of hyperactivity, tremor, spasms, and tonoclonic convulsions after 10 minutes. After 1 hour, reduced activity was observed. During the first 24 hours of dosing, impaired coordination (males), postural abnormalities, diminished elicitation of reflexes (females), reduction in grip strength and tone of the extremities (females), changes in the colour of the skin and mucous membranes, piloerection (males) and lowered body temperature were observed. Death occurred within 24 hours after dosing. The LD50 calculated for rats is 940 mg/kg for males and 800 mg/kg for females [the maximum recommended daily dosing for humans is 40 mg (20 mg bid)]. Similar reactions were observed after i.v. administration, with additional effects of cyanosis and bradypnoea. The animals died within 5 minutes after injection. The calculated LD50 is 10.7 mg/kg for males and 12.3 mg/kg for females.

Repeat-Dose Toxicity

In rats dosed orally with 200 mg/kg trospium chloride for approximately 35 weeks, body weight gain was observed.

In dogs, food consumption and body weight gain were slightly lower after receiving 60 mg/kg for 26 weeks. Mydriasis with photophobia, impaired pupillary accommodation, corneal lesions as well as raised mucus production were also observed. One male died of bacterial bronchopneumonia, possibly due to a treatment-related increase of mucus secretion.

Genotoxicity

Trospium chloride was not genotoxic in a number of in-vitro assays such as the Ames test, mouse lymphoma test and mitotic gene conversion and chinese hamster ovary assays.

In an in-vivo micronucleus test in rats, trospium chloride did not induce significant levels of micronucleated polychromatic erythrocytes in bone marrow cells following administration of a single oral dose of 400 mg/kg.

Carcinogenicity

In a 78 week study in mice, body weight gain and intestinal distension similar to that seen in rats, described below, were observed. Increased lung adenomas in males (20 mg/kg) and females (2 mg/kg) were observed. The incidences of proliferative lung lesions were most likely due to chance and not an effect of trospium chloride.

In a 24-month rat study, there was a distinct reduction in body weight gain at a 200 mg/kg doses in males and females and in females only at 20 mg/kg. Bowel distension was observed in all treated groups. Trospium chloride did not increase the overall tumor incidence, and no tumor types were found that are uncommon in the rat strain used.

Reproductive and Developmental Toxicity

Reproductive function

In the rat, trospium chloride caused no impairment of male and female fertility in treated parents (Fo) or their untreated offspring. Furthermore, the breeding and rearing behaviour and the postnatal development were entirely normal throughout.

Trospium chloride was well tolerated by dams of trospium chloride treated rats and examination of the fetuses revealed no embryotoxic or teratogenic effects.

A test on rabbits showed no compound-specific effects in either dams or fetuses.

In female rats given trospium chloride from the 15th day of gestation until the end of the lactation period, .dose-related effects occurring at doses of 2, 20 and 200 mg/kg consisted of rapid and irregular breathing, pupillary dilatation and increased excitability. Towards the end of the lactation period, two females died within one hour of dosing (200 mg/kg). Rearing performance of the dams was normal, and only the females given 200 mg/kg gained slightly less body weight in the gestation period than the controls. The postnatal development of the offspring was invariably normal.

Local Tolerance

Good local (gastro-intestinal) tolerance has been shown in various long-term studies.