Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Urinary Antispasmodic, ATC code G04BD09.

Trospium chloride is a quaternary derivative of nortropane and therefore belongs to the class of parasympatholytic or anticholinergic drugs, as it competes concentration- dependently with acetylcholine, the body's endogenous transmitter at postsynaptic, parasympathic binding sites.
Trospium chloride binds with high affinity to muscarinic receptors of the so called M1-, M2- and M3- subtypes and demonstrates negligible affinity to nicotinic receptors.

Consequently, the anticholinergic effect of trospium chloride exerts a relaxing action on smooth muscle tissue and organ functions mediated by muscarinic receptors. Both in preclinical as well as in clinical experiments, trospium chloride diminishes the contractile tone of smooth muscle in the gastrointestinal and genito-urinary tract.

Furthermore, it can inhibit the secretion of bronchial mucus, saliva, sweat and the ocular accommodation. No effects on the central nervous system have so far been observed.

In two specific safety studies in healthy volunteers trospium chloride has been proven not to affect cardiac repolarisation, but has been shown to have a consistent and dose dependent heart rate accelerating effect.

A long term clinical trial with trospium chloride 20 mg bid found an increase of QT> 60 ms in 1.5% (3/197) of included patients. The clinical relevance of these findings has not been established.

Routine safety monitoring in two other placebo-controlled clinical trials of three months duration does not support such an influence of trospium chloride: In the first study an increase of QTcF >= 60 msec was seen in 4/258 (1.6%) in trospium-treated patients vs. 9/256 (3.5%) in placebo-treated patients.
Corresponding figures in the second trial were 8/326 (2.5%) in trospium-treated patients vs. 8/325 (2.5%) in placebo-treated patients.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

After oral administration of trospium chloride maximum plasma levels are reached at 4-6 hours. Following a single dose of 20 mg the maximum plasma level is about 4 ng/mL. Within the tested interval, 20 to 60 mg as a single dose, the plasma levels are proportional to the administered dose. The absolute bioavailability of a single oral dose of 20 mg of trospium chloride (1 coated tablet Trospium 20 mg) is 9.6 ± 4.5% (mean value ± standard deviation). At steady state the intra-individual variability is 16%, the inter-individual variability is 36%.

Simultaneous intake of food, especially high fat diets, reduces the bioavailability of trospium chloride. After a high- fat meal mean Cmax and AUC are reduced to 15-20% of the values in the fasted state.
Trospium chloride exhibits diurnal variability in exposure with a decrease of both Cmax and AUC for evening relative to morning doses.

Most of the systemically available trospium chloride is excreted unchanged by the kidneys, though a small portion (10% of the renal excretion) appears in the urine as the spiroalcohol, a metabolite formed by ester hydrolysis. The terminal elimination half-life is in the range of 10-20 hours. No accumulation occurs. The plasma protein binding is 50-80%.

Pharmacokinetic data in elderly patients suggests no major differences. There are also no gender differences.

In a study in patients with severe renal impairment (creatinine clearance 8-32 mL/min) mean AUC was 4-fold higher, Cmax was 2-fold higher and the mean half-life was prolonged 2-fold compared with healthy subjects.

Pharmacokinetic results of a study with mildly and moderately hepatically impaired patients do not suggest a need for dose adjustment in patients with hepatic impairment, and are consistent with the limited role of hepatic metabolism in the elimination of trospium chloride.

The Blood Brain Barrier permeability of trospium chloride is virtually absent due to its chemical properties (low lipophilicity as a quaternary amine).