Chemical formula: C₂₅H₃₀NO₃+ Molecular mass: 392.518 g/mol PubChem compound: 5284632
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.
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 occular accommodation. No effects on the central nervous system have so far been observed.
After oral administration of trospium chloride, maximum plasma levels are reached at 4-6 hours. Following a single dose of 20mg the maximum plasma level is about 4ng/ml. Within the tested interval, 20 to 60mg 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 is 9.6 ± 4.5% (mean value ± standard deviation). At steady state the intraindividual variability is 16%, the interindividual variability is 36%.
Compared to an immediate release formulation, trospium chloride 60 mg prolonged release formulation following multiple oral dosing resulted in a further reduction of peak exposure (Cmax) and relative overall systemic exposure (AUC) by approximately 28% and 33% respectively.
Oral administration (single and multiple dosing) of trospium chloride 60 mg prolonged release formulation as once daily dosing achieved maximum plasma levels of approximately 2 ng/ml and 1.9 ng/ml (Cmax) respectively. Time to maximum concentration (Tmax) was around 5 hrs with both preparations, whereas steady state concentration differed slightly resulting at day 8 by multiple dosing of the 60 mg prolonged release formulation.
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.
Administration of trospium chloride 60 mg prolonged release formulation concomitantly with or one hour before a high (50%) fat-content meal reduced the oral bioavailability of trospium chloride by 35% or 72% for AUC(0-Tlast) and by 60% or 81% for Cmax, respecitively. Other pharmacokinetic parameters such as Tmax and t½ were unchanged in the presence of food. Coadministration with antacid, however, had no effect on the oral bioavailability of trospium chloride 60 mg prolonged release formulation.
Pivotal proof of efficacy and safety in the approved indication was obtained by administering the compound on an empty stomach or at least one hour before a meal. Based on this mode of intake in the pivitol efficacy studies, it should be taken with water on an empty stomach at least one hour before a meal despite the food effect.
Protein binding ranged from 48 to 78%, depending upon the assessment method used, when a range of concentration levels of trospium chloride (0.5-100 μg/L) were incubated in vitro with human serum.
The ratio of 3H-trospium chloride in plasma to whole blood was 1.6:1. This ratio indicates that the majority of 3H-trospium chloride is distributed in plasma.
Trospium chloride is highly distributed to non-CNS tissues, with an apparent volume of distribution >600 L.
Of a trospium chloride dose absorbed following oral administration, metabolites account for approximately 40% of the excreted dose. The major metabolic pathway of trospium is hypothesized as ester hydrolysis with subsequent conjugation of benzylic acid to form azoniaspironortropanol with glucuronic acid. Cytochrome P450 does not contribute significantly to the elimination of trospium. Data taken from in vitro studies of 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.
The terminal elimination half-life was extended after multiple dosing of trospium chloride 60 mg prolonged release formulation to approximately 38,5 hours in comparison to about 20hrs after immediate release formulations. Most of the systemically available trospium chloride is excreted unchanged mainly by glomerular filtration and tubular secretion. A small portion (10% of the renal excretion) appears in the urine as spiroalcohol, a metabolite formed by ester hydrolysis.
Pharmacokinetic data in elderly patients suggests no major differences.
There are also no gender differences.
The pharmacokinetics of trospium chloride were not evaluated in the paediatric population.
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 studies have not been done on patients with renal impairment using the prolonged-release formulation of trospium chloride. Therefore, it is not recommended for patients with renal impairment.
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.
After a single dose of 40mg of the immediate-release formulation of trospium chloride given to patients with mild (Child-Pugh 5-6) and moderate to severe (Child-Pugh 7-12) hepatic impairment, Cmax was increased 12% and 63%, respectively, in comparison to healthy controls. The AUC was, however, decreased by 5% and 15%, respectively. Mean oral and mean renal clearance were 5% and 7% higher in subjects with mild and 17% and 51% higher in patients with moderate/severe hepatic impairment. Pharmacokinetic studies have not been done on patients with hepatic impairment using the prolonged-release formulation of trospium chloride.
Non-clinical data reveal no special hazard to humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.
Placental transfer and passage of trospium chloride into the maternal milk occurs in rats.
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