Chemical formula: C₁₉H₂₂NO₄S₂ Molecular mass: 392.512 g/mol PubChem compound: 5487427
Tiotropium bromide is a long-acting, specific antagonist at muscarinic receptors. It has similar affinity to the subtypes, M1 to M5. In the airways, tiotropium bromide competitively and reversibly binds to the M3 receptors in the bronchial smooth musculature, antagonising the cholinergic (bronchoconstrictive) effects of acetylcholine, resulting in bronchial smooth muscle relaxation. The effect was dose dependent and lasted longer than 24h. As an N-quaternary anticholinergic, tiotropium bromide is topically (broncho-) selective when administered by inhalation, demonstrating an acceptable therapeutic range before systemic anticholinergic effects may occur.
The dissociation of tiotropium from especially M3-receptors is very slow, exhibiting a significantly longer dissociation halflife than ipratropium. Dissociation from M2-receptors is faster than from M3, which in functional in vitro studies, elicited (kinetically controlled) receptor subtype selectivity of M3 over M2. The high potency, very slow receptor dissociation and topical inhaled selectivity found its clinical correlate in significant and long-acting bronchodilation in patients with COPD and asthma.
In a dedicated QT study involving 53 healthy volunteers, SPIRIVA 18 mcg and 54 mcg (i.e. three times the therapeutic dose) over 12 days did not significantly prolong QT intervals of the ECG.
Tiotropium bromide is a non-chiral quaternary ammonium compound and is sparingly soluble in water.
Tiotropium bromide is administered by dry powder inhalation. Generally with the inhaled route of administration, the majority of the delivered dose is deposited in the gastro-intestinal tract, and to a lesser extent in the intended organ of the lung. Many of the pharmacokinetic data described below were obtained with higher doses than recommended for therapy.
Tiotropium bromide is also available as inhalation solution administered by the Respimat inhaler. Approximately 40% of the inhaled dose is deposited in the lungs, the target organ, the remaining amount being deposited in the gastrointestinal tract. Some of the pharmacokinetic data described below were obtained with higher doses than recommended for therapy.
Following dry powder inhalation by young healthy volunteers, the absolute bioavailability of 19.5% suggests that the fraction reaching the lung is highly bioavailable. Oral solutions of tiotropium have an absolute bioavailability of 2-3%. Maximum tiotropium plasma concentrations were observed 5-7 minutes after inhalation.
At steady state, peak tiotropium plasma levels in COPD patients were 12.9 pg/ml and decreased rapidly in a multi-compartmental manner. Steady state trough plasma concentrations were 1.71 pg/ml. Systemic exposure following the inhalation of tiotropium via the HandiHaler device was similar to tiotropium inhaled via the Respimat inhaler.
Following inhalation by young healthy volunteers, urinary excretion data suggests that approximately 33% of the inhaled dose reaches the systemic circulation. Oral solutions of tiotropium bromide have an absolute bioavailability of 2-3%. Food is not expected to influence the absorption of this quaternary ammonium compound.
Maximum tiotropium plasma concentrations were observed 5-7 minutes after inhalation.
At steady state, peak tiotropium plasma levels in COPD patients of 10.5 pg/ml were achieved and decreased rapidly in a multi-compartmental manner. Steady state trough plasma concentrations were 1.60 pg/ml.
A steady state tiotropium peak plasma concentration of 5.15 pg/ml was attained 5 minutes after the administration of the same dose to patients with asthma.
Systemic exposure to tiotropium following the inhalation of tiotropium via the Respimat inhaler was similar to tiotropium inhaled via the HandiHaler device.
Tiotropium has a plasma protein binding of 72% and shows a volume of distribution of 32 L/kg. Local concentrations in the lung are not known, but the mode of administration suggests substantially higher concentrations in the lung. Studies in rats have shown that tiotropium bromide does not penetrate the blood-brain barrier to any relevant extent.
The extent of biotransformation is small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers. The ester tiotropium bromide is nonenzymatically cleaved to the alcohol (N-methylscopine) and acid compound (dithienylglycolic acid) that are inactive on muscarinic receptors. In-vitro experiments with human liver microsomes and human hepatocytes suggest that some further drug (<20% of dose after intravenous administration) is metabolised by cytochrome P450 (CYP) dependent oxidation and subsequent glutathion conjugation to a variety of Phase II-metabolites.
In vitro studies in liver microsomes reveal that the enzymatic pathway can be inhibited by the CYP 2D6 (and 3A4) inhibitors, quinidine, ketoconazole and gestodene. Thus CYP 2D6 and 3A4 are involved in metabolic pathway that is responsible for the elimination of a smaller part of the dose. Tiotropium bromide even in supra-therapeutic concentrations does not inhibit CYP 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A in human liver microsomes.
The effective half-life of tiotropium ranges between 27–45 h following inhalation by healthy volunteers and COPD patients. The effective half-life was 34 hours in patients with asthma. Total clearance was 880 ml/min after an intravenous dose in young healthy volunteers. Intravenously administered tiotropium is mainly excreted unchanged in urine (74%).
After dry powder inhalation by COPD patients to steady-state, urinary excretion is 7% (1.3 μg) of the unchanged drug over 24 hours, the remainder being mainly non-absorbed drug in gut that is eliminated via the faeces. The renal clearance of tiotropium exceeds the creatinine clearance, indicating secretion into the urine.
After inhalation of the solution by COPD patients to steady-state, urinary excretion is 18.6% (0.93 µg) of the dose, the remainder being mainly non-absorbed drug in gut that is eliminated via the faeces. After inhalation of the solution by healthy volunteers urinary excretion is 20.1-29.4 % of the dose, the remainder being mainly non-absorbed drug in gut that is eliminated via the faeces.
In patients with asthma, 11.9% (0.595 µg) of the dose is excreted unchanged in the urine over 24 hours post dose at steady state. The renal clearance of tiotropium exceeds the creatinine clearance, indicating secretion into the urine.
After chronic once daily inhalation by COPD patients, pharmacokinetic steady-state was reached by day 7 with no accumulation thereafter.
Tiotropium demonstrates linear pharmacokinetics in the therapeutic range independent of the formulation.
As expected for all predominantly renally excreted drugs, advancing age was associated with a decrease of tiotropium renal clearance (365 mL/min in COPD patients <65 years to 271 mL/min in COPD patients ≥65 years) This did not result in a corresponding increase in AUC0-6,ss or Cmax,ss values. Exposure to tiotropium was not found to differ with age in patients with asthma.
Following once daily inhaled administrations of tiotropium to steady-state in COPD patients, mild renal impairment (CLCR 50-80 ml/min) resulted in slightly higher AUC0-6,ss (between 1.8 – 30% higher) and similar Cmax,ss values compared to patients with normal renal function (CLCR >80 ml/min).
In COPD patients with moderate to severe renal impairment (CLCR <50 ml/min), the intravenous administration of tiotropium resulted in doubling of the total exposure (82% higher AUC0-4h) and 52% higher Cmax) compared to COPD patients with normal renal function, which was confirmed by plasma concentrations after dry powder inhalation.
In asthma patients with mild renal impairment (CLCR 50-80 ml/min) inhaled tiotropium did not result in relevant increases in exposure compared to patients with normal renal function.
Liver insufficiency is not expected to have any relevant influence on tiotropium pharmacokinetics. Tiotropium is predominantly cleared by renal elimination (74% in young healthy volunteers) and simple non-enzymatic ester cleavage to pharmacologically inactive products.
In cross trial comparison, mean peak tiotropium plasma concentrations 10 minutes post-dosing at steady-state were 20% to 70% higher in Japanese compared to Caucasian COPD patients following inhalation of tiotropium but there was no signal for higher mortality or cardiac risk in Japanese patients compared to Caucasian patients. Insufficient pharmacokinetic data is available for other ethnicities or races.
The peak and total (AUC and urinary excretion) exposure to tiotropium is comparable between patients with asthma who were 6-11 years old, 12-17 years old and ≥18 years old. Based on urinary excretion, the total exposure to tiotropium in patients 1 to 5 years of age was 52 to 60% lower than in other older age groups. The total exposure data when adjusted for body surface area were found to be comparable in all age groups. Tiotropium was administered with a valved holding chamber with face mask in patients 1 to 5 years of age.
There were no paediatric patients in the COPD programme.
Following inhalation of 5 µg tiotropium, the tiotropium plasma level in CF patients ≥5 years was 10.1 pg/ml 5 minutes post-dosing at steady-state and decreased rapidly thereafter. The fraction of the dose available in CF patients <5 years old who used the spacer and mask was approximately 3- to 4-fold lower than that observed in CF patients 5 years and older. Tiotropium exposure was related to body-weight in CF patients <5 years.
There is no direct relationship between pharmacokinetics and pharmacodynamics.
Many effects observed in conventional studies of safety pharmacology, repeated dose toxicity, and reproductive toxicity could be explained by the anticholinergic properties of tiotropium bromide. Typically in animals reduced food consumption, inhibited body weight gain, dry mouth and nose, reduced lacrimation and salivation, mydriasis and increased heart rate were observed. Other relevant effects noted in repeated dose toxicity studies were: mild irritancy of the respiratory tract in rats and mice evinced by rhinitis and epithelial changes of the nasal cavity and larynx, and prostatitis along with proteinaceous deposits and lithiasis in the bladder in rats.
Harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development could only be demonstrated at maternally toxic dose levels. Tiotropium bromide was not teratogenic in rats or rabbits. In a general reproduction and fertility study in rats, there was no indication of any adverse effect on fertility or mating performance of either treated parents or their offspring at any dosage.
The respiratory (irritation) and urogenital (prostatitis) changes and reproductive toxicity were observed at local or systemic exposures more than five-fold the therapeutic exposure. Studies on genotoxicity and carcinogenic potential revealed no special hazard for humans.
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