Tiotropium in Combination With Concomitant Cimetidine or Ranitidine in Healthy Male and Female Subjects

Study Overview
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Brief Summary
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Study to investigate the effect of an inhibition of the renal cationic drug transporter on single dose pharmacokinetics of intravenous tiotropium in subjects in an age close to typical Chronic Obstructive Pulmonary Disease (COPD) population

Official Title
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The Effect of Concomitant Cimetidine p.o. 400 mg t.i.d. and p.o. Ranitidine 300 mg Once Daily on Single Dose Pharmacokinetics of Tiotropium (14.4 µg) Given Intravenously Over 15 Minutes in Healthy Male and Female Subjects of 50-65 Years (Randomized, Open Label, Two Independent Two-fold Crossover)

Conditions
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Healthy

Intervention / Treatment
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* Drug: Cimetidine + Tiotropium
* Drug: Ranitidine + Tiotropium
* Drug: Tiotropium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males or females Age range from 50 to 65 years Within 20% of their normal weight (Broca index) Exclusion Criteria: Any finding of the medical examination (including blood pressure, puls rate and ECG) deviating from normal and of clinical relevance Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders Diseases of the central nervous system (such as epilepsy) or with psychiatric disorders or neurological disorders History of orthostatic hypotension, fainting spells or blackouts Chronic or relevant acute infections History of allergy/hypersensitivity (including drug allergy) which is deemed relevant to the trial as judged by the investigator Intake of a drug with a long half-life (≥ 24 hours) within ten half-lives of the respective drug before enrolment in the study or during the study (exclusion: ovarian hormone substitution) Use of any drugs which might influence the results of the trial within four weeks prior to administration or during the trial, among these all non-selective β-blockers, cromolyn sodium, nedocromil sodium, oral β-adrenergics or long-acting β-adrenergics such as salmeterol and formoterol, and anticholinergic drugs including ATROVENT® (ipratropium) by oral inhalation or ATROVENT® Nasal Spray Participation in another study with an investigational drug within two months prior to administration or during the trial Smoker (> 10 cigarettes or 3 cigars or 3 pipes/day) Inability to refrain from smoking on study days Alcohol abuse (> 40 g/day) Drug abuse Blood donation (≥ 100 ml) within four weeks prior to administration or during the trial Excessive physical activities within 5 days prior to administration or during the trial Any laboratory value outside the reference range of clinical relevance Subjects with known hypersensitivity to anticholinergic drugs Subjects with known symptomatic prostatic hypertrophy or disturbed micturition Subjects with known narrow-angle glaucoma In addition for female subjects (if appropriate): Pregnancy Positive pregnancy test No adequate contraception e.g. oral contraceptives, sterilization, intra uterine pessary (IUP) Inability to maintain this adequate contraception during the whole study period Lactation period

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cimetidine + Tiotropium followed by Tiotropium<br> | Drug: Cimetidine + Tiotropium<br> <br> Drug: Tiotropium<br> <br> |
| Experimental: Ranitidine + Tiotropium followed by Tiotropium<br> | Drug: Ranitidine + Tiotropium<br> <br> Drug: Tiotropium<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of plasma levels of tiotropium after dosing |  | up to 8 hours after i.v. treatment | 
| Area under the curve (AUC) 0-4h of the plasma levels of tiotropium after dosing |  | 0 - 4 hours after i.v. treatment | 
| Urinary excretion 0-4h after dosing (Ae0-4h) |  | 0 - 4 hours after i.v. treatment | 
| Renal clearance of tiotropium (CLR) |  | pre-dose, 0-4 h, 4-8 h, 8-12 h, 12-24 , 24-28 h, 38-72 h and 72-96 h after i.v. treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC 0-8h of plasma levels of tiotropium after dosing |  | 0-8 hours after treatment | 
| Urinary excretion 0-96h after dosing (Ae0-96h) |  | 0-96 hours after treatment | 
| Occurrence of Adverse Events |  | up to 4 - 8 days after last i.v. treatment | 
| Changes from baseline in Laboratory Tests |  | Baseline, 4 - 8 days after last i.v. treatment | 
| Changes in 12-lead electrocardiogram (ECG) |  | up to 24 h after i.v. treatment | 
| Changes in Blood Pressure and Pulse Rate |  | up to 4 - 8 days after last i.v. treatment | 
| Changes from baseline in physical examination |  | Baseline, 4 - 8 days after last i.v. treatment |