The Pharmacokinetic, Safety and Tolerability of Tiotropium in Outpatients With Renal Impairment in Comparison to Healthy Subjects

Study Overview
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Brief Summary
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Study to investigate pharmacokinetics of a single i.v. dose of tiotropium (4.8 mcg) in patients with renal impairment in comparison to healthy subjects.

Official Title
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The Pharmacokinetic, Safety and Tolerability of Tiotropium (4.8 mcg, Single i.v. Dose) in Outpatients With Renal Impairment in Comparison to Healthy Subjects (Open Label, Group Comparison, Two-center Study)

Conditions
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Renal Insufficiency

Intervention / Treatment
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* Drug: Tiotropium, solution ampoules


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects: Subject with normal renal function ( creatinine clearance of 80% of predicted creatinine clearance in healthy volunteers), as confirmed by normal physical examination including vital signs, ECG and laboratory values Calculated creatinine clearance (male); = ((140 - age(yr)) x (Wt (kg))) / (72 x predicted serum creatinine (mg/dL)) Calculated creatinine clearance (female); = ((140 - age(yr)) x (Wt(kg))) / (85 x predicted serum creatinine (mg/dL)) Subject with impaired renal function must be of age related good health and without clinically significant abnormalities as assessed during the physical examination. Mildly impaired renal patients were defined as those with creatinine clearance of 40 - 80% of predicted creatinine clearance; moderately impaired renal patients were defined as those with creatinine clearance of 10 - 40% of predicted creatinine clearance. Laboratory values of subjects with renal impairment could have been outside the normal range if the deviations were due to the underlying renal disease. Male or female, age between 40 and 70 years with normal body - weight index (+/- 25%, Broca-index) Subjects with normal 12 - lead ECG recording Subjects with normal physical examination Subjects with normal clinical and laboratory tests (except for indicators of renal impairment) Female of child bearing potential must have a negative pregnancy test All subjects must have a negative HIV-Ab test and negative Hepatitis B test All subjects must have a negative drug screening All subjects must sign a written informed consent prior to enrollment Exclusion Criteria: Subjects with a history of more then moderate alcohol consumption (more than 1 litre of beer per day or the equivalent amount of alcohol in any other alcoholic beverage, approximately 50 g of alcohol per day). 24 hours before dosing and 24 hours post dosing, alcohol was not permitted Present or past participation in a drug detoxification program Smokers Subjects requiring any concomitant medication not compatible with this study Subjects with hypotension (systolic blood pressure less than 100 mmHg, diastolic less than 60 mmHg) or hypertension (systolic blood pressure more than 165 mmHg or diastolic more than 100 mmHg) under adequate medication Subjects who participated in a clinical trial of any other investigational drug within two months prior to the start of this study Pregnant or lactating women or women of child bearing potential not using a medically approved means contraception. (i.e., oral contraceptives, intrauterine devices, diaphragm) Subjects who donated blood within three months prior to the start of the study Subjects with a history of chronic or recurrent convulsive disorders or ongoing hepatic dysfunction Subjects with ongoing acute systemic illness or recovery from acute systemic illness Subjects with a history of cancer within the last five years Subjects with known hypersensitivity to anticholinergic drugs Subjects with known symptomatic prostatic hypertrophy or bladder neck obstruction Subjects with known narrow-angle glaucoma

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 70 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
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tiotropium<br>group comparison (healthy, renal impairment) | Drug: Tiotropium, solution ampoules<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve (AUC (0-4h) of plasma levels of tiotropium after dosing) |  | pre-dose, 7, 15 , 20, 25, 35, 45 minutes and 1, 2, 4 and 8 hours after drug administration | 
| Renal clearance of tiotropium (CLren ) |  | Day 1, 2, 3, 7, 11, 15, 18, 22 and 25 (0-4h, 4-8h), additionally -4 -0 h on day 1 | 
| Terminal half-life of tiotropium |  | pre-dose, 7, 15 , 20, 25, 35, 45 minutes and 1, 2, 4 and 8 hours after drug administration | 
| Urinary excretion (0-4h) of tiotropium, Ae 0-4h |  | Day 1, 2, 3, 7, 11, 15, 18, 22 and 25 (0-4h, 4-8h), additionally -4 -0 h on day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Pulse Rate (PR) |  | baseline, day 1, 2, 3, 7,11, 15,18, 22 and 25 | 
| Change from baseline in Blood pressure (BP) |  | baseline, day 1, 2, 3, 7,11, 15,18, 22 and 25 | 
| Number of Participants with Serious and Non-Serious Adverse Events |  | up to day 25 | 
| Change from baseline in electrocardiogram (ECG) |  | baseline, day 1, 2, 7, 15 and 25 | 
| Maximum measured concentration of the analyte in plasma (Cmax ) |  | pre-dose, 7, 15 , 20, 25, 35, 45 minutes and 1, 2, 4 and 8 hours after drug administration | 
| Time from dosing to the maximum concentration of the analyte in plasma (tmax) |  | pre-dose, 7, 15 , 20, 25, 35, 45 minutes and 1, 2, 4 and 8 hours after drug administration | 
| Change in FEV1 (Forced expiratory volume in one second) |  | baseline, day 1, 2, 3, 7,11, 15,18, 22 and 25 | 
| Change in FVC (Forced vital capacity) |  | baseline, day 1, 2, 3, 7,11, 15,18, 22 and 25 |