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

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)

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.

Study Overview

• Status: Completed
• Conditions: Renal Insufficiency
• Intervention / Treatment: Drug: Tiotropium, solution ampoules

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Subjects:

   1. 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))

   2. 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.
2. Male or female, age between 40 and 70 years with normal body - weight index (+/- 25%, Broca-index)
3. Subjects with normal 12 - lead ECG recording
4. Subjects with normal physical examination
5. Subjects with normal clinical and laboratory tests (except for indicators of renal impairment)
6. Female of child bearing potential must have a negative pregnancy test
7. All subjects must have a negative HIV-Ab test and negative Hepatitis B test
8. All subjects must have a negative drug screening
9. All subjects must sign a written informed consent prior to enrollment

Exclusion Criteria:

1. 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
2. Present or past participation in a drug detoxification program
3. Smokers
4. Subjects requiring any concomitant medication not compatible with this study
5. 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
6. Subjects who participated in a clinical trial of any other investigational drug within two months prior to the start of this study
7. Pregnant or lactating women or women of child bearing potential not using a medically approved means contraception. (i.e., oral contraceptives, intrauterine devices, diaphragm)
8. Subjects who donated blood within three months prior to the start of the study
9. Subjects with a history of chronic or recurrent convulsive disorders or ongoing hepatic dysfunction
10. Subjects with ongoing acute systemic illness or recovery from acute systemic illness
11. Subjects with a history of cancer within the last five years
12. Subjects with known hypersensitivity to anticholinergic drugs
13. Subjects with known symptomatic prostatic hypertrophy or bladder neck obstruction
14. Subjects with known narrow-angle glaucoma

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tiotropium; group comparison (healthy, renal impairment)	Drug: Tiotropium, solution ampoules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: April 1, 1998
• Primary Completion (Actual): December 1, 1998
• Study Completion: December 7, 2022

Study Registration Dates

• First Submitted: June 20, 2014
• First Submitted That Met QC Criteria: June 20, 2014
• First Posted (Estimate): June 24, 2014

Study Record Updates

• Last Update Posted (Estimate): June 24, 2014
• Last Update Submitted That Met QC Criteria: June 20, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Tiotropium Bromide
• Other Study ID Numbers: 205.134

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No