Investigation of the Metabolism and Pharmacokinetics of Ambroxol in Healthy Male Volunteers

Study Overview
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Brief Summary
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Study to determine the basic pharmacokinetics of ambroxol and [14C]-radioactivity including mass balance, excretion pathways and complete metabolism in healthy male volunteers following administration of a lozenge of 20 mg ambroxol together with an oral solution of 0.4 mg [14C]-ambroxol labelled in two different positions

Official Title
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Investigation of the Metabolism and Pharmacokinetics of an Open Label Single Dose of 20 mg Ambroxol Administered as a Lozenge Together With an Oral Solution of 0.4 mg [14C]-Ambroxol in Healthy Male Volunteers

Conditions
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Healthy

Intervention / Treatment
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* Drug: [14C]-cyclohexane ambroxol oral solution
* Drug: [14C]-benzyl ambroxol oral solution
* Drug: Ambroxol lozenge


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males according to the following criteria: Based upon a complete medical history, including the physical examination, vital signs (Blood Pressure (BP), Pulse Rate (PR)), 12-lead Electrocardiogram (ECG), clinical laboratory tests Age ≥18 and ≤65 years Body mass index (BMI) ≥18.5 and BMI ≤29.9 kg/m2 Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice (GCP) and the local legislation Exclusion Criteria: Any finding of the medical examination (including BP, PR and ECG) deviating from normal and of clinical relevance Any evidence of a clinically relevant concomitant disease Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders History of relevant orthostatic hypotension, fainting spells or blackouts Chronic or relevant acute infections History of relevant allergy/hypersensitivity (including allergy to study drug or its excipients) Intake of drugs with a long half-life (> 24 hours) within at least one month or less than ten half-lives of the respective drug prior to administration or during the trial Use of drugs which might reasonably influence the results of the trial based on the knowledge at the time of protocol preparation within ten days prior to administration until after the last sample from Visit 2 is collected Participation in another trial 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 during the stay in the trial centre Alcohol abuse (more than on average two units of alcoholic beverages per day or more than 14 units per week (one unit equals one pint [285 mL] of beer or lager, one glass [125 mL] of wine, 25 mL shot of 40% spirit)). Drug abuse Blood donation (more than 100 mL within 60 days prior to study drug administration or during the trial) Excessive physical activities (within one week prior to administration or during the Trial until follow-up examination) Any laboratory value outside the reference range that is of clinical relevance Inability to comply with dietary regimen of study centre A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 ms) Exclusion criteria specific for this study: Veins unsuitable for blood sampling PR interval >220 ms or QRS interval >120 ms Exposure to radiation for diagnostic reasons (except dental X-rays and plain X-rays of thorax and bony skeleton [excluding spinal column]), during work or during participation in a medical trial in the previous year Irregular defecation pattern (less than once per two days)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: [14C]-cyclohexane ambroxol oral solution + ambroxol lozenge<br> | Drug: [14C]-cyclohexane ambroxol oral solution<br> <br> Drug: Ambroxol lozenge<br> <br> |
| Experimental: [14C]-benzyl ambroxol oral solution + ambroxol lozenge<br> | Drug: [14C]-benzyl ambroxol oral solution<br> <br> Drug: Ambroxol lozenge<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Individual time course profiles of [14C]-radioactivity (in nmoleq/L or nmoleq/kg for faeces) in plasma |  | up to 120 hours after drug administration | 
| Individual time course profiles of ambroxol in plasma |  | up to 120 hours after drug administration | 
| Rate and extent of excretion mass balance based on the total radioactivity in urine and faeces |  | up to 216 hours after drug administration | 
| Identification of major metabolites in urine, feces and plasma in comparison with various animal species |  | up to 48 hours after drug administration | 
| Cblood cells/Cplasma ratio of [14C]-radioactivity and Cblood /Cplasma ratio of [14C]-radioactivity |  | up to 120 hours after drug administration | 
| Cmax (maximum concentration of the analyte(s) in plasma) |  | up to 120 hours after drug administration | 
| tmax (time from dosing to the maximum concentration of the analyte(s) in plasma) |  | up to 120 hours after drug administration | 
| AUC0-tz (area under the concentration-time curve of the analyte(s) in plasma over the time interval from 0 to the time of the last quantifiable data point) |  | up to 120 hours after drug administration | 
| AUC0-∞ (area under the concentration-time curve of the analyte(s) in plasma over the time interval from 0 to infinity) |  | up to 120 hours after drug administration | 
| λz (terminal rate constant in plasma) |  | up to 120 hours after drug administration | 
| t1/2 (terminal half-life of the analyte(s) in plasma) |  | up to 120 hours after drug administration | 
| MRTpo (mean residence time of the analyte(s) in the body after oral administration) |  | up to 120 hours after drug administration | 
| CL/F (total clearance of the analyte in plasma after oral administration) |  | up to 120 hours after drug administration | 
| Vz/F (apparent volume of distribution during the terminal phase λz following an oral dose) |  | up to 120 hours after drug administration | 
| Ae0-tz (amount of analyte that is eliminated in urine within the time interval zero to tz) |  | up to 216 hours after drug administration | 
| Aefaeces,0-tz (amount of analyte excreted in faeces within the time interval zero to tz) |  | up to 216 hours after drug administration | 
| fefaeces,0-tz (fraction of analyte excreted in faeces within the time interval zero to tz in % of dose) |  | up to 216 hours after drug administration | 
| CLR,t1-t2 (renal clearance of analyte from the within the time interval t1 to t2) |  | up to 216 hours after drug administration | 
| fe0-tz (fraction of analyte excreted in urine within the time interval zero to tz in % of dose) |  | up to 216 hours after drug administration | 
| Individual time course profiles of [14C]-radioactivity (in nmoleq/L or nmoleq/kg for faeces) in urine |  | up to 216 hours after drug administration | 
| Individual time course profiles of [14C]-radioactivity (in nmoleq/L or nmoleq/kg for faeces) in faeces |  | up to 216 hours after drug administration | 
| Individual time course profiles of ambroxol in urine |  | up to 216 hours after drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with clinically significant changes vital signs (blood pressure [BP], pulse rate [PR]) |  | up to 39 days | 
| Number of patients with adverse events |  | up to 39 days | 
| Number of patients with clinically significant changes in 12-lead electrocardiogram (ECG) |  | up to 39 days | 
| Number of patients with abnormal changes in laboratory parameters |  | up to 39 days | 
| Assessment of tolerability on a 4-point scale |  | Day 14 |