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

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

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

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: [14C]-cyclohexane ambroxol oral solution; Drug: Ambroxol lozenge; Drug: [14C]-benzyl ambroxol oral solution

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	Time Frame
Number of patients with adverse events	up to 39 days
Number of patients with clinically significant changes vital signs (blood pressure [BP], pulse rate [PR])	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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: October 1, 2008
• Primary Completion (Actual): December 1, 2008

Study Registration Dates

• First Submitted: July 17, 2014
• First Submitted That Met QC Criteria: July 17, 2014
• First Posted (Estimate): July 18, 2014

Study Record Updates

• Last Update Posted (Estimate): July 18, 2014
• Last Update Submitted That Met QC Criteria: July 17, 2014
• Last Verified: July 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory System Agents; Expectorants; Pharmaceutical Solutions; Ambroxol
• Other Study ID Numbers: 18.494