Relative Bioavailability of Dextromethorphan Syrup in Comparison to Dextromethorphan Soft Pastilles in Healthy Male and Female Subjects

Study Overview
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Brief Summary
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Study to investigate the relative bioavailability of orally administered dextromethorphan syrup in comparison to dextromethorphan (DMP) soft pastilles in healthy male and female subjects who are extensive metabolisers for CYP 2D6

Official Title
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A Phase I, Single Dose, Controlled Two-way Crossover Study to Evaluate the Relative Bioavailability of Orally Administered Dextromethorphan Syrup (21 mg Dextromethorphan Hydrobromide Monohydrate) in Comparison to Dextromethorphan Soft Pastilles (21 mg Dextromethorphan Hydrobromide Monohydrate) in Healthy Male and Female Subjects Who Are Extensive Metabolisers for Cytochrom P450 (CYP) 2D6

Conditions
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Healthy

Intervention / Treatment
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* Drug: Dextromethorphan syrup
* Drug: Dextromethorphan soft pastilles


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males and females 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 Age ≤55 years BMI ≥18.5 and BMI ≤30 kg/m2 (Body Mass Index) Extensive metabolisers for CYP 2D6 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 Surgery of the gastrointestinal tract (except appendectomy) 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 drug or its excipients) Intake of drugs with a long half-life (> 24 hours) within at least one month or less than 10 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 or which prolong the QT/QTc interval based on the knowledge at the time of protocol preparation within 10 days prior to administration or during the trial Participation in another trial with an investigational drug within one month prior to administration or during the trial Smoker (> 10 cigarettes or > 3 cigars or > 3 pipes/day) Inability to refrain from smoking on trial days Alcohol abuse (more than 60 g/day) Drug abuse Blood donation (more than 100 mL within four weeks prior to administration or during the trial) Excessive physical activities (within one week prior to administration or during the trial) Any laboratory value outside the reference range that is of clinical relevance Inability to comply with dietary regimen of trial site A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 ms) A history of additional risk factors for TdP (Torsades de points) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome) For female subjects: Pregnancy or planning to become pregnant within 2 months of study completion Positive pregnancy test No adequate contraception in women of childbearing potential during the study, i.e. sterilization, intrauterine device, hormonal contraception Lactation period Exclusion criteria specific for this study: Use of drugs that inhibit or induce cytochrome P 450 enzymes, especially CYP 2D6, within 30 days prior to first administration of the study medication or during the trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Dextromethorphan syrup<br>Bisoltussin® Syrup | Drug: Dextromethorphan syrup<br> <br> |
| Active Comparator: Dextromethorphan soft pastilles<br>Silomat® DMP soft pastilles | Drug: Dextromethorphan soft pastilles<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-∞ (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) - for dextromethorphan and dextrorphan (total and free) |  | predose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 32 hours after drug administration | 
| Cmax (maximum measured concentration of the analyte in plasma) - for dextromethorphan and dextrorphan (total and free) |  | predose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 32 hours after drug administration | 
| tmax (time from dosing to the maximum measured concentration of the analyte in plasma) - for dextromethorphan and dextrorphan (total and free) |  | predose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 32 hours after drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-tz (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable data point) - all analytes |  | predose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 32 hours after drug administration | 
| AUCt1-t2 (Area under the concentration time curve of the analyte in plasma over the time interval t1 to t2) - all analytes |  | predose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 32 hours after drug administration | 
| %AUCtz-∞ (percentage of the AUC0-∞ that is obtained by extrapolation) - all analytes |  | predose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 32 hours after drug administration | 
| λz (terminal rate constant in plasma) - all analytes |  | predose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 32 hours after drug administration | 
| t1/2 (terminal half-life of the analyte in plasma) - all analytes |  | predose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 32 hours after drug administration | 
| MRTpo (mean residence time of the analyte in the body after oral administration) - all analytes |  | predose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 32 hours after drug administration | 
| CL/F (apparent clearance of the analyte in the plasma after oral administration) - all analytes |  | predose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 32 hours after drug administration | 
| Vz/F (apparent volume of distribution during the terminal phase λz following an oral dose) - all analytes |  | predose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 32 hours after drug administration | 
| AUC0-∞ (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) - 3-hydroxy-morphinan (total and free) and 3- methoxy-morphinan |  | predose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 32 hours after drug administration | 
| Cmax (maximum measured concentration of the analyte in plasma) - 3-hydroxy-morphinan (total and free) and 3- methoxy-morphinan |  | predose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 32 hours after drug administration | 
| tmax (time from dosing to the maximum measured concentration of the analyte in plasma) - 3-hydroxy-morphinan (total and free) and 3- methoxy-morphinan |  | predose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 32 hours after drug administration | 
| Number of patients with adverse events |  | up to 53 days | 
| Number of patients with abnormal changes in laboratory parameters |  | Screening, 14 days after the end of last treatment period | 
| Number of patients with abnormal changes in 12-lead ECG (electrocardiogram) (including QT interval and heart rate corrected QTcF and QTcB) |  | Screening, Day 1, 14 days after the end of last treatment period | 
| Number of patients with clinically significant changes in vital signs (blood pressure (BP), pulse rate (PR)) |  | Screening, Day 1, 14 days after the end of last treatment period | 
| Assessment of tolerability on a 4-point scale |  | Day 2 of each treatment period |