Healthy
Conditions
Brief summary
The primary objective of the current study is to investigate the safety with special emphasis on ECG effects, and tolerability of dextromethorphan hydrobromide monohydrate (2mg/mL syrup) in healthy male and female subjects following oral administration of 30 mg q.i.d. and 90 mg q.i.d. for 2 days followed by a single morning dose (extensive metabolisers of CYP 2D6) and for 10 days followed by a single morning dose (poor metabolisers of CYP 2D6). Additionally pharmacokinetic properties of dextromethorphan and its main metabolites dextrorphan, 3-hydroxymorphinan, and 3-methoxymorphinan will be investigated
Interventions
DRUGDextromethorphan syrup - low dose
DRUGDextromethorphan syrup - high dose
DRUGPlacebo
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy males and females according to the following criteria: Based upon a complete medical history, including the physical examination, oral body temperature, vital signs (blood pressure, pulse rate), 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 or poor metabolisers for CYP 2D6 based on the results of a genotyping test * 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 blood pressure, pulse rate 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 that 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 first 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 first administration or during the trial) * Excessive physical activities (within one week prior to first 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 QTc interval of \>450 ms; * A history of additional risk factors for Torsades de points (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of patients with abnormal findings in physical examination | up to day 20 |
| Number of patients with clinically significant changes in vital signs (blood pressure and pulse rate) | up to day 20 |
| Number of patients with clinically significant changes in 12-lead ECG (electrocardiogram) including QT interval and heart rate corrected QTcN, QTcF (Fridericia) and QTcB (Bazett) | up to day 20 |
| Number of patients with abnormal changes in laboratory parameters | up to day 20 |
| Assessment of tolerability by investigator on a 4-point scale | day 20 (end of trial examination) |
| Number of patients with adverse events | up to 48 days |
Secondary
| Measure | Time frame |
|---|---|
| Cmax (maximum measured concentration of the analyte in plasma) after the first dose | within 5 hours after first drug administration |
| tmax (time from dosing to the maximum concentration of the analyte in plasma) after the first dose | within 5 hours after first drug administration |
| AUCt1-t2 (area under the concentration-time curve of the analyte in plasma from the time interval t1 to t2) after the first dose | within 5 hours after first drug administration |
| AUC0-5 (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 5 hours after administration) after the first dose | within 5 hours after first drug administration |
| Cmax,N (maximum measured concentration of the analyte in plasma following the Nth dose) after the last dose | up to day 13 |
| tmax,N (time from last dosing to the maximum concentration of the analyte in plasma following the Nth dose) after the last dose | up to day 13 |
| AUCt1-t2,N (area under the concentration-time curve of the analyte in plasma from the time interval t1 to t2 following the Nth dose) after the last dose | up to day 13 |
| AUC0-5,N (area under the concentration-time curve of the analyte in plasma over the time interval 0 to 5 hours following the Nth dose) after last dose | up to day 13 |
| λz,N (terminal rate constant in plasma following the Nth dose) after the last dose | up to day 13 |
| t1/2,N (terminal half-life of the analyte in plasma following the Nth dose) after the last dose | up to day 13 |
| MRTpo,N (mean residence time of the analyte in the body after oral administration of the Nth dose) after the last dose | up to day 13 |
| Cmax (maximum observed concentration of the analyte in plasma) after the second dose | Day 1 |
| tmax (Time to Cmax of the analyte in plasma) after the second dose | Day 1 |
Outcome results
None listed