To determine the potential pharmacokinetic interaction between GSE and dextromethorphan in healthy volunteers.
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
gezonde vrijwilligers
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Dextromethorphan (DM) to dextrorphan (DX) metabolic ratio (MR) in urine
collected up to 8 h after dextromethorphan administration.
MR = (0-8 h urinary output of DM) / (0-8 h urinary output of DX).
Secondary outcome
Incidence of dextromethorphan-related adverse events.
Background summary
Nowadays, the antiestrogenic agent tamoxifen is widely used for the treatment
of breast cancer. Tamoxifen becomes pharmacologically active after metabolism
to its most abundant active metabolite endoxifen. CYP2D6 is the major enzyme
involved in this biotransformation of tamoxifen.
In vitro data revealed that the herbal supplement grape seed extract (GSE,
Vitis vinifera) inhibited CYP2D6. CYP2D6 inhibition by GSE has also been
demonstrated in our laboratory at Utrecht University (unpublished data). In our
experiment GSE showed to be a potent inhibitor of CYP2D6, as its half maximal
inhibitory concentration (IC50) was even lower than the IC50 of the potent
CYP2D6 inhibitor and positive control quinidine. Thus theoretically,
concomitant use of GSE and tamoxifen might lead to decreased endoxifen plasma
levels, possibly leading to a decreased therapeutic effect of tamoxifen.
Accordingly, the specific CYP2D6 inhibitor paroxetine did lower endoxifen
plasma levels in breast cancer patients taking tamoxifen.
According to the FDA Guideline *Drug Interaction Studies*, the interaction
potential of a compound (in this case GSE) should first be investigated using
specific CYP substrates. For CYP2D6, one of the recommended substrates is
dextromethorphan. Interestingly, dextromethorphan has shown to be an adequate
predictor of endoxifen exposure in breast cancer patients taking tamoxifen
(27). Therefore, and because no clinical interaction study with GSE and
dextromethorphan has been executed yet, our aim is to perform the first
clinical study which assesses the effect of GSE on dextromethorphan
pharmacokinetics. Results of this study would provide valuable data regarding
concomitant use of GSE and tamoxifen.
Study objective
To determine the potential pharmacokinetic interaction between GSE and
dextromethorphan in healthy volunteers.
Study design
Included subjects will be randomized to cohort A (dextromethorphan alone,
followed by dextromethorphan + grapeseed extract) or cohort B (dextromethorphan
+ grapeseed extract, followed by dextromethorphan alone).
Intervention
- Administration of 15 mL 2 mg/mL dextromethorfan cough syrup on day 1 and 10.
- Ingestion of 3 times daily 1 capsule of grapeseed extract during 2 days,
followed by 1 ingestion in the morning of the third consecutive day.
Study burden and risks
Burden:
- Administration of 15 mL 2 mg/mL dextromethorfan cough syrup on day 1 and 10.
- Ingestion of 3 times daily 1 capsule of grapeseed extract during 2 days,
followed by 1 ingestion in the morning of the third consecutive day.
- Keeping a diary for registration of times of grapeseed extract intake.
- Visit the research center three times: screening visit (1x), administration
of dextromethorphan and collection of urine (2x).
- Venapunction for CYP2D6 genotyping.
Risks:
Dextromethorphan:
Incidentally, dextromethorphan can cause the following side effects:
constipation, nausea, vomiting, drowsiness and dizziness. Rarely, confusion,
excitement and allergic skin reactions can occur.
Grapeseed extract:
No adverse effects of grapeseed extract have been reported.
Venapunction:
Venapunction may cause discomfort, hemorrhage or bruising on the injection
site. Incidentally, infection of a vein can occur or the subject can lose
consciousness.
Plesmanlaan 121
1066 CX Amsterdam
NL
Plesmanlaan 121
1066 CX Amsterdam
NL
Listed location countries
Age
Inclusion criteria
1. Healthy volunteer;
2. Age 18 years or older;
3. Able and willing to give written informed consent;
4. Able and willing to undergo blood sampling for CYP2D6 genotyping;
5. Able and willing to swallow and retain oral medication;
6. Able and willing to collect urine for pharmacokinetic analysis;
7. Willing to comply to the protocol and to follow dietary restrictions.
Exclusion criteria
1. Concomitant medication known to be moderate or strong inhibitors of CYP2D6 for at least two weeks prior to study start, including bupropion, cinacalcet, fluoxetine, paroxetine, quinidine, duloxetine, sertraline, terbinafine, amiodarone and cimetidine.
2. Concomitant medication known to be moderate or strong inducers of inhibitors of CYP3A for at least two weeks prior to study start, including indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, saquinavir, telithromycine, aprepitant, erythromycin, fluconazole, grapefruit juice, verapamil, diltiazem, rifampicin, St. John*s wort and carbamazepine.
3. Any treatment with investigational drugs within two weeks prior to receiving the first dose of investigational treatment;
4. Use of alcohol (max. 2 units per day allowed), grapefruit or grapefruit juice for at least two weeks prior to study start until handing in collected urine on day 10.
5. Contra-indications for dextromethorphan use (e.g. treatment with MAO inhibitors, severely impaired liver function).
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-001274-28-NL |
| CCMO | NL40062.048.12 |