To establish the drug drug interaction of paracetamol with propranolol and the effect of this interaction on the pharmacokinetic profile and metabolites of paracetamol.
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
evaluatie AMS technologie
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pharmacokinetics of 14C-Paracetamol in blood and urine.
Secondary outcome
Pharmacokinetics of propranolol in blood serum.
Background summary
Microdosing could be an interesting method to study drug drug interactions
(DDI) of interest in early phase clinical studies without interrupting
pharmacokinetic parameters of the drug of interest. The principle of
microdosing resides in the fact that a very small dose (100 µg) of a 14C
labeled drug is administered to humans to obtain human kinetic and metabolic
information using the ultrasensitive analytical technique Accelerator Mass
Spectrometry (AMS). The sensitivity of the technique allows us to study DDI by
administering a microdose of a 14C labeled compound together with a substrate
compound at therapeutic dosage, and thus can provide information on phase II
metabolism and the interaction of the substrate hereon.
The purpose of this DDI is to evaluate the interaction between paracetamol and
propranolol. A micro dose of 100 ug paracetamol, a 3.7kBq dose of 14C added,
is administered twice during two occasions with a washout of 5 days. 80mg
propranolol is administered on one of the occasions as a substrate.
For the null hypothesis is determined that the half-life of paracetamol with
propranolol is not smaller than the half-life of paracetamol without
propranolol.
Study objective
To establish the drug drug interaction of paracetamol with propranolol and the
effect of this interaction on the pharmacokinetic profile and metabolites of
paracetamol.
Study design
An open, single dose two way cross-over design 14C-Paracetamol with and without
Propranolol in healthy male volunteers.
Intervention
Microdosing 14C paracetamol 100 microgram intavenous with and without
propranolol 80 milligram orally
Study burden and risks
Screening: physical examination, medical examination, venapunctie,
bloodpressure, ECG. No eating and drinking other than water 4 hours before
screening.
Two times 2 studydays with one overnight stay: insertion van 2 canules, 1x
venapunctie, 11-13x blooddrawing, 3x drug administration, 24 hr urine
collection. No eating and drinking other than water the night before the
drugadministration until 2 hours after the dosing.
Participation in this study may be associated with headache, often following a
period of fasting and abstinence from caffeine. For blood samples, and the
dosing two cannulae are inserted into a vein in both arms. This can be painful
and sometimes cause a bruise.
For the paracetamol is given in such low doses adverse effects are not to be
expected. The radiation burden is very low. The effective dose of 0.005 mSv is
below the maximum limit of 1 mSv per year as stated by the NRG.
Side effects of propranolol are nausea, diarrhea, bronchospasm, dyspnea, cold
extremities, exacerbation of Raynaud's syndrome, bradycardia, hypotension,
heart failure, heart block, fatigue, dizziness, alopecia (hair loss), visual
disturbances, hallucinations, insomnia, nightmares, sexual dysfunction,
erectile dysfunction and / or changes in glucose and lipid metabolism. However,
after a single dose of 80 mg propranolol is the occurrence of these side
effects are unlikely.
Utrechtseweg 48
Zeist 3704HE
NL
Utrechtseweg 48
Zeist 3704HE
NL
Listed location countries
Age
Inclusion criteria
- Men, healthy, aged 18 to 45 years
- Non-smoking
- BMI between 18 and 25 kg/m2, inclusive
- Body temperature, between 35.0ºC and 37.5ºC
- Systolic blood pressure, 90 to 150 mm Hg
- Diastolic blood pressure, 45 to 90 mm Hg
- Pulse rate, 40 to 100 bpm
Exclusion criteria
- Subject has or had, in the opinion of the investigator, clinical significant abnormalities as found in the medical history, physical examination, electrocardiogram (ECG), laboratory profile and/or blood and urine.
- Presence or history of clinically significant psychiatric diseases, as judged by the investigator.
- Gilbert's syndrome, liverfailure or -dysfunction.
- Any clinically relevant acute or chronic diseases which according to the investigator could interfere with the subject*s safety during the trial, or expose them to undue risk, or which could interfere with the study objectives.
- Presence or history of clinically significant allergy or known hypersensitivity to any component of the investigational product.
- Enrolment in any investigational study or intake of an investigational drug within 3 months prior to the start of the study or more than 4 times a year.
- Current regular user of any illicit drugs or history of drug abuse. Subjects who have a positive drug screen at screening will be excluded.
- Donation of blood/plasma outside limits of Sanquin Blood Supply Foundation guidelines.
- Is not likely to co-operate in the study, and/or has poor compliance as anticipated by the investigator
- History of alcohol abuse and/or excessive current use of alcohol (i.e., regular use of more than 21 units of alcohol/week for males), and/or unwillingness or unable to refrain from products containing alcohol from 1 days before admission and during the stay in the research unit.
- Subjects who have a positive alcohol breath test at screening will be excluded.
- Daily consumption of xanthine-containing products more than 8 units.
- Unwilling or unable to refrain from consumption of xanthine-containing foods or drinks from 2 days prior to admission and during the stay in the research unit.
- Medication used within 7 days before both and during studydays.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-003603-34-NL |
| CCMO | NL41796.056.12 |