The primary objective of this study is to determine whether the pharmacokinetics of midazolam show circadian rhythmicity.
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
NVT; stof wordt gebruikt als modelgeneesmiddel
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
By analyzing the pharmacokinetic profiles of midazolam and sorbitol (used to
estimate liver blood flow) for each administration the following parameters of
midazolam will be determined:
- CLint (intrinsic clearance)
- CLsys (systemic clearance)
- Cmax and Tmax (maximal concentration and time to reach this)
- Volume of distribution
- ERgut/ERliver: gastrointestinal/hepatic extraction ratio
Circadian profiles will be determined for each parameter and per individual
Secondary outcome
- 24hour profile of TSH plasma concentrations as a marker for circadian phase
of the subject.
Background summary
All living organisms, including humans, are equipped with timekeeping
mechanisms to adapt to the environmental 24-hour light-dark cycles.
Chronopharmacological studies have revealed circadian variability in kinetics
and dynamics of drugs, but its exact cause has not received much attention.
This is important as the changes may depend on changes in absorption,
distribution, metabolism and/or excretion. Ideally, research of circadian
rhythmicity should address all these determinants, which is done in the present
study by *semi-simultaneous administration* of the drug: the drug is first
given orally and a few hours later also intravenously. This approach has been
used to study the relative contribution of intestinal and hepatic drug
metabolism and to estimate bioavailability of compounds. Midazolam is used as a
model drug.
Study objective
The primary objective of this study is to determine whether the
pharmacokinetics of midazolam show circadian rhythmicity.
Study design
This an open-label, 6-way crossover study, in which at each of the 3 study
visits the subjects will receive midazolam orally and iv (separated by 150min)
twice at a 12 hr interval. The clock time of each study is chosen such that in
each subject the 24-hr profile is studied at 6 time points. At each dosing
epoch, the subjects will also be given an iv bolus of sorbitol. Wash-out
between study days is two weeks.
Intervention
Midazolam (2 mg) will be administered orally and 150 min later this will be
followed by an intravenous dose of 1 mg given over a 1 min period. Sorbitol (2
gram as a 1 min iv infusion) will be given 60 min after the oral midazolam
dose.
Study burden and risks
- blood withdrawal by venepuncture, once (screening)
- intravenous cannula for blood withdrawal, three times (study days)
- intravenous cannula for drug administration, three times (study days)
The total amount of blood withdrawal will be max. 500 ml
There are three study occasions, each occasion takes approximately 24hours.
Subjects will be screened by medical history, physical examination, and routine
laboratory tests. Each subject has to complete the morningness/eveningness
questionnaire. During the study, subjects have to follow a regular day night
rhythm. Subjects keep a sleep diary throughout the study. Subjects are not
allowed to use caffeinated, alcoholic, grapefruit products.
Zernikedreef 10
2333 CL Leiden
NL
Zernikedreef 10
2333 CL Leiden
NL
Listed location countries
Age
Inclusion criteria
healthy
male
18-50 yrs
Exclusion criteria
any clinically relevant medical condition
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 | EUCTR2009-010331-40-NL |
| CCMO | NL26863.058.09 |