Primary Objective:To describe the total apparent CYP3A mediated clearance (Cl/F) of midazolam in the paediatric intensive care population from the age of 0 to 6 years, as surrogate marker of intestinal and hepatic CYP3A activity.Secondary Objectives…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
intestinale absorptie en metabolisme van geneesmiddelen bij kritisch zieke kinderen
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1. Apparent clearance of midazolam (CL/F) to 1-OH-midazolam and
4-OH-midazolam.
Secondary outcome
2. Following parameters will be estimated for both formulations (IV and PO): Cl
and Vd of midazolam and metabolites in plasma and urine in relation to age and
PELOD score. For oral midazolam also: AUC, Cmax, Tmax,
Metabolites: 1-OH-midazolam (1-OHM), 1-OH-midazolam-glucuronide (1-OHMG),
4-OH-midazolam (4-OHM) 4-OH-midazolam-glucuronide (4-OHMG),
Midazolam-glucuronide (M-G)
In feces: midazolam and metabolite appearance
3. Description of feasibility of microdosing study in pediatric population.
4. Metabolic profile of oral midazolam in pediatric population.
Background summary
Numerous drugs prescribed to children are administered orally. Systemic
exposure after oral administration importantly depends on intestinal and
hepatic drug metabolism. Better knowledge on the ontogeny of these intestinal
and hepatic drug metabolizing enzymes may aid to develop age appropriate
dosing guidelines. To study the disposition of drugs, which are surrogate
markers of specific drug metabolizing enzymes, in children of different ages,
is an approach to elucidate these developmental patterns, e.g. midazolam for
CYP3A.
Oral bioavailability studies in children accompanies with several limitations,
including repeated (nontherapeutic) drug administration. The innovative
technique microdosing may overcome ethical and practical limitations of drug
studies in children. The EMA in 2003 endorsed the use of microdosing in the
pediatric drug developmental process.
Study objective
Primary Objective:
To describe the total apparent CYP3A mediated clearance (Cl/F) of midazolam in
the paediatric intensive care population from the age of 0 to 6 years, as
surrogate marker of intestinal and hepatic CYP3A activity.
Secondary Objectives:
In the pediatric intensive population from 0 to 6 years of age:
To describe the oral bioavailability and other PK parameters of midazolam and
metabolites.
To explore the impact of age and severity of illness (PELOD score) on oral and
IV midazolam pharmacokinetics.
To explore the feasibility of a microdosing study in children.
To explore the metabolic profile of oral midazolam in children.
Study design
Population pharmacokinetic microdosing study.
Intervention
A single oral 14C-labelled-midazolam microdose 20ng/kg will be given.
Study burden and risks
Patients have no potential benefit of participating in this study.
The burden of bloodsampling is mimnimized due to the use of an already in situ
arterial or central venous line or a blood sample will be collected when blood
is already drawn for clinical reasons. The maximum blood volume sampled per
patient will not exceed 5% of circulating total blood volume (the estimated
total blood volume is 80 ml/kg).
AMS analysis of a microdose requires the use of rare radioactive istopes (e.g.
14C). However the individual dose children form age 0-2 years will receive is
extremely low: 1 microSv, which is far below the yearly background exposure in
the Netherlands, as confirmed by a report form the Dutch agency Nuclear
Services for Energy, Environment and Health. For this reason, the radiation
exposure proposed in this study is approved by Erasmus MC radiation office for
pediatric use.
This study cannot be done in an adult populatoin, as we specifically aim to
study midazolam metabolism in children, and an effect of age is expected in
midazolam metabolism in children as to adults.
Wytemaweg 80
Rotterdam 3015 CN
NL
Wytemaweg 80
Rotterdam 3015 CN
NL
Listed location countries
Age
Inclusion criteria
- Age 0 to 6 years inclusive
- At least 36 weeks of post conceptual age or body weight 2.5 kg or more
- Receiving midazolam IV
- Parental informed consent
- Intravenous or intra-arterial access for blood sampling
Exclusion criteria
- Anticipated death in 48 hours
- No informed consent
- ECMO treatment
- Circulatory failure
* Receiving more than 1 vasopressor or
* Increase of vasopressor drug dose in the last 6 hours
- Chronic liver cirrhosis or chronic renal failure
- Renal failure according to the pRIFLE criteria, i.e. estimated creatinine clearance decreased by 75% or an urine output of <0.3 ml/kg/h for 24h or anuric for 12 hours.
- Acute liver failure AST/ALT >2 times the upper limit for age
- Gastrointestinal disorders
Ileus, diarrhoea, short bowel disease, underlying inflammatory bowel disease, pancreatic insufficiency (e.g. cystic fibrosis), celiac disease.
- Use of most relevant co-medication known to affect midazolam metabolism (according to the *Cytochrome P450 Drug Interactions Table*, listed in appendix 1) ;INHIBITORS
Indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, telithromycin, aprepitant, erythromycin, fluconazole, grapefruit juice, verapamil, diltiazem, cimetidine , amiodarone, chloramphenicol, ciprofloxacin, delaviridine, diethyldithiocarbamate, fluvoxamine, gestodene, imatinib, mibefradil, mifepristone, norfloxacin, norfluoxetine, star fruit, voriconazole
INDUCERS
Efavirenz, nevirapine, barbiturates, carbamazepine, efavirenz, glucocorticoids, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John*s wort, troglitazone
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 | EUCTR2014-003269-46-NL |
| CCMO | NL50470.000.14 |