Microdosing midazolam in children: age-related changes in absorption of oral drugs
- Conditions
- Age-related changes in drug absorption and metabolism in childrenTherapeutic area: Body processes [G] - Physiological processes [G07]
- Registration Number
- EUCTR2014-003269-46-NL
- Lead Sponsor
- Erasmus MC - Sophia
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- Not specified
- Target Recruitment
- 60
-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 of intra-arterial access for blood sampling
Are the trial subjects under 18? yes
Number of subjects for this age range: 60
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range
-Anticipated death in 48 hours
-No informed consent
-ECMO treatment
-Circulatory failure
* Receiving more than 1 vasporessor 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’ )
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
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main 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.;<br> Secondary Objective: To describe the oral bioavailability and other PK parameters of midazolam and metabolites.<br> To explore the impact of age and severity of illness (PELOD score) on oral and IV midazolam pharmacokinetics.<br> To explore the feasibility of a microdosing study in children.<br> ;<br> Primary end point(s): 1.Apparent clearance of midazolam (CL/F) to 1-OH-midazolam and 4-OH-midazolam.<br><br> ;Timepoint(s) of evaluation of this end point: Time after completion of the last included patient
- Secondary Outcome Measures
Name Time Method <br> Secondary end point(s): 2.Following parameters will be estimated for both formulations (IV and PO) midazolam and metabolite plasma and urinary clearance, volume of distribution in relation to age and PELOD score. For oral midazolam also: AUC, Cmax, Tmax.<br> 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)<br> In feces: midazolam and metabolite appearance.<br> 3.Description of feasibility of microdosing study in pediatric population.<br> ;Timepoint(s) of evaluation of this end point: Time after completion of the last included patient