Clinical trial NCT02904434: Gastrointestinal Implications of Voriconazole Exposure
Official title: Gastrointestinal Implications of Voriconazole Exposure: Determining Age-dependent Differences in Intestinal Metabolism Affecting Oral Bioavailability of Voriconazole in Children
Study type: OBSERVATIONAL
Overall status: WITHDRAWN
Conditions: Infection
Keywords: voriconazole
absorption
pharmacokinetic
grapefruit juice
bioavailability
intestinal first-pass metabolism
pharmacokinetics
intestinal
Lead sponsor: Children's Hospital of Philadelphia
Sponsor class: OTHER
First posted: 2016-09-19
Enrollment: 0
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Children (2-17 years old) who are being treated at The Children's Hospital of Philadelphia and receiving oral voriconazole as standard of care will be eligible to enroll in this trial.

Brief summary: Voriconazole has better response rates, improved survival and less adverse side effects compared to other drugs for the treatment of invasive fungal infections making it a desirable therapeutic option for children. However, dosing is unpredictable in children and this leads to therapeutic failure. This study aims to understand the physiological differences between children and adults that leads to therapeutic failure of voriconazole in children.

Detailed description: Voriconazole clearance in children (2-12 years old) is 3-fold higher and bioavailability is one half of adult values. An important gap in knowledge exists that explain the mechanisms that result in higher clearance and lower bioavailability of voriconazole and places children at a substantial risk for sub-therapeutic concentrations and treatment failures. Preliminary data suggests that intestinal first-pass metabolism is responsible for the lower bioavailability in children, but not in adults. By inhibiting intestinal metabolism with grapefruit juice, the extent of the effect of intestinal first-pass metabolism on voriconazole pharmacokinetics can be determined. Inpatient children at the Children's Hospital of Philadelphia who are receiving oral voriconazole as standard of care will be enrolled in an open label, cross-over clinical trial to monitor plasma voriconazole levels after voriconazole administration with and without grapefruit juice to inhibit intestinal metabolism of voriconazole. The proposed research will elucidate the role of intestinal metabolism in the reduced oral bioavailability of voriconazole in children, which can be incorporated into a model simulation to guide accurate dosing.

Eligibility criteria: Inclusion Criteria:

1. Children aged 2-17 years old
2. Receiving oral voriconazole as standard of care and at steady-state concentrations (defined as 72 hours from first-dose or 72 hours with no dose change)
3. Informed Consent/Assent when appropriate

Exclusion Criteria:

1. Allergy or inability to receive the slushy solution, which will be prepared using commercially available frozen grapefruit juice concentrate, cherry syrup, and Sprite.
2. Receiving tacrolimus and/or cyclosporine, which are affected by the furanocoumarins, during study period
3. Suspected or known hepatic dysfunction (defined as liver function tests measured at 3x upper limit of normal within the past 1 month, when measured as standard of care)
4. Receiving renal replacement therapy (example peritoneal dialysis, hemodialysis, continuous veno-venous hemofiltration, continuous veno-venous hemodialysis)
5. Receiving therapy with extracorporeal membrane oxygenation (ECMO)
6. Patients with documented pancytopenia, diarrhea, mucositis, or active infection

Primary outcomes:
measure: VoriconazoleArea Under the Curve (AUC)
timeFrame: Two days
Secondary outcomes:
measure: Voriconazole Apparent Bioavailability
timeFrame: Two days
measure: Voriconazole Apparent Clearance
timeFrame: Two days
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
Study officials:
affiliation: Children's Hospital of Philadelphia
name: Athena Zuppa, MD
role: PRINCIPAL_INVESTIGATOR
References: