Gastrointestinal Implications of Voriconazole Exposure

Infection Clinical Trial

— GIVE  

Official title:

Gastrointestinal Implications of Voriconazole Exposure: Determining Age-dependent Differences in Intestinal Metabolism Affecting Oral Bioavailability of Voriconazole in Children

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT02904434
• Other study ID #: 16-012970
• Status: Withdrawn
• Start date: September 2016
• Est. completion date: June 2020

Study information

• Verified date: April 2020
• Source: Children's Hospital of Philadelphia
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: June 2020
• Est. primary completion date: June 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 17 Years

Eligibility

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

Related Conditions & MeSH terms

• Infection

Intervention

Other:
• Grapefruit Juice
On day 1 of the study, subjects will receive their standard voriconazole dose with no grapefruit juice. On day 2 of the study, subjects will receive approximately 240mL of reconstituted grapefruit juice by mouth or via nasogastric tube 30 minutes prior to receiving a scheduled dose of voriconazole. Blood samples will be collected during the 12 hours following voriconazole dosing on both days of the study.

Locations

Country	Name	City	State
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Children's Hospital of Philadelphia

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	VoriconazoleArea Under the Curve (AUC)	Pharmacokinetic samples will be collected	Two days
Secondary	Voriconazole Apparent Bioavailability	Pharmacokinetic samples will be collected	Two days
Secondary	Voriconazole Apparent Clearance	Pharmacokinetic samples will be collected	Two days