Gastrointestinal Implications of Voriconazole Exposure

NCT ID: NCT02904434

Last Updated: 2020-04-09

Basic Information

• Recruitment Status: WITHDRAWN
• Study Classification: OBSERVATIONAL
• Study Start Date: 2016-09-30
• Study Completion Date: 2020-06-30

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.

Conditions

Infection

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Voriconazole

Children (2-17 years old) will receive oral voriconazole as prescribed by their physicians as standard of care for the duration of the study.

Grapefruit Juice

Intervention Type: OTHER

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.

Interventions

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.

Intervention Type: OTHER

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

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Children's Hospital of Philadelphia

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Athena Zuppa, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital of Philadelphia

Locations

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Countries

United States

Other Identifiers

16-012970

Identifier Type: -

Identifier Source: org_study_id