Gastrointestinal Implications of Voriconazole Exposure (GIVE)

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Infection
• Intervention / Treatment: Other: Grapefruit Juice

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.

• Study Type: Observational

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• 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.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

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.

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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
VoriconazoleArea Under the Curve (AUC)	Pharmacokinetic samples will be collected	Two days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Voriconazole Apparent Bioavailability	Pharmacokinetic samples will be collected	Two days
Voriconazole Apparent Clearance	Pharmacokinetic samples will be collected	Two days

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia
• Investigators: Principal Investigator: Athena Zuppa, MD, Children's Hospital of Philadelphia

Study record dates

Study Major Dates

• Study Start: September 1, 2016
• Primary Completion (Anticipated): June 1, 2020
• Study Completion (Anticipated): June 1, 2020

Study Registration Dates

• First Submitted: September 7, 2016
• First Submitted That Met QC Criteria: September 13, 2016
• First Posted (Estimate): September 19, 2016

Study Record Updates

• Last Update Posted (Actual): April 9, 2020
• Last Update Submitted That Met QC Criteria: April 7, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: pharmacokinetics; pharmacokinetic; bioavailability; voriconazole; absorption; grapefruit juice; intestinal; intestinal first-pass metabolism
• Other Study ID Numbers: 16-012970

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No