Gastrointestinal Implications of Voriconazole Exposure

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.

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