Voriconazole Pharmacokinetics in a
3-Year-Old Male With ALL

A 3-year-old, 13.5-kg boy with Philadelphia-chromosome positive acute lymphoblastic leukemia (ALL) was admitted with fever and pancytopenia. He was in his first remission and had just finished vincristine (reinduction block 1, Day 8 of 21) and continuous daily imatinib therapy. In the first few days of this reinduction block, the patient received vincristine, daunorubicin, cyclophosphamide, pegasparaginase, and triple intrathecal therapy with methotrexate, hydrocortisone, and cytarabine.

Along with fever and pancytopenia, the patient had cellulitis surrounding his port site, and he was placed on empiric IV antibiotics and oral posaconazole. The patient was due for another course of vincristine and triple-intrathecal therapy a week after admission and shortly thereafter he spiked with another fever. Blood cultures grew out yeast, and micafungin IV was added to his antifungal therapy. Despite being on micafungin, posaconazole, empiric antibiotics, and port removal, his condition continued to deteriorate. His fungal cultures identified fusarium as the causative organism; therefore micafungin and posaconazole were discontinued and voriconazole therapy began.

The patient's therapy was complicated by multiple drug interactions, most notably between voriconazole and the chemotherapeutic agents vincristine and imatinib. Imatinib metabolism is inhibited by voriconazole via cytochrome 3A4, contributing to hepatotoxicity and hematologic toxicities, among others. Voriconazole also inhibits the metabolism of vincristine, contributing to neurotoxicity and gastrointestinal toxicities, among others. In addition, voriconazole is notorious for its central nervous system toxicity, hepatotoxicity, and renal toxicity. During his hospital course, the team diligently followed his liver function, metabolic panels, blood panels, and voriconazole drug levels to monitor for toxicities that may have been caused by these drug interactions.

The literature suggests loading voriconazole starting at 6 mg/kg every 12 hours for 2 doses on Day 1, then 4 mg/kg every 12 hours thereafter. This dosing should achieve an exposure that approximates the adult maintenance dose of 3 mg/kg every 12 hours. Doses up to 7 mg/kg have also been used.

At this point, the patient is at maximum suggested dosing and is still subtherapeutic.

What would you do?

Mary Soliman, PharmD
PGY-2 Pediatric Pharmacy Resident
St Joseph's Children's Hospital, Tampa Florida

Kimberly Perez, PharmD
Pediatric Hematology/Oncology Clinical Pharmacist
St Joseph's Children's Hospital, Tampa, Florida