26DT052; Scaling Busulfan Dose to Body Surface Area in Children

Busulfan is a drug used in conditioning regimens for bone marrow transplantation. Busulfan levels outside the desired range can cause excessive side effects or failure of bone marrow engraftment. The initial dose of busulfan is currently scaled to body weight; on subsequent days the dose may be adjusted to achieve busulfan levels in a therapeutic range. However, only half of children receiving a busulfan dose scaled to body weight achieve therapeutic blood levels after the first dose. We performed computer simulations of alternative dosing methods for infants and children, and identified that dosing based on body surface area (BSA) could significantly increase the number of children achieving therapeutic blood levels after the first dose. This study will test whether this new dosing method results in a higher percentage of patients achieving the desired busulfan blood levels after the first dose. The study will enroll up to 38 children receiving high doses of busulfan as part of their standard conditioning regimen prior to bone marrow transplant. We will use the busulfan blood levels that are routinely measured after the first dose to determine the effectiveness of our new dosing method.

• Busulfan (BU) (Drug): Busulfan is a cell cycle non-specific alkylating agent which is approved by the Food and Drug Administration (FDA) and is commercially available.

Primary outcomes

• Number of participants who achieve a therapeutic drug exposure after the first dose of Busulfan [1 day]: Dosing for patients in Group A (BSA >=0.5m2) will be scaled to Body Surface Area, and patients in Group B (BSA <0.5m2) will be dosed based on the infant dosing table for Day 1 dose. The value range for therapeutic drug exposure is 36,000 μM/min (Lower Bound) - 6,000 μM/min (Upper Bound)

Secondary outcomes

• Glutathione sample concentration over the 4-day course of busulfan administration. [4 days]: Plasma glutathione samples will be obtained daily to determine glutathione concentration over the 4 days busulfan is administered. A 4-day total of gluathione sample concentration will be reported.
• Number of participants with sinusoidal obstruction [100 days post transplant]: Target adverse events (SOS, engraftment failure) will be tracked in all patients for the first 100 days post-transplant.
• Number of participants with engraftment failure [100 days post transplant]: Target adverse events (SOS, engraftment failure) will be tracked in all patients for the first 100 days post-transplant.

Sex: All, ages: any to 21 Years

Inclusion Criteria:

1. Subject age: ≤21 years
2. Body Surface Area (BSA):

   1. Group A: BSA ≥0.5 m2
   2. Group B: BSA <0.5 m2
3. Planned for once-daily busulfan-containing conditioning regimen pre-bone marrow transplant
4. Scheduled to have TDM after the first dose of busulfan
5. Diagnosis: both benign and malignant conditions are eligible

Exclusion Criteria:

1\. At the time of enrollment, patients may not receive medications that significantly alter busulfan clearance, as specified below.

a. If patients had received the drugs listed below prior to enrollment, the following washout periods, based on ≥ 6 times drug t½, are required.

Deferasirox: ≥7 days Metronidazole: ≥7 days Ketoconazole, voriconazole: ≥7 days Itraconazole, posaconazole: ≥14 days Phenytoin: ≥21 days