Frequency and magnitude of dose adjustment of IV busulfan in targeted dosing strategy for pediatric allogeneic transplantation

Abstract

Busulfan is an important therapuetic agent in pediatric allogeneic transplantation. The recent introduction of IV busulfan (IV Busulfex®, ESPpharma) has descreased the intra-and interpatient dose variations associated with oral absorption and allows for targeted therapy. Children have increased drug clearance and varying degrees of hepatic function both developmentally and associated with the underlying disorders for which they are being treated. Because of this variability, first dose pharmacokinetics were perfomed on all of our patients to ensure the targeted AUC was achieved. In a series of 85 consecutive children undergoing allogeneic transplant at Methodist Children’s Hospital/Texas Transplant Institute from June 2001 to October 2003, 45 children received myeloablative doses of busulfan (0.8 mg/kg for patients 3–10 kgs; 1 mg/kg for patients > 10 kgs till age 4 yrs; 0.8 mg/kg for patients > 4 yrs given every 6 hours for 16 doses) as part of a busulfan/cyclophosphamide, busulfan/melphalan or busulfan/fludarabine preparative regimen. 42/45 patients had their actual weight used for dosing calculations. Adjusted IBW was used in 3 patients. All patients received dilantin for seizure prophylaxis. First dose pharmcokinetics were performed by the Clinical Pharmokinetics Lab at Seattle Cancer Care Alliance, targetting an AUC of 900–1300 umol.min, with dose adjustments done starting with dose 7, if needed. Donor source was matched sibling donor bone marrow or cord blood in 10 and unrelated donor sources in 35 (2 marrow and 33 mismatched umbilical cord units). The median age was 4.7 yrs (range 1 month to 17 years). Patients underwent transplant for a variety of conditions: 12 AML, 5 CML, 1 JMML, 9 ALL, 1 lymphoma, 3 HLH, 10 primary immunodefiencies, 4 hematology disorders. No patients developed VOD. 32/33 patients of patients who received a fully myeloabalative preparative regimen engrafted. A targeted AUC (900–1300 umoles.min) was achieved with initial dosing in 50% of the patients. However, many children required dose adjustment to achieve the targeted AUC, mostly dose escalation (see table ). Given the variability of metabolism in children, first dose pharmacokintics are recommended. Additionally, the starting dose in infants is lower than the currently recommended dose.TableAge/ WeightStarting Dose (mg/kg)AUC μmol · min: Median (range)Final Dosing (mg/kg): Median (range)Percent of Patients Requiring Dose AdjustmentDose Increased/ Dose Decreased3–10 kg (n = 12)0.81167 (825–1869)0.93 (0.67–1.25)50%–6/12 pts4↑/2↓10 kg-4 years (n = 11)11142 (908–1518)1 (0.76–1.25)27%–3/112↑/1↓>4 years (n = 22)0.81089 (620–1827)0.82 (0.57–1.25)65%–15/2311↑/4↓ Open table in a new tab