Pharmacokinetic monitoring is still required for intravenous busulfan in SCT for small children

Abstract

Busulfan (BU) is an alkylating agent that is used in alter-native conditioning regimen for total body irradiation(TBI) before stem cell transplantation (SCT) especially toreduce its late toxicities such as growth impairment andsecond malignancy. Because its therapeutic window isnarrow and, inter- and intra-patient variability of plasmaexposure is wide in case of conventional oral formulation,therapeutic drug monitoring (TDM) is recommended toavoid severe toxicity or rejection, especially in youngerpatients in which its variability is much more [1, 2]. ByTDM, BU dose should be adjusted so that calculatedconcentration at steady state (Css) or area under the curve(AUC) is in the range of 600–900 ng/ml or 900–1500 mmol min/L. In this context, introduction of intra-venous formulation is expected to resolve these problems.For small children, recommended dose for intravenousformulation has been reported [3, 4]. However, there is arecent report that emphasizes the necessity of TDM even inintravenous formulation [5]. In this background, weinvestigated allogeneic SCT cases with BU regimen in ourinstitute retrospectively.Since 1995, 34 patients received allogeneic hematopoi-etic SCT by using BU regimen in our pediatric section.Former 29 patients received BU orally (four doses per dayfor four consecutive days; p.o.BU group), and latter fivepatients received BU intravenously (2-h infusion every 6 hfor four consecutive days; i.v.BU group).For pharmacokinetic (PK) analysis, blood samples wereobtained 1, 2, 3, 4, and 6 h after medication of BU. Inp.o.BU group, PK analysis were performed in the last 10cases, in which test dose (0.5–0.7 mg/kg) was performed2 weeks before conditioning chemotherapy, and dose wasadjusted according to the result of PK analysis up to themaximal dose of 2 mg/kg/dose (Table 1). PK analysis wasalso performed for the initial dose, and dose was adjustedin fourth day (13th dose) in case calculated Css of BUexceeded the range of 600–900 ng/ml [Only in case 3, dosewas reduced from 1.8 to 1.1 mg/kg/dose.]. In i.v.BU group,BU was administered according to the recommendation [3,4], and blood sample was taken and stored for later PKanalysis except for the last case (case 15). In case 15, testdose was performed, and dose was reduced from 1.0 to0.8 mg/kg/dose. Informed consent was obtained from all ofthe patients or patient’s guardians before conducting thetest dose. Also, we have approval for this procedure fromour IRB.Among 15 cases in which PK analysis was performed(Table 1), graft rejection was observed only in one case(case 5) of p.o.BU group, which was a patient withhemophagocytic lymphohistiocytosis. No hepatic veno-occlusive disease (HVOD) occurred in p.o.BU group, butwas observed in two out of five i.v. cases, in which onecase (case 13) had severe HVOD and died 60 days afterSCT because of hepatic failure. In case 13, the patientreceived first SCT from HLA identical sibling with TBI(12 Gy) and cyclophosphamide (60 mg/kg 9 2 days) reg-imen. After relapse in 3 months, he was treated withHperCVAD plus imatinib chemotherapy [6] and received