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Conditioning Regimens Intravenous Busulfan for Allogeneic Hematopoietic Stem Cell Transplantation in Infants: Clinical and Pharmacokinetic Results

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Conditioning Regimens Intravenous Busulfan for Allogeneic Hematopoietic Stem Cell Transplantation in Infants: Clinical and Pharmacokinetic Results Bone Marrow Transplantation (2003) 32, 647–651 & 2003 Nature Publishing Group All rights reserved 0268-3369/03 $25.00 www.nature.com/bmt Conditioning Regimens Intravenous busulfan for allogeneic hematopoietic stem cell transplantation in infants: clinical and pharmacokinetic results JH Dalle1, D Wall2, Y Theoret1, M Duval1, L Shaw3, D. Larocque1, C Taylor2, J Gardiner3, MF Vachon1 and MA Champagne1 1Service d’He´matologie et Oncologie Pe´diatrique, Hoˆpital Sainte Justine, Montre´al QC, Canada; 2Methodist Children’s Hospital of South Texas, San Antonio, TX,USA; and 3Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA Summary: tion, very wide inter- and intrapatient systemic exposure is observed with two- to sixfold of coefficient variability. High-dose busulfan is an important component of This wide bioavailability range may be linked to erratic myeloablative regimens. Variable drug exposure may intestinal absorption (7 emesis), variable hepatic metabo- occur following oral administration. Therefore, the use lism, circadianrhythm, geneticpolymorphism of a-glu- of intravenous busulfan has been advocated. Previous tathione-S-transferase, initial diagnosis, previous work has suggested a cumulative dosage of 16 mg/kg for treatment, drug–drug interaction and/or patient age. haematopoietic transplantation in children less than 3 Hepatic and renal clearance mechanisms are generally years of age, but only limited data are available in infants. underdeveloped and inefficient in the neonate, but they Pharmacokinetics of intravanous busulfan administered at may change dramatically in the months following birth. the suggested dosage were studied in 14 infants (median Thus, pharmacokinetically guided dosage adjustment age 4.7 months). Busulfan plasma concentrations were appears mandatory, particularly in children.5,7–12 measured by either GC-MS or HPLC-UV. In seven Recently, different intravenous busulfan formulations patients, the dose was decreased to target an area- under- have been developed in order to minimize variations of the- curve of 600–1300 lmol min. The median total dose inter- and intrapatient systemic exposure and to provide given was 13.8 mg/kg. All patients engrafted. Severe veno- complete dose assurance.13,14 Inadults, the recommended occlusive disease occurred in one patient. Our study dosage was 0.8 mg/kg/dose for 16 consecutive doses.13,15,16 demonstrates that a cumulative dosage of 16 mg/kg is Wall et al17 suggested a dosage of 1.0 mg/kg/dose every 6 h associated with higher exposure than expected in infants. for 16 doses for childrenless than4 years of age, whereas We suggest an initial dose of 0.8 mg/kg followed by Cremers et al18 recommended 0.8 mg/kg/dose. However, pharmacokinetically guided dose adjustment. data in infants, that is, children under 1 year of age, are Bone Marrow Transplantation (2003) 32, 647–651. scarce, precluding a recommended dosage for that parti- doi:10.1038/sj.bmt.1704209 cular age group. Inthis retrospective analysis,we report Keywords: busulfan; infants; pharmacokinetics; allogeneic clinical and pharmacokinetic results of intravenous busul- fan, prescribed off-label, in infants undergoing SCT at our institutions High-dose busulfan is widely used in conditioning regimens prior to haematopoietic stem cell transplantation (HSCT), as an alternative to total body irradiation. Although Study design busulfan may be administered once or twice daily,1,2 the most commondosage schedule is 1 mg/kg orally every 6 h Patients for 4 days to a total dosage of 16 mg/kg.3 Busulfanhas a narrow therapeutic index and veno-occlusive disease Between October 2000 and August 2002, 14 patients under (VOD) – one of the major dose-dependent toxicities – has 1 year of age and less than 10 kg received intravenous a mean incidence of 20–30% and an associated mortality busulfan as part of a conditioning regimen prior to rate from 3 to 67%.4,5 However, low drug exposure has allogeneic HSCT at the Methodist Children’s Hospital of been associated with higher recurrence rates and graft South Texas (San Antonio, TX; n ¼ 8) and at Sainte Justine failures.6,7 Following administration of the oral formula- Hospital (Montreal, Quebec; n ¼ 6). The underlying dis- eases were inherited syndromes in 10 cases, haematologic malignancies in three cases and amegakaryocytosis in one case. Grafts were one or two mismatched-unrelated cord Correspondence: Dr M Champagne, Service d’He´ matologie et Oncologie Pe´ diatrique, Hoˆ pital Sainte Justine, Coˆ te Sainte Catherine, Montreal blood (n ¼ 9), sibling bone marrow donor (n ¼ 3), matched- QC, Canada H3T 1C5. E-mail: [email protected] unrelated bone marrow donor (n ¼ 1) or haplotype Received 18 December 2002; accepted 17 March 2003 mismatch-related bone marrow donor (n ¼ 1) (Table 1). Intravenous busulfan for HSCT in infants JH Dalle et al 648 The median recipient age and body weight were 4.8 months steady state. The busulfaninfusionwascarried out over 2 h (range: 0.7–12) and 5.9 kg (range: 3.5–10), respectively via a central venous catheter using a controlled-rate (Table 2). infusion pump to mimic the time of maximum plasma concentration (about 1–2 h) observed following oral Treatment regimen administration. According to initial diagnosis and centre, different conditioning regimens were used: (1) busulfan– s An intravenous busulfan (Busulfex , OrphanMedical, cyclophosphamide association, where busulfan was given Minnetonka, MN, USA) dose of 1 mg/kg was administered ondays À9toÀ6 and cyclophosphamide 50 mg/kg once every 6 h for 16 doses in all patients but three (nos. 1, 3, 8), daily i.v. ondays À5toÀ2 (total dose 200 mg/kg) to seven inwhom a dose of 0.8 mg/kg was selected. Pharmacokine- patients (nos. 5, 9–14); (2) busulfan–fludarabine, with tically guided adjustment was usually performed , if needed, busulfan given on days –9 to –6 and fludarabine given at at dose 7, to target anarea underthe curve (AUC) of 600– 30 mg/m2 once daily i.v. on days –5 to À2 (total dose 900 mM min in children undergoing HLA-matched related 120 mg/m2) to three patients (nos. 1, 2 and 8); (3) busulfan– transplantation and 900–1300 mM mininthe others, in melphalan, with busulfan given on days –8 to –5 and melphalangivenat 45 mg/m 2 once daily i.v. on days –4 to –2 (total dose 135 mg/m2) to four patients (nos. 3, 4, 6 Table 1 Patients characteristics and 7). Intravenous busulfan was always administered as Pt no./ Age Body Weight Diagnosis Type of Seizure the first i.v. chemotherapy component of the preparative Gender (months) (Kg) Graft prophylaxis regimen; interaction with other chemotherapy agents that may interfere with PK characteristics had been avoided. All 1/F 5 5.3 SCID UCB Phenytoin patients received intravenous anticonvulsant prophylaxis as 2/M 3 6 SCID Sib Phenytoin 3/F 1 4.2 SCID UCB Phenytoin either midazolam (1.2 mg/kg/day) or phenytoin infusion 4/M 4 5.9 SCID UCB Phenytoin (dose adjusted to maintain therapeutic levels) from the day 5/M 8 6.9 Amega- UCB Phenytoin before to the day after the administration of busulfan. karyocytocis Ursodiol was administered as VOD prophylaxis. Hepatic 6/M 8 7.3 AML UCB Phenytoin VOD was defined and graded according to criteria 7/F 7 7.2 ALL UCB Phenytoin 19,20 8/M 4 6.2 SCID UCB Phenytoin described by McDonald et al. GVHD prophylaxis 9/F 0.7 3.5 Krabbe UCB Midazolam consisted of antithymocyte globulin (except for patient no. 10/M 9 9.8 AML MUD Midazolam 14), cyclosporinA andshort-course methotrexate or 11/F 4.5 4.5 SCID Haplo-Id Midazolam methylprednisolone. Patients were given standard suppor- 12/F 6 5.4 Omenn Sib Midazolam 13/M 2.9 3.8 Omenn UCB Midazolam tive care. Patients received HSCT after 1 day of rest at 14/F 12 10 FEL Sib Midazolam completionof the preparative regimen. Median4.8 6 Pharmacokinetic study Blood samples were withdrawn from central venous lines F ¼ female; M ¼ male; UCB ¼ unrelated cord blood; Sib ¼ sibling donor; MUD ¼ match-unrelated donor; Haplo-Id ¼ haplo-identical donor; into heparinized tubes immediately before and after the FEL ¼ familial lympho-erythrophagocytic histiocytosis. administration of i.v. busulfan, and at 15, 30, 60, 120, 180 Table 2 Summary of the results of i.v. busulfanpharmacokinetics Pt /Gender Age (months)/ Initial Bu dose Clearance ofBu AUC0-N Dose Adjusted AUCt Total received dose weight (kg) (mg/kg) (ml/kg/min) (mmol min) adjustment dose (mmol min) (mg/kg) after the after the 1st dose 9th dose 1/F 5/5.3 0.8 3.95 825 (1031)a No change NA ND 12.8 2/M 3/6 1 4.87 833 No change NA ND 16 3/F 1/4.2 0.8 2.98 1103 (1378)a Decrease 2.8 ND 11.52 4/M 4/5.9 1 3.09 1315 Decrease 4 ND 12.8 5/M 8/6.9 1 3.40 1203 No change NA ND 16 6/M 8/7.3 1 3.77 1077 No change NA ND 16 7/F 0.7/3.5 1 NA 1986 Decrease 2 ND 11.68 8/M 9/10.0 1 3.10 1369 Decrease 9 ND 16 9/F 4.5/4.5 1 3.30 1264 Decrease 3 768 12.8 10/F 6/5.4 1 2.80 1461 Decrease 4 806 13.3 11/M 2.9/3.8 1 3.10 1264 Decrease 3 950 13.6 12/F 12/10.0 1 3.72 1069 No change NA ND 16 13/F 7/7.2 1 4.57 889 Increase NA ND 18.25 14/M 4/6.2 0.8 4.12 794 (992) Increase NA ND 13.9 Median4.75/5.9 3.4 1234 13.75 Mean7s.d.
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