Evaluation of safety and pharmacokinetics of administering intravenous busulfan in twice-daily or daily schedule to patients with advanced hematologic malignant disease undergoing stem cell transplantation

Hugo F. Fernandez, Hai T. Tran, Federico Albrecht, Shari Lennon, Humberto Caldera, Mark Goodman

Research output: Contribution to journalArticle

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Abstract

Intravenous busulfan (IV BU) has demonstrated safety when administered at 0.8 mg/kg per dose IV every 6 hours × 16 doses. We evaluated the safety and pharmacokinetics (PK) of giving the same total daily IV BU dose (3.2 mg/kg) either divided as a twice-daily infusion or as a single infusion to patients undergoing hematopoietic stem cell transplantation (HSCT). Twelve patients with hematologic malignant disease were treated; 7 patients had non-Hodgkin's lymphoma, 4 patients had acute myeloid leukemia, and 1 patient had chronic myelogenous leukemia. The first cohort (group A) received, on the basis of actual body weight, IV BU at 1.6 mg/kg per dose over 4 hours every 12 hours for 4 days (day -7 to day -4). The second cohort (group B) received 3.2 mg/kg per dose of IV BU (same total dose as group A) as a single infusion over 4 hours daily for 4 days. In both groups the IV BU was followed by cyclophosphamide 60 mg/kg daily for 2 days (day -3 and day -2). Blood specimens were collected on the first, fifth, and seventh doses for group A and on the first and fourth doses for group B to determine the disposition of IV BU. Peripheral blood stem cells (autologous in 7 cases and HLA-matched allogeneic in 5 cases) were given 2 days after completion of cyclophosphamide administration (day 0), and granulocyte colony-stimulating factor 5 μg/kg was started on the same day. GVHD prophylaxis consisted of tacrolimus plus methotrexate for recipients of allogeneic stem cells. One patient developed presumed fungal pneumonia and died of multisystem organ dysfunction on day +21 before hematologic reconstitution could be evaluated. Another was reported to have sudden death of undetermined cause at home on day 40. The remaining patients had engraftment (absolute neutrophil count >500/μL) at a median of 11 days and sustained platelet counts >20,000/μL at a median of 14 days. Significant regimen-related toxicity (grade III-IV) was limited to hepatic toxicity (2 cases) catheter infection (2 cases), epistaxis (3 cases), diarrhea (1 case), anorexia (1 case), mucositis (1 case), hyperglycemia (1 case), pneumonia (1 case), and sepsis (1). In group B there was 1 case of mild venoocclusive disease, which resolved without sequelae. No central nervous system or pulmonary toxicity was noted. Pharmacokinetic parameters, including clearance, half-life, maximum concentration, and area under the curve, demonstrated that the first dose profile was highly predictive of later dose PK profiles. No accumulation of the drug was noted. The change in dosing schedule did not increase toxicity or end-organ damage despite higher plasma concentration-times. Although further study for long-term efficacy is warranted, IV BU can be given safely with reproducible results on a twice-daily divided or single-daily dosing schedule to patients undergoing HSCT.

Original languageEnglish
Pages (from-to)486-492
Number of pages7
JournalBiology of Blood and Marrow Transplantation
Volume8
Issue number9
StatePublished - Oct 29 2002

Fingerprint

Busulfan
Hematologic Diseases
Stem Cell Transplantation
Appointments and Schedules
Pharmacokinetics
Safety
Hematopoietic Stem Cell Transplantation
Cyclophosphamide
Pneumonia
Mucositis
Epistaxis
Anorexia
Tacrolimus
Granulocyte Colony-Stimulating Factor
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Sudden Death
Platelet Count
Acute Myeloid Leukemia
Methotrexate
Hyperglycemia

Keywords

  • Intravenous busulfan
  • Pharmacokinetics
  • Transplantation

ASJC Scopus subject areas

  • Transplantation

Cite this

Evaluation of safety and pharmacokinetics of administering intravenous busulfan in twice-daily or daily schedule to patients with advanced hematologic malignant disease undergoing stem cell transplantation. / Fernandez, Hugo F.; Tran, Hai T.; Albrecht, Federico; Lennon, Shari; Caldera, Humberto; Goodman, Mark.

In: Biology of Blood and Marrow Transplantation, Vol. 8, No. 9, 29.10.2002, p. 486-492.

Research output: Contribution to journalArticle

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