Safety, efficacy, and pharmacokinetics of intravenous busulfan in children undergoing allogeneic hematopoietic stem cell transplantation

Donna A. Wall, Ka Wah Chan, Michael L. Nieder, Robert J. Hayashi, Andrew M Yeager, Richard Kadota, Donna Przepiorka, Khaled Mezzi, Morris Kletzel

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Purpose. To determine the safety, efficacy, and PK profile of intravenous busulfan (Bu) in the context of a Bu and cyclophosphamide (IVBuCy) preparative regimen in children undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Methods. Twenty-four children were enrolled in an open-label, multicenter trial of IVBuCy as the preparative regimen for HLA-matched sibling allogeneic HSCT. IVBu was administered q6 hr for 16 doses with a targeted area under the curve (AUC) of 900-1,350 μMol-min. The initial dose was 0.8 mg/kg for children >4 years of age and 1 mg/kg for those <4 years of age. PK of the first dose IVBu was determined to calculate a single dosage adjustment, and with the 9th and 13th doses to confirm steady-state PK. Results. The targeted AUC was achieved with the first dose in 17/ 24 (71%) of the children using the age-adjusted dosing approach. Dosing was increased in five patients, and reduced in two patients to achieve target values. After dose adjustment based on PK, 91% of the children had an AUC within the target range at steady state (AUCss). Median final dosing and clearance (CL) of IVBu were 1.1 mg/kg and 4.1 ml/min/kg in patients <4 years, and 0.9 mg/kg and 2.9 ml/min/kg in patients >4 years. All children were engrafted with documented donor chimerism. No late rejections or graft failures occurred. Four patients had veno-occlusive disease, three of which resolved within 2 weeks of onset. Two children died from transplantrelated causes unrelated to Bu. Conclusion. IVBu is a safe and effective and offers the benefit of predictable and consistent systemic exposure.

Original languageEnglish (US)
Pages (from-to)291-298
Number of pages8
JournalPediatric Blood and Cancer
Volume54
Issue number2
DOIs
StatePublished - Feb 2010

Fingerprint

Busulfan
Hematopoietic Stem Cell Transplantation
Pharmacokinetics
Safety
Chimerism
Graft Rejection
Cyclophosphamide
Multicenter Studies
Area Under Curve
Siblings
Tissue Donors

Keywords

  • Bone marrow transplantation
  • Children
  • Hematopoietic stem cell transplantation
  • Intravenous busulfan
  • Pharmacokinetics

ASJC Scopus subject areas

  • Oncology
  • Pediatrics, Perinatology, and Child Health
  • Hematology

Cite this

Safety, efficacy, and pharmacokinetics of intravenous busulfan in children undergoing allogeneic hematopoietic stem cell transplantation. / Wall, Donna A.; Chan, Ka Wah; Nieder, Michael L.; Hayashi, Robert J.; Yeager, Andrew M; Kadota, Richard; Przepiorka, Donna; Mezzi, Khaled; Kletzel, Morris.

In: Pediatric Blood and Cancer, Vol. 54, No. 2, 02.2010, p. 291-298.

Research output: Contribution to journalArticle

Wall, Donna A. ; Chan, Ka Wah ; Nieder, Michael L. ; Hayashi, Robert J. ; Yeager, Andrew M ; Kadota, Richard ; Przepiorka, Donna ; Mezzi, Khaled ; Kletzel, Morris. / Safety, efficacy, and pharmacokinetics of intravenous busulfan in children undergoing allogeneic hematopoietic stem cell transplantation. In: Pediatric Blood and Cancer. 2010 ; Vol. 54, No. 2. pp. 291-298.
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T1 - Safety, efficacy, and pharmacokinetics of intravenous busulfan in children undergoing allogeneic hematopoietic stem cell transplantation

AU - Wall, Donna A.

AU - Chan, Ka Wah

AU - Nieder, Michael L.

AU - Hayashi, Robert J.

AU - Yeager, Andrew M

AU - Kadota, Richard

AU - Przepiorka, Donna

AU - Mezzi, Khaled

AU - Kletzel, Morris

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N2 - Purpose. To determine the safety, efficacy, and PK profile of intravenous busulfan (Bu) in the context of a Bu and cyclophosphamide (IVBuCy) preparative regimen in children undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Methods. Twenty-four children were enrolled in an open-label, multicenter trial of IVBuCy as the preparative regimen for HLA-matched sibling allogeneic HSCT. IVBu was administered q6 hr for 16 doses with a targeted area under the curve (AUC) of 900-1,350 μMol-min. The initial dose was 0.8 mg/kg for children >4 years of age and 1 mg/kg for those <4 years of age. PK of the first dose IVBu was determined to calculate a single dosage adjustment, and with the 9th and 13th doses to confirm steady-state PK. Results. The targeted AUC was achieved with the first dose in 17/ 24 (71%) of the children using the age-adjusted dosing approach. Dosing was increased in five patients, and reduced in two patients to achieve target values. After dose adjustment based on PK, 91% of the children had an AUC within the target range at steady state (AUCss). Median final dosing and clearance (CL) of IVBu were 1.1 mg/kg and 4.1 ml/min/kg in patients <4 years, and 0.9 mg/kg and 2.9 ml/min/kg in patients >4 years. All children were engrafted with documented donor chimerism. No late rejections or graft failures occurred. Four patients had veno-occlusive disease, three of which resolved within 2 weeks of onset. Two children died from transplantrelated causes unrelated to Bu. Conclusion. IVBu is a safe and effective and offers the benefit of predictable and consistent systemic exposure.

AB - Purpose. To determine the safety, efficacy, and PK profile of intravenous busulfan (Bu) in the context of a Bu and cyclophosphamide (IVBuCy) preparative regimen in children undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Methods. Twenty-four children were enrolled in an open-label, multicenter trial of IVBuCy as the preparative regimen for HLA-matched sibling allogeneic HSCT. IVBu was administered q6 hr for 16 doses with a targeted area under the curve (AUC) of 900-1,350 μMol-min. The initial dose was 0.8 mg/kg for children >4 years of age and 1 mg/kg for those <4 years of age. PK of the first dose IVBu was determined to calculate a single dosage adjustment, and with the 9th and 13th doses to confirm steady-state PK. Results. The targeted AUC was achieved with the first dose in 17/ 24 (71%) of the children using the age-adjusted dosing approach. Dosing was increased in five patients, and reduced in two patients to achieve target values. After dose adjustment based on PK, 91% of the children had an AUC within the target range at steady state (AUCss). Median final dosing and clearance (CL) of IVBu were 1.1 mg/kg and 4.1 ml/min/kg in patients <4 years, and 0.9 mg/kg and 2.9 ml/min/kg in patients >4 years. All children were engrafted with documented donor chimerism. No late rejections or graft failures occurred. Four patients had veno-occlusive disease, three of which resolved within 2 weeks of onset. Two children died from transplantrelated causes unrelated to Bu. Conclusion. IVBu is a safe and effective and offers the benefit of predictable and consistent systemic exposure.

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KW - Pharmacokinetics

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