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Pharmacokinetics of a test dose of intravenous busulfan guide dose modifications to achieve an optimal area under the curve of a single daily dose of intravenous busulfan in children undergoing a reduced-intensity conditioning regimen with hematopoietic stem cell transplantation.
Biol Blood Marrow Transplant. 2006 Apr; 12(4):472-9.BB

Abstract

We studied 30 pediatric patients with malignant (n = 16) or nonmalignant (n = 14) conditions. The preparative regimen consisted of fludarabine, intravenous (IV) busulfan (Bu) for 2 daily doses, and antithymocyte globulin before stem cell transplantation. A test dose of IV Bu (0.8 mg/kg), anticipated to target an area under the concentration-time curve (AUC) of 800 to 1200 micromol.min, was followed later by 2 daily doses adjusted according to the pharmacokinetics (PK) to target an AUC of 3200 to 4800 micromol.min. The median test dose AUC was 953 micromol.min (range, 439-1315 micromol.min). The median AUC of single daily doses was 3798 micromol.min (range, 1511-7254 micromol.min). PK-based dose modification was required in 20 patients: 12 were adjusted to a higher dose, and in 8 the dose was decreased. Nausea and vomiting were noted in 15 patients. No patient developed hepatic veno-occlusive disease or seizures. Full donor chimerism was attained in 20 patients (mean of 24.5 days), 3 achieved partial chimerism, 5 did not engraft, and in 2 it is too early to assess chimerism. Acute graft-versus-host disease developed in 11 patients, grades I to II developed in 10 patients, and grade III developed in 1. Four patients died of infection and 5 of progressive disease. Thus, PK of a test dose of IV Bu provided information to adjust subsequent daily doses of IV Bu: this resulted in a regimen that was feasible, safe, and convenient for administration to children.

Authors+Show Affiliations

Stem Cell Transplant Program, Children's Memorial Hospital, Feinberg School of Medicine, Department of Pediatrics, Northwestern University, Chicago, IL 60614, USA. mkletzel@northwestern.eduNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16545731

Citation

Kletzel, Morris, et al. "Pharmacokinetics of a Test Dose of Intravenous Busulfan Guide Dose Modifications to Achieve an Optimal Area Under the Curve of a Single Daily Dose of Intravenous Busulfan in Children Undergoing a Reduced-intensity Conditioning Regimen With Hematopoietic Stem Cell Transplantation." Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, vol. 12, no. 4, 2006, pp. 472-9.
Kletzel M, Jacobsohn D, Duerst R. Pharmacokinetics of a test dose of intravenous busulfan guide dose modifications to achieve an optimal area under the curve of a single daily dose of intravenous busulfan in children undergoing a reduced-intensity conditioning regimen with hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2006;12(4):472-9.
Kletzel, M., Jacobsohn, D., & Duerst, R. (2006). Pharmacokinetics of a test dose of intravenous busulfan guide dose modifications to achieve an optimal area under the curve of a single daily dose of intravenous busulfan in children undergoing a reduced-intensity conditioning regimen with hematopoietic stem cell transplantation. Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, 12(4), 472-9.
Kletzel M, Jacobsohn D, Duerst R. Pharmacokinetics of a Test Dose of Intravenous Busulfan Guide Dose Modifications to Achieve an Optimal Area Under the Curve of a Single Daily Dose of Intravenous Busulfan in Children Undergoing a Reduced-intensity Conditioning Regimen With Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2006;12(4):472-9. PubMed PMID: 16545731.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacokinetics of a test dose of intravenous busulfan guide dose modifications to achieve an optimal area under the curve of a single daily dose of intravenous busulfan in children undergoing a reduced-intensity conditioning regimen with hematopoietic stem cell transplantation. AU - Kletzel,Morris, AU - Jacobsohn,David, AU - Duerst,Reggie, PY - 2005/06/29/received PY - 2005/12/07/accepted PY - 2006/3/21/pubmed PY - 2006/12/23/medline PY - 2006/3/21/entrez SP - 472 EP - 9 JF - Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation JO - Biol Blood Marrow Transplant VL - 12 IS - 4 N2 - We studied 30 pediatric patients with malignant (n = 16) or nonmalignant (n = 14) conditions. The preparative regimen consisted of fludarabine, intravenous (IV) busulfan (Bu) for 2 daily doses, and antithymocyte globulin before stem cell transplantation. A test dose of IV Bu (0.8 mg/kg), anticipated to target an area under the concentration-time curve (AUC) of 800 to 1200 micromol.min, was followed later by 2 daily doses adjusted according to the pharmacokinetics (PK) to target an AUC of 3200 to 4800 micromol.min. The median test dose AUC was 953 micromol.min (range, 439-1315 micromol.min). The median AUC of single daily doses was 3798 micromol.min (range, 1511-7254 micromol.min). PK-based dose modification was required in 20 patients: 12 were adjusted to a higher dose, and in 8 the dose was decreased. Nausea and vomiting were noted in 15 patients. No patient developed hepatic veno-occlusive disease or seizures. Full donor chimerism was attained in 20 patients (mean of 24.5 days), 3 achieved partial chimerism, 5 did not engraft, and in 2 it is too early to assess chimerism. Acute graft-versus-host disease developed in 11 patients, grades I to II developed in 10 patients, and grade III developed in 1. Four patients died of infection and 5 of progressive disease. Thus, PK of a test dose of IV Bu provided information to adjust subsequent daily doses of IV Bu: this resulted in a regimen that was feasible, safe, and convenient for administration to children. SN - 1083-8791 UR - https://www.unboundmedicine.com/medline/citation/16545731/Pharmacokinetics_of_a_test_dose_of_intravenous_busulfan_guide_dose_modifications_to_achieve_an_optimal_area_under_the_curve_of_a_single_daily_dose_of_intravenous_busulfan_in_children_undergoing_a_reduced_intensity_conditioning_regimen_with_hematopoietic_stem_cell_transplantation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1083-8791(05)01411-4 DB - PRIME DP - Unbound Medicine ER -