Busulfan pharmacokinetics, toxicity, and low-dose conditioning for autologous transplantation of genetically modified hematopoietic stem cells in the rhesus macaque model Journal Article


Authors: Kang, E. M.; Hsieh, M. M.; Metzger, M.; Krouse, A.; Donahue, R. E.; Sadelain, M.; Tisdale, J. F.
Article Title: Busulfan pharmacokinetics, toxicity, and low-dose conditioning for autologous transplantation of genetically modified hematopoietic stem cells in the rhesus macaque model
Abstract: Objective. Gene transfer to hematopoietic stem cells has recently been demonstrated to benefit a small number of patients in whom a selective advantage is conferred upon genetically modified cells; however, in disorders where no such selective advantage is conferred, conditioning appears necessary to allow adequate engraftment. To decrease the toxicity profile, we sought to develop nonmyeloablative conditioning regimens and in this work, explored the use of intravenous busulfan in a large animal model. Methods. Busulfan pharmacokinetics and toxicity were monitored in young rhesus macaques at two dosing levels (4 and 6 mg/kg). These doses were then employed to condition two animals at each dose level prior to autologous transplantation of genetically modified cells using our standard methods. Methods. Busulfan pharmacokinetic (PK) data showed the area under the curve (AUC), drug half-life, and drug clearance were consistent within each dose group and similar to those reported in children. Single doses of busulfan were well tolerated and produced dose-dependent myelosuppression, most notably in the neutrophil and platelet counts. Although marking levels reached over 1% early in one animal, the long-term marking was low but detectable at 0.01 to 0.001%. Conclusions. We conclude that low-dose intravenous bolus infusion of busulfan is well tolerated, has dose-dependent effects on peripheral blood counts, and allows long-term engraftment of genetically modified cells, but at levels too low for most clinical disorders. © 2006 International Society for Experimental Hematology. Published by Elsevier Inc.
Keywords: controlled study; busulfan; area under the curve; dose response; nonhuman; animals; bone marrow suppression; animal experiment; animal model; hematopoietic stem cell transplantation; dose-response relationship, drug; animalia; neutrophil; drug mechanism; hematopoietic stem cells; transplantation conditioning; thrombocyte count; drug clearance; drug half life; macaca; macaca mulatta; infusions, intravenous; transplantation, autologous; autotransplantation
Journal Title: Experimental Hematology
Volume: 34
Issue: 2
ISSN: 0301-472X
Publisher: Elsevier Science, Inc.  
Date Published: 2006-02-01
Start Page: 132
End Page: 139
Language: English
DOI: 10.1016/j.exphem.2005.10.010
PUBMED: 16459181
PROVIDER: scopus
PMCID: PMC2676898
DOI/URL:
Notes: --- - "Cited By (since 1996): 15" - "Export Date: 4 June 2012" - "CODEN: EXHEB" - "Source: Scopus"
Altmetric
Citation Impact
MSK Authors
  1. Michel W J Sadelain
    538 Sadelain