Busulfan Pharmacokinetics in Adenosine Deaminase-Deficient Severe Combined Immunodeficiency Gene Therapy.

Details

Serval ID
serval:BIB_4BA60F08CDFC
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Busulfan Pharmacokinetics in Adenosine Deaminase-Deficient Severe Combined Immunodeficiency Gene Therapy.
Journal
Biology of blood and marrow transplantation
Author(s)
Bradford K.L., Liu S., Krajinovic M., Ansari M., Garabedian E., Tse J., Wang X., Shaw K.L., Gaspar H.B., Candotti F., Kohn D.B.
ISSN
1523-6536 (Electronic)
ISSN-L
1083-8791
Publication state
Published
Issued date
10/2020
Peer-reviewed
Oui
Volume
26
Number
10
Pages
1819-1827
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
The pharmacokinetics of low-dose busulfan (BU) were investigated as a nonmyeloablative conditioning regimen for autologous gene therapy (GT) in pediatric subjects with adenosine deaminase-deficient severe combined immunodeficiency disease (ADA SCID). In 3 successive clinical trials, which included either γ-retroviral (γ-RV) or lentiviral (LV) vectors, subjects were conditioned with BU using different dosing nomograms. The first cohort received BU doses based on body surface area (BSA), the second cohort received doses based on actual body weight (ABW), and in the third cohort, therapeutic drug monitoring (TDM) was used to target a specific area under the concentration-time curve (AUC). Neither BSA-based nor ABW-based dosing achieved a consistent cumulative BU AUC; in contrast, TDM-based dosing led to more consistent AUC. BU clearance increased as subject age increased from birth to 18 months. However, weight and age alone were insufficient to accurately predict the dose that would consistently achieve a target AUC. Furthermore, various clinical, laboratory, and genetic factors (eg, genotypes for glutathione-S-transferase isozymes known to participate in BU metabolism) were analyzed, but no single finding predicted subjects with rapid versus slow clearance. Analysis of BU AUC and the postengraftment vector copy number (VCN) in granulocytes, a surrogate marker of the level of engrafted gene-modified hematopoietic stem and progenitor cells (HSPCs), demonstrated gene marking at levels sufficient for therapeutic benefit in the subjects who had achieved the target BU AUC. Although many factors determine the ultimate engraftment following GT, this work demonstrates that the BU AUC correlated with the eventual level of engrafted gene-modified HSPCs within a vector group (γ-RV versus LV), with significantly higher levels of granulocyte VCN in the recipients of LV-modified grafts compared to recipients of γ-RV-transduced grafts. Taken together, these findings provide insight into low-dose BU pharmacokinetics in the unique setting of autologous GT for ADA SCID, and these dosing principles may be applied to future GT trials using low-dose BU to open the bone marrow niche.
Keywords
Adenosine deaminase, Clinical trials, Gene therapy, SCID, busulfan, pharmacokinetics, Busulfan, Pharmacokinetics
Pubmed
Open Access
Yes
Create date
24/07/2020 11:07
Last modification date
23/10/2020 5:23
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