Busulfan Pharmacokinetics in Adenosine Deaminase-Deficient Severe Combined Immunodeficiency Gene Therapy.
Busulfan Pharmacokinetics in Adenosine Deaminase-Deficient Severe Combined Immunodeficiency Gene Therapy.
复制标题
腺苷脱氨酸酶缺陷的严重合并免疫缺陷基因治疗中的Busulfan药代动力学。
DOI：
10.1016/j.bbmt.2020.07.004
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发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
Kohn DB
中科院分区：
文献类型：
--
作者：
Bradford KL;Liu S;Krajinovic M;Ansari M;Garabedian E;Tse J;Wang X;Shaw KL;Gaspar HB;Candotti F;Kohn DB
The pharmacokinetics of low dose busulfan (BU) were investigated as a non-myeloablative conditioning regimen for autologous gene therapy (GT) in pediatric subjects with adenosine deaminase-deficient severe combined immunodeficiency (ADA SCID). In three 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 based on actual body weight (ABW), and the third utilized therapeutic drug monitoring (TDM) to target a specific area under the concentration-time curve (AUC). Neither BSA nor ABW-based dosing achieved consistent cumulative BU AUC; in contrast, use of TDM-based dosing led to more consistent AUC. BU clearance increased as subject age increased from birth to eighteen months. However, weight and age alone were insufficient to accurately predict a single dose to administer that would consistently achieve a target AUC. Furthermore, various clinical, laboratory and genetic factors (i.e. genotypes for glutathione-S-transferase isozymes known to participate in BU metabolism) were analyzed; no single finding predicted subjects with rapid vs. slow clearance. Analysis of BU AUC and the post-engraftment vector copy number (VCN) in granulocytes, a surrogate marker of the level of engrafted gene-modified hematopoietic stem and progenitor cell (HSPC), demonstrated gene marking at levels sufficient for therapeutic benefit in the subjects who had achieved target BU AUC. While many factors ultimately determine the ultimate engraftment following GT, this work demonstrated that the BU AUC correlated with the eventual level of engrafted gene-modified HSPC within a vector group (γ-RV vs. LV), with significantly higher levels of granulocyte VCN in the recipients of LV-modified grafts compared to 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 that utilize low dose BU to open the bone marrow niche.
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影响因子：
--
作者：
Ansari, Marc;Curtis, Patricia Huezo-Diaz;Krajinovic, Maja
通讯作者：
Krajinovic, Maja
影响因子：
4.4
作者：
Aiuti, Alessandro;Brigida, Immacolata;Roncarolo, Maria-Grazia
通讯作者：
Roncarolo, Maria-Grazia
影响因子：
24.7
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通讯作者：
Boelens, Jaap Jan
影响因子：
17.1
作者：
Gaspar, H. Bobby;Cooray, Samantha;Thrasher, Adrian J.
通讯作者：
Thrasher, Adrian J.
影响因子：
5.7
作者：
Iwanoto, T;Hiraku, Y;Kawanishi, S
通讯作者：
Kawanishi, S