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

Autor: Kit L. Shaw, Kathryn L. Bradford, Maja Krajinovic, Siyu Liu, Xiaoyan Wang, Elizabeth Garabedian, John Tse, Donald B. Kohn, Marc Ansari, Fabio Candotti, H. Bobby Gaspar
Rok vydání: 2020
Předmět:
Oncology
Transplantation Conditioning
Adenosine Deaminase
Genetic enhancement
Severe Combined Immunodeficiency / therapy
Regenerative Medicine
Adenosine Deaminase / genetics
Clinical trials
0302 clinical medicine
Agammaglobulinemia
Stem Cell Research - Nonembryonic - Human
Child
Body surface area
ddc:618
medicine.diagnostic_test
Hematopoietic Stem Cell Transplantation
Hematology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Stem Cell Research - Nonembryonic - Non-Human
Biotechnology
medicine.drug
medicine.medical_specialty
Clinical Trials and Supportive Activities
Clinical Sciences
Immunology
SCID
03 medical and health sciences
Gene therapy
Pharmacokinetics
Clinical Research
Internal medicine
Genetics
medicine
Humans
Dosing
Busulfan
Transplantation
Severe combined immunodeficiency
business.industry
Infant
Genetic Therapy
Stem Cell Research
medicine.disease
Severe Combined Immunodeficiency / genetics
Therapeutic drug monitoring
Severe Combined Immunodeficiency
Bone marrow
business
030215 immunology
Zdroj: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, vol 26, iss 10
Biology of blood and marrow transplantation, Vol. 26, No 10 (2020) pp. 1819-1827
ISSN: 1083-8791
Popis: 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.
Databáze: OpenAIRE
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