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Challenges with sirolimus experimental data to inform QSP model of post-transplantation cyclophosphamide regimens.
Mohanan, Ezhilpavai; Shen, Guofang; Ren, Suping; Fan, Hsuan-Hao; Moua, Kao Tang Ying; Karolak, Aleksandra; Rockne, Russell C; Nakamura, Ryotaro; Horne, David A; Kanakry, Christopher G; Mager, Donald E; McCune, Jeannine S.
Afiliación
  • Mohanan E; Department of Hematologic Malignancies Translational Sciences, City of Hope, Duarte, California, USA.
  • Shen G; Department of Hematologic Malignancies Translational Sciences, City of Hope, Duarte, California, USA.
  • Ren S; Department of Hematologic Malignancies Translational Sciences, City of Hope, Duarte, California, USA.
  • Fan HH; Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York, USA.
  • Moua KTY; Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, California, USA.
  • Karolak A; Department of Hematologic Malignancies Translational Sciences, City of Hope, Duarte, California, USA.
  • Rockne RC; Department of Computational and Quantitative Medicine, City of Hope, Duarte, California, USA.
  • Nakamura R; Department of Computational and Quantitative Medicine, City of Hope, Duarte, California, USA.
  • Horne DA; Department of Hematologic Malignancies Translational Sciences, City of Hope, Duarte, California, USA.
  • Kanakry CG; Department of Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, California, USA.
  • Mager DE; Department of Cancer Biology and Molecular Medicine, City of Hope, Duarte, California, USA.
  • McCune JS; Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Clin Transl Sci ; 17(8): e70014, 2024 Aug.
Article en En | MEDLINE | ID: mdl-39162578
ABSTRACT
Dose optimization of sirolimus may further improve outcomes in allogeneic hematopoietic cell transplant (HCT) patients receiving post-transplantation cyclophosphamide (PTCy) to prevent graft-versus-host disease (GVHD). Sirolimus exposure-response association studies in HCT patients (i.e., the association of trough concentration with clinical outcomes) have been conflicting. Sirolimus has important effects on T-cells, including conventional (Tcons) and regulatory T-cells (Tregs), both of which have been implicated in the mechanisms by which PTCy prevents GVHD, but there is an absence of validated biomarkers of sirolimus effects on these cell subsets. Considering the paucity of existing biomarkers and the complexities of the immune system, we conducted a literature review to inform a quantitative systems pharmacology (QSP) model of GVHD. The published literature presented multiple challenges. The sirolimus pharmacokinetic models insufficiently describe sirolimus distribution to relevant physiological compartments. Despite multiple publications describing sirolimus effects on Tcons and Tregs in preclinical and human ex vivo models, consistent parameters relating sirolimus concentrations to circulating Tcons and Tregs could not be found. Each aspect presents a challenge in building a QSP model of sirolimus and its temporal effects on T-cell subsets and GVHD prevention. To optimize GVHD prevention regimens, phase I studies and systematic studies of immunosuppressant concentration-effect association are needed for QSP modeling.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trasplante de Células Madre Hematopoyéticas / Sirolimus / Ciclofosfamida / Enfermedad Injerto contra Huésped / Inmunosupresores Límite: Animals / Humans Idioma: En Revista: Clin Transl Sci Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trasplante de Células Madre Hematopoyéticas / Sirolimus / Ciclofosfamida / Enfermedad Injerto contra Huésped / Inmunosupresores Límite: Animals / Humans Idioma: En Revista: Clin Transl Sci Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos