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Population-based cellular kinetic characterization of ciltacabtagene autoleucel in subjects with relapsed or refractory multiple myeloma.
Wu, Liviawati S; Su, Yaming; Li, Claire; Zhou, Wangda; Jackson, Carolyn C; Sun, Yu-Nien; Zhou, Honghui.
Afiliación
  • Wu LS; Janssen Research & Development, Brisbane, California, USA.
  • Su Y; Janssen Research and Development, Raritan, New Jersey, USA.
  • Li C; Janssen Research and Development, Spring House, Pennsylvania, USA.
  • Zhou W; Janssen Research and Development, Spring House, Pennsylvania, USA.
  • Jackson CC; Janssen Research and Development, Raritan, New Jersey, USA.
  • Sun YN; Janssen Research and Development, Spring House, Pennsylvania, USA.
  • Zhou H; Cognigen Division, Simulations Plus, Buffalo, New York, USA.
Clin Transl Sci ; 15(12): 3000-3011, 2022 12.
Article en En | MEDLINE | ID: mdl-36204820
The aims of this work were to develop a population pharmacokinetic (PK) model for chimeric antigen receptor (CAR) transgene after single intravenous infusion administration of ciltacabtagene autoleucel in adult patients with relapsed or refractory multiple myeloma. CAR transgene level in blood were measured by quantitative polymerase chain reaction (qPCR) from 97 subjects in a phase Ib/II CARTITUDE-1 study (NCT03548207), with a targeted cilta-cel dose of 0.75 × 106 (range 0.5-1.0 × 106 ) CAR positive viable T-cells per kg body weight. The population PK model development was primarily guided by the current mechanistic understanding of CAR-T kinetics and the principles of building a parsimonious model. Cilta-cel PK was adequately described by a two-compartment model (with a fast and a slow apparent decline rate from each compartment, respectively) and a chain of four transit compartments with a lag time empirically representing the process from infused CAR-T cell to measurable CAR transgene. No apparent relationship was observed between cilta-cel dose (i.e., the actual number of CAR positive viable T-cells infused), given the narrow dose range, and the observed transgene level. Based on covariate search and subgroup analysis of maximum systemic CAR transgene level (Cmax ) and area under curve from the first dose to day 28 (AUC0-28d ), none of the investigated subjects' demographics, baseline characteristics, and manufactured product characteristics had significant effects on cilta-cel PK. The developed model is deemed robust and adequate for enabling subsequent exposure-safety and exposure-efficacy analyses.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Quiméricos de Antígenos / Mieloma Múltiple Tipo de estudio: Prognostic_studies Límite: Adult / Humans Idioma: En Revista: Clin Transl Sci Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Quiméricos de Antígenos / Mieloma Múltiple Tipo de estudio: Prognostic_studies Límite: Adult / Humans Idioma: En Revista: Clin Transl Sci Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos