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A Preclinical Population Pharmacokinetic Model for Anti‐CD20/CD3 T‐Cell‐Dependent Bispecific Antibodies

CD20 is a cell‐surface receptor expressed by healthy and neoplastic B cells and is a well‐established target for biologics used to treat B‐cell malignancies. Pharmacokinetic (PK) and pharmacodynamic (PD) data for the anti‐CD20/CD3 T‐cell‐dependent bispecific antibody BTCT4465A were collected in tran...

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Autores principales: Ferl, Gregory Z., Reyes, Arthur, Sun, Liping L., Cheu, Melissa, Oldendorp, Amy, Ramanujan, Saroja, Stefanich, Eric G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944627/
https://www.ncbi.nlm.nih.gov/pubmed/29351372
http://dx.doi.org/10.1111/cts.12535
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author Ferl, Gregory Z.
Reyes, Arthur
Sun, Liping L.
Cheu, Melissa
Oldendorp, Amy
Ramanujan, Saroja
Stefanich, Eric G.
author_facet Ferl, Gregory Z.
Reyes, Arthur
Sun, Liping L.
Cheu, Melissa
Oldendorp, Amy
Ramanujan, Saroja
Stefanich, Eric G.
author_sort Ferl, Gregory Z.
collection PubMed
description CD20 is a cell‐surface receptor expressed by healthy and neoplastic B cells and is a well‐established target for biologics used to treat B‐cell malignancies. Pharmacokinetic (PK) and pharmacodynamic (PD) data for the anti‐CD20/CD3 T‐cell‐dependent bispecific antibody BTCT4465A were collected in transgenic mouse and nonhuman primate (NHP) studies. Pronounced nonlinearity in drug elimination was observed in the murine studies, and time‐varying, nonlinear PK was observed in NHPs, where three empirical drug elimination terms were identified using a mixed‐effects modeling approach: i) a constant nonsaturable linear clearance term (7 mL/day/kg); ii) a rapidly decaying time‐varying, linear clearance term (t(½) = 1.6 h); and iii) a slowly decaying time‐varying, nonlinear clearance term (t(½) = 4.8 days). The two time‐varying drug elimination terms approximately track with time scales of B‐cell depletion and T‐cell migration/expansion within the central blood compartment. The mixed‐effects NHP model was scaled to human and prospective clinical simulations were generated.
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spelling pubmed-59446272018-05-14 A Preclinical Population Pharmacokinetic Model for Anti‐CD20/CD3 T‐Cell‐Dependent Bispecific Antibodies Ferl, Gregory Z. Reyes, Arthur Sun, Liping L. Cheu, Melissa Oldendorp, Amy Ramanujan, Saroja Stefanich, Eric G. Clin Transl Sci Research CD20 is a cell‐surface receptor expressed by healthy and neoplastic B cells and is a well‐established target for biologics used to treat B‐cell malignancies. Pharmacokinetic (PK) and pharmacodynamic (PD) data for the anti‐CD20/CD3 T‐cell‐dependent bispecific antibody BTCT4465A were collected in transgenic mouse and nonhuman primate (NHP) studies. Pronounced nonlinearity in drug elimination was observed in the murine studies, and time‐varying, nonlinear PK was observed in NHPs, where three empirical drug elimination terms were identified using a mixed‐effects modeling approach: i) a constant nonsaturable linear clearance term (7 mL/day/kg); ii) a rapidly decaying time‐varying, linear clearance term (t(½) = 1.6 h); and iii) a slowly decaying time‐varying, nonlinear clearance term (t(½) = 4.8 days). The two time‐varying drug elimination terms approximately track with time scales of B‐cell depletion and T‐cell migration/expansion within the central blood compartment. The mixed‐effects NHP model was scaled to human and prospective clinical simulations were generated. John Wiley and Sons Inc. 2018-01-19 2018-05 /pmc/articles/PMC5944627/ /pubmed/29351372 http://dx.doi.org/10.1111/cts.12535 Text en © 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research
Ferl, Gregory Z.
Reyes, Arthur
Sun, Liping L.
Cheu, Melissa
Oldendorp, Amy
Ramanujan, Saroja
Stefanich, Eric G.
A Preclinical Population Pharmacokinetic Model for Anti‐CD20/CD3 T‐Cell‐Dependent Bispecific Antibodies
title A Preclinical Population Pharmacokinetic Model for Anti‐CD20/CD3 T‐Cell‐Dependent Bispecific Antibodies
title_full A Preclinical Population Pharmacokinetic Model for Anti‐CD20/CD3 T‐Cell‐Dependent Bispecific Antibodies
title_fullStr A Preclinical Population Pharmacokinetic Model for Anti‐CD20/CD3 T‐Cell‐Dependent Bispecific Antibodies
title_full_unstemmed A Preclinical Population Pharmacokinetic Model for Anti‐CD20/CD3 T‐Cell‐Dependent Bispecific Antibodies
title_short A Preclinical Population Pharmacokinetic Model for Anti‐CD20/CD3 T‐Cell‐Dependent Bispecific Antibodies
title_sort preclinical population pharmacokinetic model for anti‐cd20/cd3 t‐cell‐dependent bispecific antibodies
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944627/
https://www.ncbi.nlm.nih.gov/pubmed/29351372
http://dx.doi.org/10.1111/cts.12535
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