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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Bibliographic Details
Published in:Clinical and translational science 2018-05, Vol.11 (3), p.296-304
Main Authors: Ferl, Gregory Z., Reyes, Arthur, Sun, Liping L., Cheu, Melissa, Oldendorp, Amy, Ramanujan, Saroja, Stefanich, Eric G.
Format: Article
Language:English
Subjects:
Animals
Antibodies, Bispecific - pharmacology
Antigens, CD20 - immunology
Bispecific antibodies
CD20 antigen
CD3 antigen
CD3 Complex - antagonists & inhibitors
CD3 Complex - immunology
Cell migration
Cell Movement - drug effects
Cell surface
Computer simulation
Depletion
Drug dosages
Drug Evaluation, Preclinical
FDA approval
Female
Humans
Immunoglobulins
Lymphocytes B
Macaca fascicularis
Male
Mice
Mice, Transgenic
Nonlinear systems
Nonlinearity
Pharmacodynamics
Pharmacokinetics
Population
Simulation
Studies
T-Lymphocytes - drug effects
T-Lymphocytes - immunology
T-Lymphocytes - metabolism
Transgenic animals
Transgenic mice
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Summary: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 (t½ = 1.6 h); and iii) a slowly decaying time‐varying, nonlinear clearance term (t½ = 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.
ISSN:1752-8054
1752-8062
DOI:10.1111/cts.12535