A Preclinical Population Pharmacokinetic Model for Anti-CD20/CD3 T-Cell-Dependent Bispecific Antibodies.
Clin Transl Sci
; 11(3): 296-304, 2018 05.
Article
in En
| MEDLINE
| ID: mdl-29351372
ABSTRACT
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.
Full text:
1
Database:
MEDLINE
Main subject:
T-Lymphocytes
/
Antibodies, Bispecific
Language:
En
Journal:
Clin Transl Sci
Year:
2018
Type:
Article
Affiliation country:
United States