1. Academic Validation
  2. A Preclinical Population Pharmacokinetic Model for Anti-CD20/CD3 T-Cell-Dependent Bispecific Antibodies

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

  • Clin Transl Sci. 2018 May;11(3):296-304. doi: 10.1111/cts.12535.
Gregory Z Ferl 1 Arthur Reyes 1 Liping L Sun 1 Melissa Cheu 1 Amy Oldendorp 1 Saroja Ramanujan 1 Eric G Stefanich 1
Affiliations

Affiliation

  • 1 Genentech, Inc., Genentech Research and Early Development, South San Francisco, California, USA.
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.

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