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Pharmacokinetic and Pharmacodynamic Relationship of Blinatumomab in Patients with Non-Hodgkin Lymphoma

[ Vol. 13 , Issue. 1 ]

Author(s):

Youssef Hijazi, Matthias Klinger, Andrea Kratzer, Benjamin Wu, Patrick A. Baeuerle, Peter Kufer, Andreas Wolf, Dirk Nagorsen and Min Zhu* Pages 55-64 (10)

Abstract:


Background: Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct targeting CD3ε on T cells and CD19 on B cells. We describe the relationship between pharmacokinetics (PK) of blinatumomab and pharmacodynamic (PD) changes in peripheral lymphocytes, serum cytokines, and tumor size in patients with non-Hodgkin lymphoma (NHL).

Methods: In a phase 1 study, 76 patients with relapsed/refractory NHL received blinatumomab by continuous intravenous infusion at various doses (0.5 to 90 µg/m2/day). PD changes were analyzed with respect to dose, blinatumomab concentration at steady state (Css), and cumulative area under the concentration-versus-time curve (AUCcum).

Results: B-cell depletion occurred within 48 hours at doses ≥5 µg/m2/day, followed first-order kinetics, and was blinatumomab exposure-dependent. Change in tumor size depended on systemic blinatumomab exposure and treatment duration and could be fitted to an Emax model, which predicted a 50% reduction in tumor size at AUCcum of ≥1,340 h×µg/L and Css of ≥1,830 pg/mL, corresponding to a blinatumomab dose of 47 µg/m2/day for 28 days. The magnitude of transient cytokine elevation, observed within 1-2 days of infusion start, was dose-dependent, with less pronounced elevation at low starting doses.

Conclusion: B-lymphocyte depletion following blinatumomab infusion was exposure-dependent. Transient cytokine elevation increased with dose; it was less pronounced at low starting doses. Tumor response was a function of exposure, suggesting utility for the PK/PD relationship in dose selection for future studies, including NHL and other malignant settings.

Keywords:

Blinatumomab, BiTE®, non-Hodgkin lymphoma, exposure-response, pharmacokinetics, pharmacodynamics.

Affiliation:

Amgen Research (Munich) GmbH, Munich, Amgen Research (Munich) GmbH, Munich, Amgen Research (Munich) GmbH, Munich, Amgen Inc., Thousand Oaks, CA, Amgen Research (Munich) GmbH, Munich, Amgen Research (Munich) GmbH, Munich, Amgen Research (Munich) GmbH, Munich, Amgen Inc., Thousand Oaks, CA, Amgen Inc., Thousand Oaks, CA

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