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Blinatumomab, a Bispecific T-cell Engager (BiTE®) for CD-19 Targeted Cancer Immunotherapy: Clinical Pharmacology and Its Implications

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Abstract

Background and Objectives

Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct that transiently links CD19-positive B cells to CD3-positive T cells, resulting in induction of T-cell-mediated serial lysis of B cells and concomitant T-cell proliferation. Blinatumomab showed anti-leukemia activity in clinical trials and was approved by the US Food and Drug Administration for the treatment of Philadelphia chromosome-negative relapsed/refractory B-cell precursor acute lymphoblastic leukemia (r/r ALL). The objectives of this work were to characterize blinatumomab pharmacokinetics and pharmacodynamics and to evaluate dosing regimens.

Methods

Data from six phase I and II trials in patients with r/r ALL, minimal residual disease-positive ALL, and non-Hodgkin’s lymphoma (NHL) were analyzed. Blinatumomab pharmacokinetics was characterized by non-compartmental and population pharmacokinetic analyses and pharmacodynamics was described graphically.

Results

Blinatumomab exhibited linear pharmacokinetics under continuous intravenous infusion for 4–8 weeks per cycle over a dose range of 5–90 µg/m2/day, without target-mediated disposition. Estimated mean (standard deviation) volume of distribution, clearance, and elimination half-life were 4.52 (2.89) L, 2.72 (2.71) L/h, and 2.11 (1.42) h, respectively. Pharmacokinetics was similar in patients with ALL and NHL and was not affected by patient demographics, supporting fixed dosing in adults. Although creatinine clearance was a significant covariate of drug clearance, no dose adjustment was required in patients with mild or moderate renal impairment. Incidence of neutralizing antidrug antibodies was <1 %. Blinatumomab pharmacodynamics featured T-cell redistribution and activation, B-cell depletion, and transient dose-dependent cytokine elevation. Blinatumomab did not affect cytochrome P450 enzymes directly; cytokines may trigger transient cytochrome P450 suppression with low potential for inducing drug interactions.

Conclusions

Blinatumomab has unique pharmacokinetic and immunological features that require indication-dependent dosing regimens. Stepped dosing is required to achieve adequate efficacy and minimize cytokine release in diseases with high tumor burden.

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Acknowledgments

The authors acknowledge Yu-Nien (Tom) Sun and Juan Jose Perez Ruixo for helpful comments during analyses. Micah Robinson (Amgen Inc.) provided medical writing support.

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Authors and Affiliations

  1. Amgen Inc., Thousand Oaks, CA, 91320, USA

    Min Zhu, Benjamin Wu, Jessica Johnson, Andrew Chow & Sameer Doshi

  2. Amgen Research Munich, Munich, Germany

    Christian Brandl & Andreas Wolf

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  1. Min Zhu
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  2. Benjamin Wu
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  4. Jessica Johnson
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Corresponding author

Correspondence to Min Zhu.

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Funding

This study was funded by Amgen Inc.

Clinical studies

The clinical studies included in this manuscript have the following ClinicalTrials.gov identifiers: NCT00274742, NCT00560794, NCT01207388, NCT01209286, NCT01741792, and NCT01466179.

Author disclosures

Min Zhu, Benjamin Wu, Christian Brandl, Jessica Johnson, Andreas Wolf, Andrew Chow, and Sameer Doshi are employees of and shareholders in Amgen Inc.

Ethical approval

All procedures performed in the studies involving human participants described here were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the studies described here. Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.

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Zhu, M., Wu, B., Brandl, C. et al. Blinatumomab, a Bispecific T-cell Engager (BiTE®) for CD-19 Targeted Cancer Immunotherapy: Clinical Pharmacology and Its Implications. Clin Pharmacokinet 55, 1271–1288 (2016). https://doi.org/10.1007/s40262-016-0405-4

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