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21.05.2016 | Original Research Article | Ausgabe 10/2016

Clinical Pharmacokinetics 10/2016

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

Zeitschrift:
Clinical Pharmacokinetics > Ausgabe 10/2016
Autoren:
Min Zhu, Benjamin Wu, Christian Brandl, Jessica Johnson, Andreas Wolf, Andrew Chow, Sameer Doshi
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s40262-016-0405-4) contains supplementary material, which is available to authorized users.

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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Zusatzmaterial
Supplementary material 1 (pdf 1.09 mb)
40262_2016_405_MOESM1_ESM.pdf
Literatur
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