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

Clin Pharmacokinet. 2016 Oct;55(10):1271-1288. doi: 10.1007/s40262-016-0405-4.


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/m(2)/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.

Trial registration: NCT00274742 NCT00560794 NCT01207388 NCT01209286 NCT01741792 NCT01466179.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Antibodies, Bispecific / pharmacokinetics*
  • Antibodies, Bispecific / therapeutic use*
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / therapeutic use*
  • B-Lymphocytes / immunology
  • Body Weight
  • Cytokines / drug effects
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Half-Life
  • Humans
  • Lymphoma, Non-Hodgkin / drug therapy*
  • Male
  • Metabolic Clearance Rate
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Renal Insufficiency / metabolism
  • T-Lymphocytes / immunology


  • Antibodies, Bispecific
  • Antineoplastic Agents
  • Cytokines
  • blinatumomab

Associated data