title: Blinatumomab, a Bispecific T-cell Engager (BiTE(®)) for CD-19 Targeted Cancer Immunotherapy: Clinical Pharmacology and Its Implications.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Amgen Inc., Thousand Oaks, CA, 91320, USA. min.zhu@amgen.com.
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Amgen Inc., Thousand Oaks, CA, 91320, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wu
authors.affiliation: Amgen Research Munich, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Brandl
authors.affiliation: Amgen Inc., Thousand Oaks, CA, 91320, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Johnson
authors.affiliation: Amgen Research Munich, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Wolf
authors.affiliation: Amgen Inc., Thousand Oaks, CA, 91320, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Chow
authors.affiliation: Amgen Inc., Thousand Oaks, CA, 91320, USA.
authors.forename: Sameer
authors.initials: S
authors.lastname: Doshi
mesh_terms: D000367:Age Factors; D018033:Antibodies, Bispecific / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000276:immunology; D001835:Body Weight; D016207:Cytokines / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D008297:Male; D008657:Metabolic Clearance Rate; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D051437:Renal Insufficiency / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents; D016207:Cytokines; C510808:blinatumomab