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

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.