Blinatumomab is a bispecific T-cell engager molecule that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T-cells. It activates endogenous T-cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on benign and malignant B-cells. The anti-tumour activity of blinatumomab immunotherapy is not dependent on T-cells bearing a specific TCR or on peptide antigens presented by cancer cells, but is polyclonal in nature and independent of human leukocyte antigen (HLA) molecules on target cells. Blinatumomab mediates the formation of a cytolytic synapse between the T-cell and the tumour cell, releasing proteolytic enzymes to kill both proliferating and resting target cells. Blinatumomab is associated with transient upregulation of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T-cells, and results in elimination of CD19+ cells.
Consistent immune-pharmacodynamic responses were observed in patients studied. During the continuous intravenous infusion over 4 weeks, the pharmacodynamic response was characterised by T-cell activation and initial redistribution, rapid peripheral B-cell depletion, and transient cytokine elevation.
Peripheral T-cell redistribution (i.e. T-cell adhesion to blood vessel endothelium and/or transmigration into tissue) occurred after start of blinatumomab infusion or dose escalation. T-cell counts initially declined within 1 to 2 days and then returned to baseline levels within 7 to 14 days in the majority of patients. Increase of T-cell counts above baseline (T-cell expansion) was observed in few patients.
Peripheral B-cell counts decreased rapidly to an undetectable level during treatment at doses ≥5 mcg/m²/day or ≥9 mcg/day in the majority of patients. No recovery of peripheral B-cell counts was observed during the 2-week treatment-free period between treatment cycles. Incomplete depletion of B-cells occurred at doses of 0.5 mcg/m²/day and 1.5 mcg/m²/day and in a few non-responders at higher doses.
Peripheral lymphocytes were not measured in paediatric subjects.
Cytokines including IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-α and IFN-γ were measured and, IL-6, IL-10 and IFN-γ were most elevated. Transient elevation of cytokines was observed in the first 2 days following start of blinatumomab infusion. The elevated cytokine levels returned to baseline within 24 to 48 hours during the infusion. In subsequent treatment cycles, cytokine elevation occurred in fewer patients with lesser intensity compared to the initial 48 hours of the first treatment cycle.
The pharmacokinetics of blinatumomab appear linear over a dose range from 5 to 90 mcg/m²/day (approximately equivalent to 9-162 mcg/day) in adult patients. Following continuous intravenous infusion, the steady state serum concentration (Css) was achieved within a day and remained stable over time. The increase in mean Css values was approximately proportional to the dose in the range tested. At the clinical doses of 9 mcg/day and 28 mcg/day for the treatment of relapsed or refractory ALL, the mean (SD) Css was 228 (356) pg/mL and 616 (537) pg/mL, respectively. The pharmacokinetics of blinatumomab in patients with MRD positive B-cell precursor ALL was similar to patients with relapsed or refractory ALL.
The estimated mean (SD) volume of distribution based on terminal phase (Vz) was 4.35 (2.45) L with the continuous intravenous infusion of blinatumomab.
The metabolic pathway of blinatumomab has not been characterised. Like other protein therapeutics, blinatumomab is expected to be degraded into small peptides and amino acids via catabolic pathways.
The estimated mean (SD) systemic clearance with continuous intravenous infusion in patients receiving blinatumomab in clinical studies was 3.11 (2.98) L/hour. The mean (SD) half-life was 2.10 (1.41) hours. Negligible amounts of blinatumomab were excreted in the urine at the tested clinical doses.
A population pharmacokinetic analysis was performed to evaluate the effects of demographic characteristics on blinatumomab pharmacokinetics. Results suggest that age (7 months to 80 years) and gender do not influence the pharmacokinetics of blinatumomab. Body surface area (0.37 to 2.70 m²) influences the pharmacokinetics of blinatumomab. However, the influence is negligible in adults and body surface area based dosing is recommended in the paediatric population.
No formal pharmacokinetic studies of blinatumomab have been conducted in patients with renal impairment.
Pharmacokinetic analyses showed an approximately 2-fold difference in mean blinatumomab clearance values between patients with moderate renal dysfunction and normal renal function. However high inter-patient variability was discerned (CV% up to 96.8%), and clearance values in renal impaired patients were essentially within the range observed in patients with normal renal function, no clinically meaningful impact of renal function on clinical outcomes is expected.
No formal pharmacokinetic studies of blinatumomab have been conducted in patients with hepatic impairment. Baseline ALT and AST levels were used to assess the effect of hepatic impairment on the clearance of blinatumomab. Population pharmacokinetic analysis suggested that there was no association between ALT or AST levels and the clearance of blinatumomab.
The pharmacokinetics of blinatumomab appear linear over a dose range from 5 to 30 mcg/m²/day in paediatric patients with relapsed or refractory B-cell precursor ALL. At the recommended doses of 5 and 15 mcg/m²/day, the mean (SD) steady state concentration (Css) values were 162 (179) and 533 (392) pg/mL, respectively. The estimated mean (SD) volume of distribution (Vz), clearance (CL) and terminal half-life (t1/2,z) were 3.91 (3.36) L/m², 1.88 (1.90) L/hr/m² and 2.19 (1.53) hours, respectively.
The pharmacokinetics of blinatumomab in patients with high-risk first relapsed B-cell precursor ALL was characterised with an estimated mean (SD) Css at 15 mcg/m²/day and CL were 921 (1 010) pg/mL and 0.988 (0.450) L/hr/m², respectively; the observed values are not considered to be clinically different from those in patients with relapsed or refractory B-cell precursor ALL. Volume of distribution and half-life could not be estimated.
Repeat-dose toxicity studies conducted with blinatumomab and the murine surrogate revealed the expected pharmacologic effects (including release of cytokines, decreases in leukocyte counts, depletion of B-cells, decreases in T-cells, decreased cellularity in lymphoid tissues). These changes reversed after cessation of treatment.
Reproductive toxicity studies have not been conducted with blinatumomab. In an embryo-foetal developmental toxicity study performed in mice, the murine surrogate crossed the placenta to a limited extent (foetal-to-maternal serum concentration ratio <1%) and did not induce embryo-foetal toxicity or teratogenicity. The expected depletions of B- and T-cells were observed in the pregnant mice but haematological effects were not assessed in foetuses. No studies have been conducted to evaluate treatment-related effects on fertility. There were no effects on male or female reproductive organs in toxicity studies with the murine surrogate.
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