entration (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/refractory ALL, the mean (SD) Css was 211 (258) pg/mL and 621 (502) pg/mL, respectively.
Distribution
The estimated mean (SD) volume of distribution based on terminal phase (Vz) was 4.52 (2.89) L with continuous intravenous infusion of blinatumomab.
Metabolism
The metabolic pathway of blinatumomab has not been characterized. Like other protein therapeutics, BLINCYTO is expected to be degraded into small peptides and amino acids via catabolic pathways.
Elimination
The estimated mean (SD) systemic clearance with continuous intravenous infusion in patients receiving blinatumomab in clinical studies was 2.92 (2.83) L/hour. The mean (SD) half-life was 2.11 (1.42) hours. Negligible amounts of blinatumomab were excreted in the urine at the tested clinical doses.
Body Weight, Body Surface Area, Gender, and Age
Results of population pharmacokinetic analyses indicate that age (18 to 80 years of age), gender, body weight (44 to 134 kg), and body surface area (1.39 to 2.57 m2) do not influence the pharmacokinetics of blinatumomab.
Renal Impairment
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 impairment (CrCL ranging from 30 to 59 mL/min, N = 21) and normal renal function (CrCL more than 90 mL/min, N = 215). However, high interpatient variability was discerned (CV% up to 95.6%), and clearance values in renal impaired patients were essentially within the range observed in patients with normal renal function. There is no information available in patients with severe renal impairment (CrCL less than 30 mL/min) or patients on hemodialysis.
Drug Interactions
Transient elevation of cytokines may suppress CYP450 enzyme activities [see Drug Interactions (7) and Clinical Pharmacology (12.2)].
13. NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityNo carcinogenicity or genotoxicity studies have been conducted with blinatumomab.
No studies have been conducted to eva luate the effects of blinatumomab on fertility. A murine surrogate molecule had no adverse effects on male and female reproductive organs in a 13-week repeat-dose toxicity study in mice.
14. CLINICAL STUDIES
14.1 Acute Lymphoblastic LeukemiaThe safety and efficacy of BLINCYTO were eva luated in an open-label, multicenter, single-arm study. Eligible patients were ≥ 18 years of age with Philadelphia chromosome-negative relapsed or refractory B‑precursor ALL (relapsed with first remission duration of ≤ 12 months in first salvage or relapsed or refractory after first salvage therapy or relapsed within 12 months of allogeneic hematopoietic stem cell transplantation [HSCT], and had ≥ 10% blasts in bone marrow).
BLINCYTO was administered as a continuous intravenous infusion. In the first cycle, the initial dose was 9 mcg/day for week 1, then 28 mcg/day for the remaining 3 weeks. The target dose of 28 mcg/day was administered in cycle 2 and subsequent cycles starting on day 1 of each cycle |
