Population Pharmacokinetics of Blinatumomab in Pediatric and Adult Patients with Hematological Malignancies

Abstract

Background and objectives: Blinatumomab (BLINCYTO®) is a novel bispecific T cell engager (BiTE®) approved in the USA for the treatment of relapsed or refractory B cell precursor acute lymphoblastic leukemia (ALL) in children and adults, as well as minimal residual disease ALL in adults. This analysis characterized the population pharmacokinetics of intravenous blinatumomab in pediatric and adult patients.

Methods: A total of 2417 serum concentrations of blinatumomab from 674 patients, including adult (n = 628) and pediatric patients (n = 46), from eight clinical studies were analyzed. The impact of covariates on pharmacokinetic parameters were explored, and significant covariates were further evaluated using a simulation approach.

Results: Blinatumomab pharmacokinetics were described by a one-compartment linear model with first-order elimination, a clearance (CL) of 2.22 L/h, and a central volume of 5.98 L. A statistically significant effect of body surface area (BSA) on CL was observed. The smallest BSA of 0.37 m2 in the pediatric population was associated with a 63% reduction in blinatumomab systemic CL, relative to an adult patient with the median BSA (1.88 m2), supporting the use of BSA-based dosing in patients of lower bodyweight. The BSA effect was minimal, with a ≤ 25% change in CL over the range of BSA in adults, supporting no need for BSA-based dosing.

Conclusions: Blinatumomab pharmacokinetics were adequately described by a one-compartment linear model with first-order elimination. No covariates other than BSA on CL were identified as significant. BSA-based dosing should be considered for lightweight patients to minimize inter-subject variability in blinatumomab exposure.

Conflict of interest statement

John D. Clements, Bianca Terminello, and Sameer Doshi are employees of and shareholders in Amgen Inc. Min Zhu and Mita Kuchimanchi were employees of and shareholders in Amgen Inc. when the analysis was conducted. Min Zhu is currently employed by Regeneron. Mita Kuchimanchi is currently employed by Biogen.

Figures

Fig. 1

Relationships between blinatumomab clearances and demographic, treatment, and disease-related factors. a Clearance versus body surface area. b Body surface area-normalized clearance versus age in pediatrics. c Clearance by race. d Clearance by treatment cycle after administration of 5 µg/m2/day or 9 µg/day in adults. e Clearance by dose after cycle 1 dose administration in adults. f Clearance by disease. The top, middle, and bottom of the boxes in figures c–f are the third quartile, median, and first quartile, respectively. The whiskers are drawn to the nearest value not beyond 1.5 × (upper hinge—lower hinge). In figures d–e individual blinatumomab clearance values were calculated as R0/Css where Css is the individual Css. Height or weight data was not collected for four subjects in the clinical dataset. ALL acute lymphoblastic leukemia, BSA body surface area, CL clearance, Css steady-state concentration, d day, MRD minimal residual disease, NHL non-Hodgkin’s lymphoma, PH Philadelphia chromosome, R0 infusion rate, R/R relapsed or refractory

Fig. 2

Prediction-corrected visual predictive check, using 100 replicates, for all studies using the final model. Dashed black lines are the medians and 90% prediction intervals of observed data, which are shown as grey open circles. The shaded regions represent the 95% confidence intervals of the orange solid lines (median and 90% prediction intervals of simulated data)

Fig. 3

Simulated serum steady-state concentration for fixed dosing (28 μg/day, red dashed line), body surface area-based dosing (15 μg/m2/day, blue dot-dashed line), and per label-based (15 μg/m2/day for patients < 45 kg, and 28 μg/day for patients ≥ 45 kg, green solid line) regimens in virtual patients having a broad range of bodyweights using a weight/body surface area multivariate distribution. Body weights were binned for each 10 kg interval between 5 and 105 kg, with 1000 patients simulated for each bin resulting in a total of 10,000 simulated patients. The top, middle, and bottom of the boxes are the third quartile, median, and first quartile, respectively. The whiskers are drawn to the nearest value not beyond 1.5 × (upper hinge—lower hinge). BSA body surface area