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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.

SUBMITTER: Clements JD

PROVIDER: S-EPMC7109194 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Clements John David JD Zhu Min M Kuchimanchi Mita M Terminello Bianca B Doshi Sameer S

Clinical pharmacokinetics 20200401 4

<h4>Background and objectives</h4>Blinatumomab (BLINCYTO<sup>®</sup>) is a novel bispecific T cell engager (BiTE<sup>®</sup>) 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.<h4>Methods</h4>A total of 2417 serum concentrations of blinatu ...[more]

PMID: 31679130

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Project description:Imipenem is widely used for the treatment of children with serious infections. Currently, studies on the pharmacokinetics of imipenem in children with hematological malignancies are lacking. Given the significant impact of disease on pharmacokinetics and increased resistance, we aimed to conduct a population pharmacokinetic study of imipenem and optimize the dosage regimens for this vulnerable population. After children were treated with imipenem-cilastatin (IMP-CS), blood samples were collected from the children and the concentrations of imipenem were quantified using high-performance liquid chromatography with UV detection. Then, a population-level pharmacokinetic analysis was conducted using NONMEM software. Data were collected from 56 children (age range, 2.03 to 11.82 years) with hematological malignancies to conduct a population pharmacokinetic analysis. In this study, a two-compartment model that followed first-order elimination was found to be the most suitable. The parameters of current weight, age, and creatinine elimination rate were significant covariates that influenced imipenem pharmacokinetics. As a result, 41.4%, 56.1%, and 67.1% of the children reached the pharmacodynamic target (the percentage of the time during the total dosing interval that the free drug concentration remains above the MIC of 70%) against sensitive pathogens with an MIC of 0.5 mg/liter with imipenem at 15, 20, and 25 mg/kg of body weight every 6 h (q6h), respectively. However, only 11.1% of the children achieved the pharmacodynamic target against Pseudomonas aeruginosa isolates with an MIC of 2 mg/liter at a dose of 25 mg/kg q6h. The population pharmacokinetics of imipenem were assessed in children. The current dosage regimens of imipenem result in underdosing against resistant pathogens, including Pseudomonas aeruginosa and Acinetobacter baumannii However, for sensitive pathogens, imipenem has an acceptable pharmacodynamic target rate at a dosage of 25 mg/kg q6h. (The study discussed in this paper has been registered at ClinicalTrials.gov under identifier NCT03113344.).

Dataset Information

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

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

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