Cargando…

Population Pharmacokinetic Modeling of Benralizumab in Adult and Adolescent Patients with Asthma

INTRODUCTION: Benralizumab, an interleukin-5 receptor alpha–directed cytolytic anti-eosinophil monoclonal antibody, was recently approved as add-on maintenance treatment for patients aged 12 years and older with uncontrolled asthma with eosinophilic inflammation. METHODS: Pharmacokinetic (PK) data f...

Descripción completa

Detalles Bibliográficos
Autores principales: Yan, Li, Wang, Bing, Chia, Yen Lin, Roskos, Lorin K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584252/
https://www.ncbi.nlm.nih.gov/pubmed/30854591
http://dx.doi.org/10.1007/s40262-019-00738-4
_version_ 1783428493332185088
author Yan, Li
Wang, Bing
Chia, Yen Lin
Roskos, Lorin K.
author_facet Yan, Li
Wang, Bing
Chia, Yen Lin
Roskos, Lorin K.
author_sort Yan, Li
collection PubMed
description INTRODUCTION: Benralizumab, an interleukin-5 receptor alpha–directed cytolytic anti-eosinophil monoclonal antibody, was recently approved as add-on maintenance treatment for patients aged 12 years and older with uncontrolled asthma with eosinophilic inflammation. METHODS: Pharmacokinetic (PK) data from nine clinical trials for patients with asthma were pooled and analyzed to further characterize the PK of benralizumab and evaluate demographic covariate effects. RESULTS: Population modeling results demonstrated that the PK of benralizumab were dose-proportional across a wide dosage range and were adequately described by a two-compartment model with first-order absorption from the subcutaneous dosing site and a first-order elimination pathway from the central compartment. Following subcutaneous administration, the absorption half-life of benralizumab was 3.54 days, and the absolute bioavailability was 58.9%. Estimated clearance (CL; 0.291 L/day), central volume of distribution (V(c); 3.13 L), and peripheral volume of distribution (V(p); 2.52 L) were typical for therapeutic immunoglobulins. Elimination half-life was approximately 15.5 days for patients with asthma. Age, sex, race, liver function, renal function, baseline blood eosinophil count, anatomic injection site, and commonly used small-molecule drugs had no clinically relevant impact on benralizumab CL. Only body weight and antidrug antibodies (ADAs) were identified as relevant PK covariates. Power parameters (exponent) of body weight on CL, V(c), and V(p) were 0.807, 0.803, and 0.528, respectively, and the presence of ADAs increased benralizumab CL by 124%. CONCLUSIONS: Over 5–20 weeks, the PK of benralizumab were dose-proportional across a dosage range of 0.03–3 mg/kg intravenously and 2–200 mg subcutaneously administered every 4 weeks or every 8 weeks (first three doses every 4 weeks). Body weight and ADA status were identified as relevant PK covariates. Baseline eosinophil count, hepatic and renal functions, anatomical subcutaneous injection site, and commonly used small-molecule drugs had no impact on the PK of benralizumab.
format Online
Article
Text
id pubmed-6584252
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Springer International Publishing
record_format MEDLINE/PubMed
spelling pubmed-65842522019-07-05 Population Pharmacokinetic Modeling of Benralizumab in Adult and Adolescent Patients with Asthma Yan, Li Wang, Bing Chia, Yen Lin Roskos, Lorin K. Clin Pharmacokinet Original Research Article INTRODUCTION: Benralizumab, an interleukin-5 receptor alpha–directed cytolytic anti-eosinophil monoclonal antibody, was recently approved as add-on maintenance treatment for patients aged 12 years and older with uncontrolled asthma with eosinophilic inflammation. METHODS: Pharmacokinetic (PK) data from nine clinical trials for patients with asthma were pooled and analyzed to further characterize the PK of benralizumab and evaluate demographic covariate effects. RESULTS: Population modeling results demonstrated that the PK of benralizumab were dose-proportional across a wide dosage range and were adequately described by a two-compartment model with first-order absorption from the subcutaneous dosing site and a first-order elimination pathway from the central compartment. Following subcutaneous administration, the absorption half-life of benralizumab was 3.54 days, and the absolute bioavailability was 58.9%. Estimated clearance (CL; 0.291 L/day), central volume of distribution (V(c); 3.13 L), and peripheral volume of distribution (V(p); 2.52 L) were typical for therapeutic immunoglobulins. Elimination half-life was approximately 15.5 days for patients with asthma. Age, sex, race, liver function, renal function, baseline blood eosinophil count, anatomic injection site, and commonly used small-molecule drugs had no clinically relevant impact on benralizumab CL. Only body weight and antidrug antibodies (ADAs) were identified as relevant PK covariates. Power parameters (exponent) of body weight on CL, V(c), and V(p) were 0.807, 0.803, and 0.528, respectively, and the presence of ADAs increased benralizumab CL by 124%. CONCLUSIONS: Over 5–20 weeks, the PK of benralizumab were dose-proportional across a dosage range of 0.03–3 mg/kg intravenously and 2–200 mg subcutaneously administered every 4 weeks or every 8 weeks (first three doses every 4 weeks). Body weight and ADA status were identified as relevant PK covariates. Baseline eosinophil count, hepatic and renal functions, anatomical subcutaneous injection site, and commonly used small-molecule drugs had no impact on the PK of benralizumab. Springer International Publishing 2019-03-11 2019 /pmc/articles/PMC6584252/ /pubmed/30854591 http://dx.doi.org/10.1007/s40262-019-00738-4 Text en © The Author(s) 2019 OpenAccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Research Article
Yan, Li
Wang, Bing
Chia, Yen Lin
Roskos, Lorin K.
Population Pharmacokinetic Modeling of Benralizumab in Adult and Adolescent Patients with Asthma
title Population Pharmacokinetic Modeling of Benralizumab in Adult and Adolescent Patients with Asthma
title_full Population Pharmacokinetic Modeling of Benralizumab in Adult and Adolescent Patients with Asthma
title_fullStr Population Pharmacokinetic Modeling of Benralizumab in Adult and Adolescent Patients with Asthma
title_full_unstemmed Population Pharmacokinetic Modeling of Benralizumab in Adult and Adolescent Patients with Asthma
title_short Population Pharmacokinetic Modeling of Benralizumab in Adult and Adolescent Patients with Asthma
title_sort population pharmacokinetic modeling of benralizumab in adult and adolescent patients with asthma
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584252/
https://www.ncbi.nlm.nih.gov/pubmed/30854591
http://dx.doi.org/10.1007/s40262-019-00738-4
work_keys_str_mv AT yanli populationpharmacokineticmodelingofbenralizumabinadultandadolescentpatientswithasthma
AT wangbing populationpharmacokineticmodelingofbenralizumabinadultandadolescentpatientswithasthma
AT chiayenlin populationpharmacokineticmodelingofbenralizumabinadultandadolescentpatientswithasthma
AT roskoslorink populationpharmacokineticmodelingofbenralizumabinadultandadolescentpatientswithasthma