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...
Autores principales: | , , , |
---|---|
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 |