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Semimechanistic Clearance Models of Oncology Biotherapeutics and Impact of Study Design: Cetuximab as a Case Study
This study aimed to explore the currently competing and new semimechanistic clearance models for monoclonal antibodies and the impact of clearance model misspecification on exposure metrics under different study designs exemplified for cetuximab. Six clearance models were investigated under four dif...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679074/ https://www.ncbi.nlm.nih.gov/pubmed/33015996 http://dx.doi.org/10.1002/psp4.12558 |
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author | Grisic, Ana‐Marija Khandelwal, Akash Bertolino, Mauro Huisinga, Wilhelm Girard, Pascal Kloft, Charlotte |
author_facet | Grisic, Ana‐Marija Khandelwal, Akash Bertolino, Mauro Huisinga, Wilhelm Girard, Pascal Kloft, Charlotte |
author_sort | Grisic, Ana‐Marija |
collection | PubMed |
description | This study aimed to explore the currently competing and new semimechanistic clearance models for monoclonal antibodies and the impact of clearance model misspecification on exposure metrics under different study designs exemplified for cetuximab. Six clearance models were investigated under four different study designs (sampling density and single/multiple‐dose levels) using a rich data set from two cetuximab clinical trials (226 patients with metastatic colorectal cancer) and using the nonlinear mixed‐effects modeling approach. A two‐compartment model with parallel Michaelis–Menten and time‐decreasing linear clearance adequately described the data, the latter being related to post‐treatment response. With respect to bias in exposure metrics, the simplified time‐varying linear clearance (CL) model was the best alternative. Time‐variance of the linear CL component should be considered for biotherapeutics if response impacts pharmacokinetics. Rich sampling at steady‐state was crucial for unbiased estimation of Michaelis–Menten elimination in case of the reference (parallel Michaelis–Menten and time‐varying linear CL) model. |
format | Online Article Text |
id | pubmed-7679074 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-76790742020-11-27 Semimechanistic Clearance Models of Oncology Biotherapeutics and Impact of Study Design: Cetuximab as a Case Study Grisic, Ana‐Marija Khandelwal, Akash Bertolino, Mauro Huisinga, Wilhelm Girard, Pascal Kloft, Charlotte CPT Pharmacometrics Syst Pharmacol Research This study aimed to explore the currently competing and new semimechanistic clearance models for monoclonal antibodies and the impact of clearance model misspecification on exposure metrics under different study designs exemplified for cetuximab. Six clearance models were investigated under four different study designs (sampling density and single/multiple‐dose levels) using a rich data set from two cetuximab clinical trials (226 patients with metastatic colorectal cancer) and using the nonlinear mixed‐effects modeling approach. A two‐compartment model with parallel Michaelis–Menten and time‐decreasing linear clearance adequately described the data, the latter being related to post‐treatment response. With respect to bias in exposure metrics, the simplified time‐varying linear clearance (CL) model was the best alternative. Time‐variance of the linear CL component should be considered for biotherapeutics if response impacts pharmacokinetics. Rich sampling at steady‐state was crucial for unbiased estimation of Michaelis–Menten elimination in case of the reference (parallel Michaelis–Menten and time‐varying linear CL) model. John Wiley and Sons Inc. 2020-10-09 2020-11 /pmc/articles/PMC7679074/ /pubmed/33015996 http://dx.doi.org/10.1002/psp4.12558 Text en © 2020 Merck Healthcare KGaA. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Grisic, Ana‐Marija Khandelwal, Akash Bertolino, Mauro Huisinga, Wilhelm Girard, Pascal Kloft, Charlotte Semimechanistic Clearance Models of Oncology Biotherapeutics and Impact of Study Design: Cetuximab as a Case Study |
title | Semimechanistic Clearance Models of Oncology Biotherapeutics and Impact of Study Design: Cetuximab as a Case Study |
title_full | Semimechanistic Clearance Models of Oncology Biotherapeutics and Impact of Study Design: Cetuximab as a Case Study |
title_fullStr | Semimechanistic Clearance Models of Oncology Biotherapeutics and Impact of Study Design: Cetuximab as a Case Study |
title_full_unstemmed | Semimechanistic Clearance Models of Oncology Biotherapeutics and Impact of Study Design: Cetuximab as a Case Study |
title_short | Semimechanistic Clearance Models of Oncology Biotherapeutics and Impact of Study Design: Cetuximab as a Case Study |
title_sort | semimechanistic clearance models of oncology biotherapeutics and impact of study design: cetuximab as a case study |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679074/ https://www.ncbi.nlm.nih.gov/pubmed/33015996 http://dx.doi.org/10.1002/psp4.12558 |
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