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Changing Body Weight–Based Dosing to a Flat Dose for Avelumab in Metastatic Merkel Cell and Advanced Urothelial Carcinoma

Avelumab, an anti–programmed death‐ligand 1 monoclonal antibody approved for the treatment of metastatic Merkel cell carcinoma and platinum‐treated urothelial carcinoma, was initially approved with a 10 mg/kg weight‐based dose. We report pharmacokinetic (PK)/pharmacodynamic analyses for avelumab com...

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Autores principales: Novakovic, Ana M., Wilkins, Justin J., Dai, Haiqing, Wade, Janet R., Neuteboom, Berend, Brar, Satjit, Bello, Carlo L., Girard, Pascal, Khandelwal, Akash
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027979/
https://www.ncbi.nlm.nih.gov/pubmed/31553054
http://dx.doi.org/10.1002/cpt.1645
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author Novakovic, Ana M.
Wilkins, Justin J.
Dai, Haiqing
Wade, Janet R.
Neuteboom, Berend
Brar, Satjit
Bello, Carlo L.
Girard, Pascal
Khandelwal, Akash
author_facet Novakovic, Ana M.
Wilkins, Justin J.
Dai, Haiqing
Wade, Janet R.
Neuteboom, Berend
Brar, Satjit
Bello, Carlo L.
Girard, Pascal
Khandelwal, Akash
author_sort Novakovic, Ana M.
collection PubMed
description Avelumab, an anti–programmed death‐ligand 1 monoclonal antibody approved for the treatment of metastatic Merkel cell carcinoma and platinum‐treated urothelial carcinoma, was initially approved with a 10 mg/kg weight‐based dose. We report pharmacokinetic (PK)/pharmacodynamic analyses for avelumab comparing weight‐based dosing and a flat 800 mg dose, developed using data from 1,827 patients enrolled in 3 clinical trials (NCT01772004, NCT01943461, and NCT02155647). PK metrics were simulated for weight‐based and flat‐dosing regimens and summarized by quartiles of weight. Derived exposure metrics were used in simulations of exposure‐safety (various tumors) and exposure‐efficacy (objective responses; Merkel cell or urothelial carcinoma). Flat dosing was predicted to provide similar exposure to weight‐based dosing, with slightly lower variability. Exposure‐safety and exposure‐efficacy simulations suggested similar benefit:risk profiles for the two dosing regimens. These pharmacometric analyses provided the basis for the US Food and Drug Administration approval of a flat dose of avelumab 800 mg every 2 weeks in approved indications.
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spelling pubmed-70279792020-02-19 Changing Body Weight–Based Dosing to a Flat Dose for Avelumab in Metastatic Merkel Cell and Advanced Urothelial Carcinoma Novakovic, Ana M. Wilkins, Justin J. Dai, Haiqing Wade, Janet R. Neuteboom, Berend Brar, Satjit Bello, Carlo L. Girard, Pascal Khandelwal, Akash Clin Pharmacol Ther Research Avelumab, an anti–programmed death‐ligand 1 monoclonal antibody approved for the treatment of metastatic Merkel cell carcinoma and platinum‐treated urothelial carcinoma, was initially approved with a 10 mg/kg weight‐based dose. We report pharmacokinetic (PK)/pharmacodynamic analyses for avelumab comparing weight‐based dosing and a flat 800 mg dose, developed using data from 1,827 patients enrolled in 3 clinical trials (NCT01772004, NCT01943461, and NCT02155647). PK metrics were simulated for weight‐based and flat‐dosing regimens and summarized by quartiles of weight. Derived exposure metrics were used in simulations of exposure‐safety (various tumors) and exposure‐efficacy (objective responses; Merkel cell or urothelial carcinoma). Flat dosing was predicted to provide similar exposure to weight‐based dosing, with slightly lower variability. Exposure‐safety and exposure‐efficacy simulations suggested similar benefit:risk profiles for the two dosing regimens. These pharmacometric analyses provided the basis for the US Food and Drug Administration approval of a flat dose of avelumab 800 mg every 2 weeks in approved indications. John Wiley and Sons Inc. 2019-11-18 2020-03 /pmc/articles/PMC7027979/ /pubmed/31553054 http://dx.doi.org/10.1002/cpt.1645 Text en © 2019 MERCK KGAA. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. 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
Novakovic, Ana M.
Wilkins, Justin J.
Dai, Haiqing
Wade, Janet R.
Neuteboom, Berend
Brar, Satjit
Bello, Carlo L.
Girard, Pascal
Khandelwal, Akash
Changing Body Weight–Based Dosing to a Flat Dose for Avelumab in Metastatic Merkel Cell and Advanced Urothelial Carcinoma
title Changing Body Weight–Based Dosing to a Flat Dose for Avelumab in Metastatic Merkel Cell and Advanced Urothelial Carcinoma
title_full Changing Body Weight–Based Dosing to a Flat Dose for Avelumab in Metastatic Merkel Cell and Advanced Urothelial Carcinoma
title_fullStr Changing Body Weight–Based Dosing to a Flat Dose for Avelumab in Metastatic Merkel Cell and Advanced Urothelial Carcinoma
title_full_unstemmed Changing Body Weight–Based Dosing to a Flat Dose for Avelumab in Metastatic Merkel Cell and Advanced Urothelial Carcinoma
title_short Changing Body Weight–Based Dosing to a Flat Dose for Avelumab in Metastatic Merkel Cell and Advanced Urothelial Carcinoma
title_sort changing body weight–based dosing to a flat dose for avelumab in metastatic merkel cell and advanced urothelial carcinoma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027979/
https://www.ncbi.nlm.nih.gov/pubmed/31553054
http://dx.doi.org/10.1002/cpt.1645
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