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Model-Based Characterization of the Bidirectional Interaction Between Pharmacokinetics and Tumor Growth Dynamics in Patients with Metastatic Merkel Cell Carcinoma Treated with Avelumab
PURPOSE: Empirical time-varying clearance models have been reported for several immune checkpoint inhibitors, including avelumab (anti–programmed death ligand 1). To investigate the exposure-response relationship for avelumab, we explored semimechanistic pharmacokinetic (PK)–tumor growth dynamics (T...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9365383/ https://www.ncbi.nlm.nih.gov/pubmed/34921021 http://dx.doi.org/10.1158/1078-0432.CCR-21-2662 |
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author | Grisic, Ana-Marija Xiong, Wenyuan Tanneau, Lénaïg Jönsson, Siv Friberg, Lena E. Karlsson, Mats O. Dai, Haiqing Zheng, Jenny Girard, Pascal Khandelwal, Akash |
author_facet | Grisic, Ana-Marija Xiong, Wenyuan Tanneau, Lénaïg Jönsson, Siv Friberg, Lena E. Karlsson, Mats O. Dai, Haiqing Zheng, Jenny Girard, Pascal Khandelwal, Akash |
author_sort | Grisic, Ana-Marija |
collection | PubMed |
description | PURPOSE: Empirical time-varying clearance models have been reported for several immune checkpoint inhibitors, including avelumab (anti–programmed death ligand 1). To investigate the exposure-response relationship for avelumab, we explored semimechanistic pharmacokinetic (PK)–tumor growth dynamics (TGD) models. PATIENTS AND METHODS: Plasma PK data were pooled from three phase I and II trials (JAVELIN Merkel 200, JAVELIN Solid Tumor, and JAVELIN Solid Tumor JPN); tumor size (TS) data were collected from patients with metastatic Merkel cell carcinoma (mMCC) enrolled in JAVELIN Merkel 200. A PK model was developed first, followed by TGD modeling to investigate interactions between avelumab exposure and TGD. A PK-TGD feedback loop was evaluated with simultaneous fitting of the PK and TGD models. RESULTS: In total, 1,835 PK observations and 338 TS observations were collected from 147 patients. In the final PK-TGD model, which included the bidirectional relationship between PK and TGD, avelumab PK was described by a two-compartment model with a positive association between clearance and longitudinal TS, with no additional empirical time-varying clearance identified. TGD was described by first-order tumor growth/shrinkage rates, with the tumor shrinkage rate decreasing exponentially over time; the exponential time-decay constant decreased with increasing drug concentration, representing the treatment effect through tumor shrinkage inhibition. CONCLUSIONS: We developed a TGD model that mechanistically captures the prevention of loss of antitumor immunity (i.e., T-cell suppression in the tumor microenvironment) by avelumab, and a bidirectional interaction between PK and TGD in patients with mMCC treated with avelumab, thus mechanistically describing previously reported time variance of avelumab elimination. |
format | Online Article Text |
id | pubmed-9365383 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-93653832023-01-05 Model-Based Characterization of the Bidirectional Interaction Between Pharmacokinetics and Tumor Growth Dynamics in Patients with Metastatic Merkel Cell Carcinoma Treated with Avelumab Grisic, Ana-Marija Xiong, Wenyuan Tanneau, Lénaïg Jönsson, Siv Friberg, Lena E. Karlsson, Mats O. Dai, Haiqing Zheng, Jenny Girard, Pascal Khandelwal, Akash Clin Cancer Res Clinical Trials: Immunotherapy PURPOSE: Empirical time-varying clearance models have been reported for several immune checkpoint inhibitors, including avelumab (anti–programmed death ligand 1). To investigate the exposure-response relationship for avelumab, we explored semimechanistic pharmacokinetic (PK)–tumor growth dynamics (TGD) models. PATIENTS AND METHODS: Plasma PK data were pooled from three phase I and II trials (JAVELIN Merkel 200, JAVELIN Solid Tumor, and JAVELIN Solid Tumor JPN); tumor size (TS) data were collected from patients with metastatic Merkel cell carcinoma (mMCC) enrolled in JAVELIN Merkel 200. A PK model was developed first, followed by TGD modeling to investigate interactions between avelumab exposure and TGD. A PK-TGD feedback loop was evaluated with simultaneous fitting of the PK and TGD models. RESULTS: In total, 1,835 PK observations and 338 TS observations were collected from 147 patients. In the final PK-TGD model, which included the bidirectional relationship between PK and TGD, avelumab PK was described by a two-compartment model with a positive association between clearance and longitudinal TS, with no additional empirical time-varying clearance identified. TGD was described by first-order tumor growth/shrinkage rates, with the tumor shrinkage rate decreasing exponentially over time; the exponential time-decay constant decreased with increasing drug concentration, representing the treatment effect through tumor shrinkage inhibition. CONCLUSIONS: We developed a TGD model that mechanistically captures the prevention of loss of antitumor immunity (i.e., T-cell suppression in the tumor microenvironment) by avelumab, and a bidirectional interaction between PK and TGD in patients with mMCC treated with avelumab, thus mechanistically describing previously reported time variance of avelumab elimination. American Association for Cancer Research 2022-04-01 2021-12-16 /pmc/articles/PMC9365383/ /pubmed/34921021 http://dx.doi.org/10.1158/1078-0432.CCR-21-2662 Text en ©2021 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
spellingShingle | Clinical Trials: Immunotherapy Grisic, Ana-Marija Xiong, Wenyuan Tanneau, Lénaïg Jönsson, Siv Friberg, Lena E. Karlsson, Mats O. Dai, Haiqing Zheng, Jenny Girard, Pascal Khandelwal, Akash Model-Based Characterization of the Bidirectional Interaction Between Pharmacokinetics and Tumor Growth Dynamics in Patients with Metastatic Merkel Cell Carcinoma Treated with Avelumab |
title | Model-Based Characterization of the Bidirectional Interaction Between Pharmacokinetics and Tumor Growth Dynamics in Patients with Metastatic Merkel Cell Carcinoma Treated with Avelumab |
title_full | Model-Based Characterization of the Bidirectional Interaction Between Pharmacokinetics and Tumor Growth Dynamics in Patients with Metastatic Merkel Cell Carcinoma Treated with Avelumab |
title_fullStr | Model-Based Characterization of the Bidirectional Interaction Between Pharmacokinetics and Tumor Growth Dynamics in Patients with Metastatic Merkel Cell Carcinoma Treated with Avelumab |
title_full_unstemmed | Model-Based Characterization of the Bidirectional Interaction Between Pharmacokinetics and Tumor Growth Dynamics in Patients with Metastatic Merkel Cell Carcinoma Treated with Avelumab |
title_short | Model-Based Characterization of the Bidirectional Interaction Between Pharmacokinetics and Tumor Growth Dynamics in Patients with Metastatic Merkel Cell Carcinoma Treated with Avelumab |
title_sort | model-based characterization of the bidirectional interaction between pharmacokinetics and tumor growth dynamics in patients with metastatic merkel cell carcinoma treated with avelumab |
topic | Clinical Trials: Immunotherapy |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9365383/ https://www.ncbi.nlm.nih.gov/pubmed/34921021 http://dx.doi.org/10.1158/1078-0432.CCR-21-2662 |
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