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Clinical-Based vs. Model-Based Adaptive Dosing Strategy: Retrospective Comparison in Real-World mRCC Patients Treated with Sunitinib

Different target exposures with sunitinib have been proposed in metastatic renal cell carcinoma (mRCC) patients, such as trough concentrations or AUCs. However, most of the time, rather than therapeutic drug monitoring (TDM), clinical evidence is preferred to tailor dosing, i.e., by reducing the dos...

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Autores principales: Ferrer, Florent, Chauvin, Jonathan, DeVictor, Bénédicte, Lacarelle, Bruno, Deville, Jean-Laurent, Ciccolini, Joseph
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224810/
https://www.ncbi.nlm.nih.gov/pubmed/34073681
http://dx.doi.org/10.3390/ph14060494
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author Ferrer, Florent
Chauvin, Jonathan
DeVictor, Bénédicte
Lacarelle, Bruno
Deville, Jean-Laurent
Ciccolini, Joseph
author_facet Ferrer, Florent
Chauvin, Jonathan
DeVictor, Bénédicte
Lacarelle, Bruno
Deville, Jean-Laurent
Ciccolini, Joseph
author_sort Ferrer, Florent
collection PubMed
description Different target exposures with sunitinib have been proposed in metastatic renal cell carcinoma (mRCC) patients, such as trough concentrations or AUCs. However, most of the time, rather than therapeutic drug monitoring (TDM), clinical evidence is preferred to tailor dosing, i.e., by reducing the dose when treatment-related toxicities show, or increasing dosing if no signs of efficacy are observed. Here, we compared such empirical dose adjustment of sunitinib in mRCC patients, with the parallel dosing proposals of a PK/PD model with TDM support. In 31 evaluable patients treated with sunitinib, 53.8% had an empirical change in dosing after treatment started (i.e., 46.2% decrease in dosing, 7.6% increase in dosing). Clinical benefit was observed in 54.1% patients, including 8.3% with complete response. Overall, 58.1% of patients experienced treatment discontinuation eventually, either because of toxicities or progressive disease. When choosing 50–100 ng/mL trough concentrations as a target exposure (i.e., sunitinib + active metabolite N-desethyl sunitinib), 45% patients were adequately exposed. When considering 1200–2150 ng/mL.h as a target AUC (i.e., sunitinib + active metabolite N-desethyl sunitinib), only 26% patients were in the desired therapeutic window. TDM with retrospective PK/PD modeling would have suggested decreasing sunitinib dosing in a much larger number of patients as compared with empirical dose adjustment. Indeed, when using target trough concentrations, the model proposed reducing dosing for 61% patients, and up to 84% patients based upon target AUC. Conversely, the model proposed increasing dosing in 9.7% of patients when using target trough concentrations and in 6.5% patients when using target AUC. Overall, TDM with adaptive dosing would have led to tailoring sunitinib dosing in a larger number of patients (i.e., 53.8% vs. 71–91%, depending on the chosen metrics for target exposure) than a clinical-based decision. Interestingly, sunitinib dosing was empirically reduced in 41% patients who displayed early-onset severe toxicities, whereas model-based recommendations would have immediately proposed to reduce dosing in more than 80% of those patients. This observation suggests that early treatment-related toxicities could have been partly avoided using prospective PK/PD modeling with adaptive dosing. Conversely, the possible impact of model-based adapted dosing on efficacy could not be fully evaluated because no clear relationship was found between baseline exposure levels and sunitinib efficacy measured at 3 months.
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spelling pubmed-82248102021-06-25 Clinical-Based vs. Model-Based Adaptive Dosing Strategy: Retrospective Comparison in Real-World mRCC Patients Treated with Sunitinib Ferrer, Florent Chauvin, Jonathan DeVictor, Bénédicte Lacarelle, Bruno Deville, Jean-Laurent Ciccolini, Joseph Pharmaceuticals (Basel) Article Different target exposures with sunitinib have been proposed in metastatic renal cell carcinoma (mRCC) patients, such as trough concentrations or AUCs. However, most of the time, rather than therapeutic drug monitoring (TDM), clinical evidence is preferred to tailor dosing, i.e., by reducing the dose when treatment-related toxicities show, or increasing dosing if no signs of efficacy are observed. Here, we compared such empirical dose adjustment of sunitinib in mRCC patients, with the parallel dosing proposals of a PK/PD model with TDM support. In 31 evaluable patients treated with sunitinib, 53.8% had an empirical change in dosing after treatment started (i.e., 46.2% decrease in dosing, 7.6% increase in dosing). Clinical benefit was observed in 54.1% patients, including 8.3% with complete response. Overall, 58.1% of patients experienced treatment discontinuation eventually, either because of toxicities or progressive disease. When choosing 50–100 ng/mL trough concentrations as a target exposure (i.e., sunitinib + active metabolite N-desethyl sunitinib), 45% patients were adequately exposed. When considering 1200–2150 ng/mL.h as a target AUC (i.e., sunitinib + active metabolite N-desethyl sunitinib), only 26% patients were in the desired therapeutic window. TDM with retrospective PK/PD modeling would have suggested decreasing sunitinib dosing in a much larger number of patients as compared with empirical dose adjustment. Indeed, when using target trough concentrations, the model proposed reducing dosing for 61% patients, and up to 84% patients based upon target AUC. Conversely, the model proposed increasing dosing in 9.7% of patients when using target trough concentrations and in 6.5% patients when using target AUC. Overall, TDM with adaptive dosing would have led to tailoring sunitinib dosing in a larger number of patients (i.e., 53.8% vs. 71–91%, depending on the chosen metrics for target exposure) than a clinical-based decision. Interestingly, sunitinib dosing was empirically reduced in 41% patients who displayed early-onset severe toxicities, whereas model-based recommendations would have immediately proposed to reduce dosing in more than 80% of those patients. This observation suggests that early treatment-related toxicities could have been partly avoided using prospective PK/PD modeling with adaptive dosing. Conversely, the possible impact of model-based adapted dosing on efficacy could not be fully evaluated because no clear relationship was found between baseline exposure levels and sunitinib efficacy measured at 3 months. MDPI 2021-05-24 /pmc/articles/PMC8224810/ /pubmed/34073681 http://dx.doi.org/10.3390/ph14060494 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ferrer, Florent
Chauvin, Jonathan
DeVictor, Bénédicte
Lacarelle, Bruno
Deville, Jean-Laurent
Ciccolini, Joseph
Clinical-Based vs. Model-Based Adaptive Dosing Strategy: Retrospective Comparison in Real-World mRCC Patients Treated with Sunitinib
title Clinical-Based vs. Model-Based Adaptive Dosing Strategy: Retrospective Comparison in Real-World mRCC Patients Treated with Sunitinib
title_full Clinical-Based vs. Model-Based Adaptive Dosing Strategy: Retrospective Comparison in Real-World mRCC Patients Treated with Sunitinib
title_fullStr Clinical-Based vs. Model-Based Adaptive Dosing Strategy: Retrospective Comparison in Real-World mRCC Patients Treated with Sunitinib
title_full_unstemmed Clinical-Based vs. Model-Based Adaptive Dosing Strategy: Retrospective Comparison in Real-World mRCC Patients Treated with Sunitinib
title_short Clinical-Based vs. Model-Based Adaptive Dosing Strategy: Retrospective Comparison in Real-World mRCC Patients Treated with Sunitinib
title_sort clinical-based vs. model-based adaptive dosing strategy: retrospective comparison in real-world mrcc patients treated with sunitinib
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224810/
https://www.ncbi.nlm.nih.gov/pubmed/34073681
http://dx.doi.org/10.3390/ph14060494
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