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Pharmacokinetic/Pharmacodynamic Model of Neutropenia in Real-Life Palbociclib-Treated Patients
Palbociclib is an oral CDK4/6 inhibitor indicated in HR+/HER2- advanced or metastatic breast cancer in combination with hormonotherapy. Its main toxicity is neutropenia. The aim of our study was to describe the kinetics of circulating neutrophils from real-life palbociclib-treated patients. A popula...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537267/ https://www.ncbi.nlm.nih.gov/pubmed/34684001 http://dx.doi.org/10.3390/pharmaceutics13101708 |
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author | Marouille, Alexandre Le Petit, Emma Kaderbhaï, Courèche Desmoulins, Isabelle Hennequin, Audrey Mayeur, Didier Fumet, Jean-David Ladoire, Sylvain Tharin, Zoé Ayati, Siavoshe Ilie, Silvia Royer, Bernard Schmitt, Antonin |
author_facet | Marouille, Alexandre Le Petit, Emma Kaderbhaï, Courèche Desmoulins, Isabelle Hennequin, Audrey Mayeur, Didier Fumet, Jean-David Ladoire, Sylvain Tharin, Zoé Ayati, Siavoshe Ilie, Silvia Royer, Bernard Schmitt, Antonin |
author_sort | Marouille, Alexandre Le |
collection | PubMed |
description | Palbociclib is an oral CDK4/6 inhibitor indicated in HR+/HER2- advanced or metastatic breast cancer in combination with hormonotherapy. Its main toxicity is neutropenia. The aim of our study was to describe the kinetics of circulating neutrophils from real-life palbociclib-treated patients. A population pharmacokinetic (popPK) model was first constructed to describe palbociclib pharmacokinetic (PK). Individual PK parameters obtained were then used in the pharmacokinetic/pharmacodynamic (PK/PD) model to depict the relation between palbociclib concentrations and absolute neutrophil counts (ANC). The models were built with a population of 143 patients. Palbociclib samples were routinely collected during therapeutic drug monitoring, whereas ANC were retrospectively retrieved from the patient files. The optimal popPK model was a mono-compartmental model with a first-order absorption constant of 0.187 h(−1) and an apparent clearance Cl/F of 57.09 L (32.8% of inter individuality variability (IIV)). The apparent volume of distribution (1580 L) and the lag-time (T(lag): 0.658 h) were fixed to values from the literature. An increase in creatinine clearance and a decrease in alkaline phosphatase led to an increase in palbociclib Cl/F. To describe ANC kinetics during treatment, Friberg’s PK/PD model, with linear drug effect, was used. Parameters estimated were Base (2.92 G/L; 29.6% IIV), Slope (0.0011 L/µg; 28.8% IIV), Mean Transit Time (MTT; 5.29 days; 17.9% IIV) and γ (0.102). The only significant covariate was age on the initial ANC (Base), with lower ANC in younger patients. PK/PD model-based simulations show that the higher the estimated C(ressSS) (trough concentration at steady state), the higher the risk of developing neutropenia. In order to present a risk lower than 20% to developing a grade 4 neutropenia, the patient should show an estimated C(ressSS) lower than 100 µg/L. |
format | Online Article Text |
id | pubmed-8537267 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-85372672021-10-24 Pharmacokinetic/Pharmacodynamic Model of Neutropenia in Real-Life Palbociclib-Treated Patients Marouille, Alexandre Le Petit, Emma Kaderbhaï, Courèche Desmoulins, Isabelle Hennequin, Audrey Mayeur, Didier Fumet, Jean-David Ladoire, Sylvain Tharin, Zoé Ayati, Siavoshe Ilie, Silvia Royer, Bernard Schmitt, Antonin Pharmaceutics Article Palbociclib is an oral CDK4/6 inhibitor indicated in HR+/HER2- advanced or metastatic breast cancer in combination with hormonotherapy. Its main toxicity is neutropenia. The aim of our study was to describe the kinetics of circulating neutrophils from real-life palbociclib-treated patients. A population pharmacokinetic (popPK) model was first constructed to describe palbociclib pharmacokinetic (PK). Individual PK parameters obtained were then used in the pharmacokinetic/pharmacodynamic (PK/PD) model to depict the relation between palbociclib concentrations and absolute neutrophil counts (ANC). The models were built with a population of 143 patients. Palbociclib samples were routinely collected during therapeutic drug monitoring, whereas ANC were retrospectively retrieved from the patient files. The optimal popPK model was a mono-compartmental model with a first-order absorption constant of 0.187 h(−1) and an apparent clearance Cl/F of 57.09 L (32.8% of inter individuality variability (IIV)). The apparent volume of distribution (1580 L) and the lag-time (T(lag): 0.658 h) were fixed to values from the literature. An increase in creatinine clearance and a decrease in alkaline phosphatase led to an increase in palbociclib Cl/F. To describe ANC kinetics during treatment, Friberg’s PK/PD model, with linear drug effect, was used. Parameters estimated were Base (2.92 G/L; 29.6% IIV), Slope (0.0011 L/µg; 28.8% IIV), Mean Transit Time (MTT; 5.29 days; 17.9% IIV) and γ (0.102). The only significant covariate was age on the initial ANC (Base), with lower ANC in younger patients. PK/PD model-based simulations show that the higher the estimated C(ressSS) (trough concentration at steady state), the higher the risk of developing neutropenia. In order to present a risk lower than 20% to developing a grade 4 neutropenia, the patient should show an estimated C(ressSS) lower than 100 µg/L. MDPI 2021-10-16 /pmc/articles/PMC8537267/ /pubmed/34684001 http://dx.doi.org/10.3390/pharmaceutics13101708 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 Marouille, Alexandre Le Petit, Emma Kaderbhaï, Courèche Desmoulins, Isabelle Hennequin, Audrey Mayeur, Didier Fumet, Jean-David Ladoire, Sylvain Tharin, Zoé Ayati, Siavoshe Ilie, Silvia Royer, Bernard Schmitt, Antonin Pharmacokinetic/Pharmacodynamic Model of Neutropenia in Real-Life Palbociclib-Treated Patients |
title | Pharmacokinetic/Pharmacodynamic Model of Neutropenia in Real-Life Palbociclib-Treated Patients |
title_full | Pharmacokinetic/Pharmacodynamic Model of Neutropenia in Real-Life Palbociclib-Treated Patients |
title_fullStr | Pharmacokinetic/Pharmacodynamic Model of Neutropenia in Real-Life Palbociclib-Treated Patients |
title_full_unstemmed | Pharmacokinetic/Pharmacodynamic Model of Neutropenia in Real-Life Palbociclib-Treated Patients |
title_short | Pharmacokinetic/Pharmacodynamic Model of Neutropenia in Real-Life Palbociclib-Treated Patients |
title_sort | pharmacokinetic/pharmacodynamic model of neutropenia in real-life palbociclib-treated patients |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537267/ https://www.ncbi.nlm.nih.gov/pubmed/34684001 http://dx.doi.org/10.3390/pharmaceutics13101708 |
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