Association of cabozantinib pharmacokinetics, progression and toxicity in metastatic renal cell carcinoma patients: results from a pharmacokinetics/pharmacodynamics study.
cabozantinib
dose-exposure
kidney cancer
pharmacokinetics
therapeutic failure
toxicity
Journal
ESMO open
ISSN: 2059-7029
Titre abrégé: ESMO Open
Pays: England
ID NLM: 101690685
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
20
07
2021
revised:
13
10
2021
accepted:
25
10
2021
pubmed:
6
12
2021
medline:
25
3
2022
entrez:
5
12
2021
Statut:
ppublish
Résumé
Cabozantinib is a tyrosine kinase inhibitor with a substantial efficacy in metastatic renal cell carcinoma, and is associated with a challenging toxicity profile leading to frequent drug discontinuations. Whereas an exposure/safety relationship was demonstrated for this drug, an exposure/efficacy relationship is still unknown. We carried out a monocentric, observational, pharmacokinetics/pharmacodynamics (PK/PD) study in patients with metastatic renal cell carcinoma (INDS MR 5612140520). We used measured blood concentrations of cabozantinib (C We enrolled 76 patients, including 35 who experienced disease progression and 30 with grade 3-4 toxicity. Patients with progressive disease had a significantly lower median C We first demonstrate the PK/PD relationship for cabozantinib. Severe toxicities are associated with a higher drug exposure, whereas inefficacy is associated with a lower drug exposure. Cabozantinib plasma drug monitoring may be useful to optimize clinical practice.
Sections du résumé
BACKGROUND
Cabozantinib is a tyrosine kinase inhibitor with a substantial efficacy in metastatic renal cell carcinoma, and is associated with a challenging toxicity profile leading to frequent drug discontinuations. Whereas an exposure/safety relationship was demonstrated for this drug, an exposure/efficacy relationship is still unknown.
PATIENTS AND METHODS
We carried out a monocentric, observational, pharmacokinetics/pharmacodynamics (PK/PD) study in patients with metastatic renal cell carcinoma (INDS MR 5612140520). We used measured blood concentrations of cabozantinib (C
RESULTS
We enrolled 76 patients, including 35 who experienced disease progression and 30 with grade 3-4 toxicity. Patients with progressive disease had a significantly lower median C
CONCLUSION
We first demonstrate the PK/PD relationship for cabozantinib. Severe toxicities are associated with a higher drug exposure, whereas inefficacy is associated with a lower drug exposure. Cabozantinib plasma drug monitoring may be useful to optimize clinical practice.
Identifiants
pubmed: 34864351
pii: S2059-7029(21)00274-X
doi: 10.1016/j.esmoop.2021.100312
pmc: PMC8645912
pii:
doi:
Substances chimiques
Anilides
0
Pyridines
0
cabozantinib
1C39JW444G
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
100312Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.
Déclaration de conflit d'intérêts
Disclosures EA reports personal financial interest from Genzyme and Mundipharma, outside the submitted work. EC reports personal financial interest from Bristol Myers Squibb (BMS), Brazil Clovis Oncology, GlaxoSmithKline, Ipsen, Merck, Pfizer outside the submitted work. OM reports personal financial interest from Bayer, Blueprint Medicines, BMS, Eli Lilly, Ipsen, Merck Sharp & Dohme (MSD), Pfizer, Roche, Servier and institutional financial interest from Bayer, Blueprint Medicines, Eli Lilly and Epizyme outside the submitted work. BE reports personal financial interest from AVEO, BMS, EUSA Pharma, Ipsen, MSD, Novartis, Oncorena, Pfizer; Roche/Genentech and institutional consulting fees compensated to their institution from BMS France, all outside the submitted work. LA reports consulting fees compensated to their institution from Amgen, Astellas, AstraZeneca, BMS, Corvus Pharmaceuticals, Exelixis, Ipsen, Merck KGaA, Merck & Co., Novartis, Peloton Therapeutics, Roche and Pfizer outside the submitted work. All other authors have declared no conflicts of interest.