Clinical implications of nintedanib pharmacokinetics in patients with pulmonary fibrosis.

Autor: Agema BC; Dept. of Medical Oncology, Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, the Netherlands. Electronic address: b.agema@erasmusmc.nl., Berrich M; Dept. of Medical Oncology, Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, the Netherlands., Seuren L; Dept. of Medical Oncology, Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, the Netherlands., Sassen SDT; Dept. of Clinical Pharmacy, Erasmus MC, Rotterdam, the Netherlands., Miedema JR; Dept. of Pulmonology, Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, the Netherlands., Koch BCP; Dept. of Clinical Pharmacy, Erasmus MC, Rotterdam, the Netherlands., Wijsenbeek MS; Dept. of Pulmonology, Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, the Netherlands., Koolen SLW; Dept. of Medical Oncology, Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, the Netherlands; Dept. of Clinical Pharmacy, Erasmus MC, Rotterdam, the Netherlands., Mathijssen RHJ; Dept. of Medical Oncology, Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, the Netherlands., Veerman GDM; Dept. of Medical Oncology, Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, the Netherlands; Dept. of Pulmonology, Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, the Netherlands.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2024 Oct; Vol. 179, pp. 117341. Date of Electronic Publication: 2024 Aug 26.
DOI: 10.1016/j.biopha.2024.117341
Abstrakt: Background: Nintedanib is used to treat both idiopathic and progressive pulmonary fibrosis (IPF/PPF). Evidence of both an exposure-response relationship and an exposure-toxicity relationship has been found, suggesting the potential value of therapeutic drug monitoring (TDM). We aimed to define the therapeutic window of nintedanib in a real-world cohort.
Methods: Data from two clinical studies were pooled for this analysis. To quantify exposure to nintedanib, a population-pharmacokinetic (PK) model was developed. Associations between PK and decline in forced vital capacity (FVC) and diffusing capacity (DLCO) were performed using linear-mixed-effect models (LMEM). The exposure-toxicity relationship was evaluated using a Cox proportional hazards model.
Results: In total, 911 PK samples from 99 patients were used to develop the PK model. The LMEM with random slopes and intercepts included 517 pulmonary function tests (PFT) from 81 patients. The average administered nintedanib dose was associated with the rate of FVC decline (p=0.002). Per 50 mg decrease of daily dosage, the rate of FVC decline increased by 53.5 mL/year. Neither nintedanib exposure nor dose significantly affected DLCO decline and they were also not significantly associated with the occurrence of a dose-limiting toxicity (DLT). This may be explained by a large inter- and intrapatient variability in nintedanib PK.
Conclusion: Nintedanib dose was significantly associated with FVC loss. However, no significant relationship between nintedanib exposure and the occurrence of DLTs was found in this real-world population, and no therapeutic window could be established. The findings in this study indicate that nintedanib is an unsuitable candidate for performing TDM.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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