1. Clinical implications of nintedanib pharmacokinetics in patients with pulmonary fibrosis.
- Author
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Agema BC, Berrich M, Seuren L, Sassen SDT, Miedema JR, Koch BCP, Wijsenbeek MS, Koolen SLW, Mathijssen RHJ, and Veerman GDM
- Subjects
- Humans, Male, Female, Aged, Middle Aged, Vital Capacity drug effects, Pulmonary Fibrosis drug therapy, Pulmonary Fibrosis chemically induced, Drug Monitoring methods, Idiopathic Pulmonary Fibrosis drug therapy, Idiopathic Pulmonary Fibrosis physiopathology, Respiratory Function Tests, Dose-Response Relationship, Drug, Protein Kinase Inhibitors pharmacokinetics, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors adverse effects, Indoles pharmacokinetics, Indoles administration & dosage, Indoles adverse effects
- Abstract
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.)
- Published
- 2024
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