Abstract
After the commercialization of nintedanib in Japan, a high incidence of hepatotoxicity resulting in treatment interruption was noted in idiopathic pulmonary fibrosis (IPF) patients treated with nintedanib in our hospital. This study aimed to clarify the risk factors for hepatotoxicity of nintedanib. Sixty-eight consecutive cases of IPF newly treated with nintedanib at a dose of 150 mg twice daily from September 2015 to September 2016 were enrolled: 46 patients (67.6%) exhibited aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) elevation and 16 patients (23.5%) also had a Common Terminology Criteria for Adverse Events (CTCAE) grade ≥2. Body surface area (BSA) was significantly lower in the CTCAE grade ≥2 group than in another group. A multivariate logistic regression analysis showed that the association between BSA and AST/ALT elevation with CTCAE grade ≥2 was statistically significant. Eight of 10 patients who resumed nintedanib at a reduced dose of 100 mg twice daily after interruption due to hepatotoxicity did not again develop AST/ALT elevation. In conclusion, a low BSA was associated with hepatotoxicity of nintedanib at a dose of 150 mg twice daily. It would be a good option for patients with a small physique to start nintedanib at a dose of 100 mg twice daily and then increase if possible after confirming its safety.
Highlights
Nintedanib is a small-molecule tyrosine kinase inhibitor that inhibits vascular endothelial growth factor, TM platelet-derived growth factor, and fibroblast growth factor[1, 2]
A low body surface area (BSA) was associated with AST and/or ALT elevation with a Common Terminology Criteria for Adverse Events (CTCAE) grade ≥2 when treated with nintedanib at a dose of 150 mg twice daily
The present study suggested that a low BSA predicts an AST and/or ALT elevation with a CTCAE grade ≥2 when treating with nintedanib at a dose of 150 mg twice daily
Summary
Nintedanib is a small-molecule tyrosine kinase inhibitor that inhibits vascular endothelial growth factor, TM platelet-derived growth factor, and fibroblast growth factor[1, 2]. Two randomized phase III trials (INPULSIS -1 and -2) showed that nintedanib reduced the decline in forced vital capacity (FVC) in patients with idiopathic pulmonary fibrosis (IPF) with a manageable side effect profile[3,4,5]. Based on these trial results, nintedanib was approved for IPF by the Pharmaceutical and Medical Devices Agency in Japan and was clinically deployed from September 2015.
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