OBJECTIVES: IPF is a progressive disease occurring in adults, limited to the lungs for which nintedanib and pirfenidone are approved drugs by the FDA. In this review, we aim to evaluate the incidence of hepatic adverse events (AEs) with pirfenidone and nintedanib.

METHODS: A comprehensive search was conducted between 2012-2022 using biomedical databases (MEDLINE®, EMBASE®, PubMed) with additional searches executed to summarize evidence from conferences, registries, and grey literature. Two independent researchers performed the analysis of the included studies.

RESULTS: Out of 331 studies identified from literature, a total of 25 studies were eligible. Most of the included studies were retrospective (n=10) or phase 2/3 (n=12) studies. In patients receiving nintedanib, highest incidence was reported for hepatic toxicity (42%) followed by 36.1% and 25.5% for elevated alanine transaminase (ALT) and aspartate transaminase (AST), respectively (all grade <3). Higher grades of ALT and AST elevations were also reported with the incidence of ≥5x upper limit of normal (ULN) and ≥8x ULN being 2.2% and 0.8% respectively. In the case of pirfenidone, elevation in gamma-glutamyl transpeptidase (g-GTP) reported the highest incidence (17.1- 27.4%) followed by elevated ALT and AST with an incidence of 20.0% (grade 1-2). For some hepatic AEs like gamma-glutamyl transferase (GGT) elevation (2.7%), glutamic oxaloacetic transaminase (GOT) elevation (5.5%), hepatoma (1.4%), hepatobiliary disorders (0.3%) and hepatic toxicity (1.4% to 8.3%), the grade was not specified. Serious hepatic AEs were elevated- ALT (0.3%), AST (0.1%), GGT (0.3%), elevated hepatic enzymes (0.26% to 0.3%) and hepatic toxicity (0.6%).

CONCLUSIONS: Both nintedanib and pirfenidone are associated with a significant incidence of hepatic AEs, although most belonged to lower grades (grade 1 and 2). These AEs were tolerable by the patients and in most cases, did not require treatment discontinuation. Close clinical observation during treatment phase can be effective in managing these AEs without further complications.