Safety of nintedanib added to pirfenidone treatment for idiopathic pulmonary fibrosis

Abstract

We assessed safety and tolerability of treatment with pirfenidone (1602–2403 mg·day−1) and nintedanib (200–300 mg·day−1) in patients with idiopathic pulmonary fibrosis (IPF).This 24-week, single-arm, open-label, phase IV study (ClinicalTrials.gov identifier NCT02598193) enrolled patients with IPF with forced vital capacity % pred ≥50% and diffusing capacity of the lung for carbon monoxide % pred ≥30%. Before initiating nintedanib, patients had received pirfenidone for ≥16 weeks and tolerated a stable dose of ≥1602 mg·day−1 for ≥28 days. The primary end-point was the proportion of patients who completed 24 weeks of combination treatment on pirfenidone (1602–2403 mg·day−1) and nintedanib (200–300 mg·day−1). Investigators recorded treatment-emergent adverse events (TEAEs), attributing them to pirfenidone, nintedanib, both or neither.89 patients were enrolled; 73 completed 24 weeks of treatment (69 meeting the primary end-point) and 16 discontinued treatment prematurely (13 due to TEAEs). 74 patients had 418 treatment-related TEAEs, of which diarrhoea, nausea and vomiting were the most common. Two patients had serious treatment-related TEAEs.Combined pirfenidone and nintedanib use for 24 weeks was tolerated by the majority of patients with IPF and associated with a similar pattern of TEAEs expected for either treatment alone. These results encourage further study of combination treatment with pirfenidone and nintedanib in patients with IPF.

Pirfenidone in patients with idiopathic pulmonary fibrosis and more advanced lung function impairment

“…Overall, our observations support the inclusion of patients with more advanced lung function impairment in future IPF trials investigating novel therapies, as well as combination antifibrotic therapy [28,29]. Whether patients with even greater lung function impairment than those included in this analysis should be included in future clinical trials is open to speculation, but it is certainly a concept for further investigation.…”

Guidelines of the Polish Respiratory Society for Diagnosis and Treatment of Idiopathic Pulmonary Fibrosis

“…The necessity of exerting pharmacological action on different profibrotic signalling pathways as a result of the multifactorial and complex pathogenesis of IPF suggest that better outcomes could be achieved with combination therapy. In recent years, several studies have been published assessing the safety, tolerability and pharmacokinetics of combination therapy with pirfenidone and nintedanib in IPF patients [244][245][246][247]. In a randomised, double-blind phase 2 study conducted in a small group of 50 IPF patients, Ogura et al [30,57] demonstrated that combination therapy with pirfenidone and nintedanib had acceptable safety and tolerability profiles, which was confirmed in other studies [245][246][247].…”

“…In recent years, several studies have been published assessing the safety, tolerability and pharmacokinetics of combination therapy with pirfenidone and nintedanib in IPF patients [244][245][246][247]. In a randomised, double-blind phase 2 study conducted in a small group of 50 IPF patients, Ogura et al [30,57] demonstrated that combination therapy with pirfenidone and nintedanib had acceptable safety and tolerability profiles, which was confirmed in other studies [245][246][247]. A Japanese study, however, revealed reduced values of the peak serum plasma concentration and area under the curve (AUC) of nintedanib when it was used simultaneously with pirfenidone [244].…”

“…A Japanese study, however, revealed reduced values of the peak serum plasma concentration and area under the curve (AUC) of nintedanib when it was used simultaneously with pirfenidone [244]. However, further studies of the pharmacokinetics and safety of combination therapy with pirfenidone and nintedanib failed to reveal any pharmacokinetic interactions between these agents [245][246][247]. No randomised studies assessing the efficacy of combination therapy with pirfenidone and nintedanib compared with monotherapy with either of the agents have been performed to date.…”

Systematic review and network meta-analysis of approved medicines for the treatment of idiopathic pulmonary fibrosis

“…Flaherty et al 42 examined the tolerability of pirfenidonenintedanib combination therapy, assessing the occurrence of treatment-emergent adverse events (TEAEs). Of the 89 patients, 78% completed the 24 week single-arm, open label study, with the profile and rate of TEAEs proportionally similar to that of monotherapies.…”