Prolonged release pirfenidone pharmacokinetics is modified in cirrhosis GENESIS study

Abstract

BackgroundIn both clinical and experimental trials, pirfenidone (PFD) showed anti-inflammatory and antifibrogenic effects. Considering the wide variation in hepatic functional reserve in patients with cirrhosis, we decided to learn more about the pharmacokinetics of a new formulation of prolonged release PFD in this population (PR-PFD), focusing on assessing changes on AUC0–∞, AUC0–t, and Cmax. MethodsIn this study, 24 subjects with cirrhosis were included: eight subjects with mild liver impairment (Child–Pugh A) and eight with moderate liver impairment (Child–Pugh B), and a third group of eight age-matched subjects without fibrosis. All participants were under fasting conditions before receiving orally two 600-mg tablets of a prolonged-release formulation of pirfenidone (PR-PFD) and remained in the clinical unit for 36 h after PR-PFD administration. Serial blood samples were collected after dosing (0.5-36 h). A validated high-performance liquid chromatography–mass spectrometry method was used to determine PFD plasma concentrations. ResultsThe exposure to PR-PFD was 3.6- and 4.4-fold greater in subjects with Child–Pugh A and Child–Pugh B than in subjects without cirrhosis, and Cmax was 1.6- and 1.8-fold greater in subjects with Child–Pugh B and Child–Pugh-A than in patients without cirrhosis, without significant differences between the two cirrhotic groups. PFD was well tolerated. ConclusionThe pharmacokinetic parameters of PR-PFD are significantly modified in patients with cirrhosis compared with those in controls, indicating that liver impairment should be considered in clinical practice.