Prolonged release pirfenidone pharmacokinetics is modified in cirrhosis GENESIS study.

BACKGROUND: In 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. METHODS: In 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. RESULTS: The 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. CONCLUSION: The 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.

Reference Datasets for Studies in a Replicate Design Intended for Average Bioequivalence with Expanding Limits.

In order to help companies qualify and validate the software used to evaluate bioequivalence trials in a replicate design intended for average bioequivalence with expanding limits, this work aims to define datasets with known results. This paper releases 30 reference datasets into the public domain along with proposed consensus results. A proposal is made for results that should be used as validation targets. The datasets were evaluated by seven different software packages according to methods proposed by the European Medicines Agency. For the estimation of CVwR and Method A, all software packages produced results that are in agreement across all datasets. Due to different approximations of the degrees of freedom, slight differences were observed in two software packages for Method B in highly incomplete datasets. All software packages were suitable for the estimation of CVwR and Method A. For Method B, different methods for approximating the denominator degrees of freedom could lead to slight differences, which eventually could lead to contrary decisions in very rare borderline cases.