Pharmacokinetics and Safety of Fenofibrate in Participants with Mild Hepatic Impairment or with Advanced Fibrosis due to Metabolic-Associated Fatty Liver Disease.

Abstract

Fenofibrate is contraindicated in patients with advanced hepatic fibrosis due to limited clinical data. We evaluated the pharmacokinetics and safety of fenofibrate in participants with mild hepatic impairment (phase 1 study) or advanced fibrosis due to metabolic-associated fatty liver disease (MAFLD; phase 2a study). In the phase 1 study, participants with mild hepatic impairment and healthy matched controls (each n = 10) received a single, oral dose of fenofibrate 48 mg. In the phase 2a study, participants with hypertriglyceridemia and advanced fibrosis due to MAFLD were randomly assigned (1:1) fenofibrate 48 mg (n = 15) or fenofibrate 145 mg (n = 16) combined with firsocostat 20 mg, taken orally once daily for 24 weeks. Pharmacokinetics and safety were assessed in both studies. In the phase 1 study, the AUC_inf of fenofibric acid was 25% higher in participants with mild hepatic impairment than in healthy matched participants. In the phase 2a study, the AUC_ss,0-24 of fenofibric acid (fenofibrate 48 mg dose) in participants with F3 fibrosis and F4 cirrhosis was approximately 60% and 80%, respectively, higher than the AUC_inf in healthy participants in the phase 1 study, and was 20% higher in participants with F4 cirrhosis than in participants with F3 fibrosis. In both studies, most adverse events and laboratory abnormalities were grade 1-2. In the phase 2a study, three participants had grade 3 hypertriglyceridemia. Fenofibrate was well tolerated, and modest differences were observed in fenofibric acid exposure in participants with mild hepatic impairment or advanced fibrosis due to MAFLD.