Mechanistic Investigations Support Liver Safety of Ubrogepant

Small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated therapeutic efficacy for the treatment of migraine. However, previously investigated CGRP receptor antagonists, telcagepant and MK-3207, were discontinued during clinical development because of concerns about drug-induced liver injury. A subsequent effort to identify novel CGRP receptor antagonists less likely to cause hepatotoxicity led to the development of ubrogepant. The selection of ubrogepant, following a series of mechanistic studies conducted with MK-3207 and telcagepant, was focused on key structural modifications suggesting that ubrogepant was less prone to forming reactive metabolites than previous compounds. The potential for each drug to cause liver toxicity was subsequently assessed using a quantitative systems toxicology approach (DILIsym) that incorporates quantitative assessments of mitochondrial dysfunction, disruption of bile acid homeostasis, and oxidative stress, along with estimates of dose-dependent drug exposure to and within liver cells. DILIsym successfully modeled liver toxicity for telcagepant and MK-3207 at the dosing regimens used in clinical trials. In contrast, DILIsym predicted no hepatotoxicity during treatment with ubrogepant, even at daily doses up to 1000 mg (10-fold higher than the approved clinical dose of 100 mg). These predictions are consistent with clinical trial experience showing that ubrogepant has lower potential to cause hepatotoxicity than has been observed with telcagepant and MK-3207.

Body Fat Changes and Liver Safety in Obese and Overweight Women Supplemented with Conjugated Linoleic Acid: A 12-Week Randomised, Double-Blind, Placebo-Controlled Trial

Preliminary evidence suggests that conjugated linoleic acid (CLA) may reduce body weight and affect body composition. The present study assessed the effect of CLA supplementation on body fat composition in overweight and obese women, while also evaluating the liver safety of CLA use. Seventy-four obese or overweight women were randomly assigned to receive 3 g/day CLA or placebo for 12 weeks. Body composition (dual-energy X-ray absorptiometry) and liver function (13C-methacetin breath test and serum liver enzymes) were assessed before and after the trial. Patients receiving CLA experienced a significant reduction of total body fat expressed as mass (p = 0.0007) and percentage (p = 0.0006), android adipose tissue (p = 0.0002), gynoid adipose tissue (p = 0.0028), and visceral adipose tissue (p = 4.2 × 10−9) as well as a significant increase in lean body mass to height (p = 6.1 × 10−11) when compared to those receiving a placebo. The maximum momentary 13C recovery changes and end-point values were significantly higher in the CLA group when compared to the placebo group (p = 0.0385 and p = 0.0076, respectively). There were no significant changes in alanine aminotransferase, asparagine aminotransferase, and gamma-glutamyl transpeptidase activities between the groups. In conclusion, CLA supplementation was well tolerated and safe for the liver, which shows beneficial effects on fat composition in overweight and obese women.

Safety and efficacy of dronedarone from clinical trials to real-world evidence: implications for its use in atrial fibrillation

Efficacy and safety of dronedarone was shown in the ATHENA trial for paroxysmal or persistent atrial fibrillation (AF) patients. Further trials revealed safety concerns in patients with heart failure and permanent AF. This review summarizes insights from recent real-world studies and meta-analyses, including reports on efficacy, with focus on liver safety, mortality risk in patients with paroxysmal/persistent AF, and interactions of dronedarone with direct oral anticoagulants. Reports of rapidly progressing liver failure in dronedarone-prescribed patients in 2011 led to regulatory cautions about potential liver toxicity. Recent real-world evidence suggests dronedarone liver safety profile is similar to other antiarrhythmics and liver toxicity could be equally common with many Class III antiarrhythmics. Dronedarone safety concerns (increased mortality in patients with permanent AF) were raised based on randomized controlled trials (RCT) (ANDROMEDA and PALLAS), but comedication with digoxin may have increased the mortality rates in PALLAS, considering the dronedarone–digoxin pharmacokinetic (PK) interaction. Real-world data on apixaban–dronedarone interactions and edoxaban RCT observations suggest no significant safety risks for these drug combinations. Median trough plasma concentrations of dabigatran 110 mg during concomitant use with dronedarone are at acceptable levels, while PK data on the rivaroxaban–dronedarone interaction are unavailable. In RCTs and real-world studies, dronedarone significantly reduces AF burden and cardiovascular hospitalizations, and demonstrates a low risk for proarrhythmia in patients with paroxysmal or persistent AF. The concerns on liver safety must be balanced against the significant reduction in hospitalizations in patients with non-permanent AF and low risk for proarrhythmias following dronedarone treatment.