Liver Injury with Ulipristal Acetate: Exploring the Underlying Pharmacological Basis

Abstract

Introduction The European Medicines Agency has suspended the use of ulipristal acetate (UPA) in the treatment of uterine fibroids and is reassessing its association with a risk of liver injury. Objectives Our objectives were to characterize the post-marketing reporting of drug-induced liver injury (DILI) with UPA and investigate the underlying pharmacological basis. Methods We queried the worldwide FDA Adverse Event Reporting System and performed a disproportionality analysis, selecting only hepatic designated medical events (DMEs) where UPA was reported as suspect. The reporting odds ratios (RORs) were calculated, and we considered a lower limit of the 95% confidence interval (LL95% CI) > 1 as significant. Physiochemical/pharmacokinetic features were extracted to assess the risk of hepatotoxicity by applying predictive DILI risk models. Mifepristone and leuprolide were selected as comparators. Results A significantly higher proportion of liver disorders was reported for UPA than for mifepristone (2.9 vs. 0.8%; p < 0.00001) and leuprolide (2.9 vs. 1.6%; p = 0.015). As regards hepatic DMEs, statistically significant RORs were found for autoimmune hepatitis (N = 5; LL95% CI 16.8), DILI (n = 5; LL95% CI 5.9), and acute hepatic failure (N = 5; LL95% CI 9.3). No signals of DILI emerged for mifepristone and leuprolide acetate. UPA and mifepristone showed high lipophilicity and hepatic metabolism (predicted intermediate DILI risk). Leuprolide exhibited contrasting features, resulting in no DILI concern. Inhibition of different liver transporters and the presence of a reactive metabolite were also recognised for UPA. Conclusion Different drug properties previously linked to the occurrence of DILI may partially explain the reporting pattern observed with UPA. Our "bedside-to-bench" approach may support regulators in the risk-benefit assessment of UPA.

Liver Injury with Nintedanib: A Pharmacovigilance–Pharmacokinetic Appraisal

“…Considering the expanding use of nintedanib, post-marketing surveillance is pivotal for early detection of clinically important hepatic events, as exemplified by a recent case report of suggestive acute hepatitis by nintedanib used for more than 4 months for suspected pulmonary fibrosis after coronavirus disease (COVID)-19 [ 9 ]. In this setting, pharmacology may be used to explore the potential underlying mechanisms of DILI, starting from estimating the extent of reporting in post-marketing surveillance, the so-called “bedside-to-bench” approach [ 10 ].…”

Acute liver failure requiring transplantation: A possible link to ulipristal acetate treatment?

“…Recently, the mechanisms (if any) involved in UPA as a DILI trigger are being attentively reviewed 7,18–20 but very far from being clearly understood. They are probably of an idiosyncratic nature, but they can also be dose dependent and related to the formation of reactive metabolites at the hepatic level, accumulation of UPA and/or its metabolites due to their long half‐life and high lipophilicity, inhibition of liver transporters, and previous cirrhosis caused by alcohol abuse or chronic viral infection, which may predispose patients to cholestatic disease that decreases biliary excretion 7,19–23 …”

Investigation of Inherited Chromosomally Integrated Human Herpesvirus-6A+ and -6B+ in a Patient with Ulipristal Acetate-Induced Fulminant Hepatic Failure

“…However, whether reactivation from iciHHV-6 could have worsened drug-induced liver injury due to ulipristal acetate [42], a selective progesterone receptor modulator used to treat uterine fibroids before 2020 and now suspended by the European Medicines Agency, remains elusive [43]. Indeed, cases of drug-induced hypersensitivity syndrome in iciHHV-6+ patients have rarely been reported [44,45].…”