Liver Injury with Ulipristal Acetate: Exploring the Underlying Pharmacological Basis
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ORIGINAL RESEARCH ARTICLE
Liver Injury with Ulipristal Acetate: Exploring the Underlying Pharmacological Basis Milo Gatti1 · Elisabetta Poluzzi1 · Fabrizio De Ponti1 · Emanuel Raschi1
© The Author(s) 2020
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 1 with at least three cases of interest reported [10]. Cases were manually checked for duplicates using case identification and overlapping information among records, and, for ROR calculation, a case counts as many-fold as the number of hepatic events reported. Case-by-case assessment for concomitant drugs with hepatotoxic potential was also performed based on classification proposed by Björnsson et al. [11], focusing on agents in category A and B. For comparison, we also extracted data on mifepristone, a well-known progesterone-receptor antagonist available for pregnancy termination [12], and leuprolide acetate, a synthetic agonist analogue of gonadotropin-releasing hormone first approved for the treatment of advanced prostatic cancer and also currently used for the management of uterine fibroids [13]. Mifepristone and leuprolide acetate were, respectively, selected according to affinity of chemical structure and comparable therapeutic indication (i.e., uterine fibroids).
3.2 Pharmacological Assessment To investigate the potential underlying mechanisms of DILI associated with UPA, we performed a review of the physiochemical and pharmacokinetic features known to be potentially involved in DILI. In particular, properties such as threshold dose, lipophilicity, formation of reactive metabolites, oxidative stress, mitochondrial liability, hepatic
Liver Injury Associated with Ulipristal Acetate
metabolism, and inhibition of hepatic transporters can confer a risk for DILI, which may increase susceptibility to hepatotoxicity because of host-related factors such as female sex and age [14, 15]. We also queried public online prediction tools (namely, ADVERPred [16] and Vienna LiverTox Workspace [17]) to investigate the existence of physiochemical features associated with DILI and the in
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