578 Interplay of Gender, Age and Drug Properties in Drug-Induced Liver Injury: Analysis of Adverse Event Reporting at Who Vigibase™

Abstract

[Background] Clinical hepatotoxicity is highly associated with specific drug properties (e.g., lipophilicity, transport, and metabolism) and daily dose (>100mg). However, how these drug properties interact with age and gender in drug-induced liver injury (DILI) remains unclear. [Aim] To generate hypotheses on drug-patient interactions in DILI, we performed a data-mining analysis using the WHO VigiBaseTM to 1) identify drugs with genderand age-biased reporting frequency (RF) of liver events and 2) explore the association between the groups of identified drugs and drug properties relevant to hepatotoxicity. [Methods] Empirical Bayes Geometric Mean of relative reporting ratio of liver events (EBGM) with 90% confidence interval (CI) was calculated for 375 drugs with established clinical DILI potential (Suzuki, Drug safety 2010; Chen, Drug Discovery Today 2011), partitioning all reported cases into 4 groups by gender and age 50 yrs. Drugs with gender-biased indications were manually excluded from the analysis. Combining Medical Dictionary for Regulatory Activities terms (Hunt, Regul Tox Pharm, 2014), customized liver event terms were created for hepatocellular injury, cholestatic injury, acute liver failure, and overall liver events. Comparing EBGM and 90% CI of overall liver events among the 4 groups, drugs with significant differences in genderand age-specific RF were identified. The groups of identified drugs were then associated with distinct drug properties in the Liver Toxicity Knowledge Base (Chen, Clin Pharm & Ther, 2013). [Results] Overall liver events were 13-20% more frequently reported in women compared tomen. Compared to age-matched men, women<50 yrs exhibited a 40% increased RF of acute liver failure. Across all ages, we identified 43 drugs with an increased RF among women, which were significantly associated with transporter inhibition, mitochondrial liability, and reactive metabolite formation, compared to 186 drugs with no gender difference in RF. Fourteen drugs with an increased RF among men tended to have a higher proportion causing cholestatic injury, while 57 drugs with an increased RF among women only before age 50 yrs were associated with a higher proportion causing hepatocellular injury. Regardless of gender, seventeen drugs with an increased RF in age ≥ 50 yrs were associated with transporter inhibition, lipophilicity, high daily dose (≥100mg), and higher Cmax and plasma protein binding, yet shorter plasma elimination T1/2. [Conclusions] This data-mining analysis identified specific drug properties associated with genderand age-related RF of liver events, suggesting a potential physiologic interplay between these drug properties, gender and age. The discovered associations of gender and age-related DILI and the specific drug properties should be further evaluated for drug-patient interaction in DILI susceptibility.