title: Comedications alter drug-induced liver injury reporting frequency: Data mining in the WHO VigiBase™.
abstract: Polypharmacy is common, and may modify mechanisms of drug-induced liver injury. We examined the effect of these drug-drug interactions on liver safety reports of four drugs highly associated with hepatotoxicity. In the WHO VigiBase™, liver event reports were examined for acetaminophen, isoniazid, valproic acid, and amoxicillin/clavulanic acid. Then, we evaluated the liver event reporting frequency of these 4 drugs in the presence of co-reported medications. Each of the 4 primary drugs was reported as having more than 2000 liver events, and co-reported with more than 600 different medications. Overall, the effect of 2275 co-reported drugs (316 drug classes) on the reporting frequency was analyzed. Decreased liver event reporting frequency was associated with 245 drugs/122 drug classes, including anti-TNFα, opioids, and folic acid. Increased liver event reporting frequency was associated with 170 drugs/82 drug classes; in particular, halogenated hydrocarbons, carboxamides, and bile acid sequestrants. After adjusting for age, gender, and other co-reported drug classes, multiple co-reported drug classes were significantly associated with decreased/increased liver event reporting frequency in a drug-specific/unspecific manner. In conclusion, co-reported medications were associated with changes in the liver event reporting frequency of drugs commonly associated with hepatotoxicity, suggesting that comedications may modify drug hepatic safety.
authors.affiliation: Gastroenterology, Central Arkansas Veterans Healthcare System and Gastroenterology and Hepatology, Univ. of Arkansas for Med. Sciences, Little Rock, AR, United States. Electronic address: asuzuki@uams.edu.
authors.forename: Ayako
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Clinical Safety, GlaxoSmithKline, Research Triangle Park, NC, United States.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Yuen
authors.affiliation: Pharmacovigilance and Risk Management, Raptor Pharmaceuticals, CA, United States.
authors.forename: Katarina
authors.initials: K
authors.lastname: Ilic
authors.affiliation: Safety Assessment, GlaxoSmithKline, Research Triangle Park, NC, United States.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Miller
authors.affiliation: Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, NC, United States.
authors.forename: Melinda J
authors.initials: MJ
authors.lastname: Reese
authors.affiliation: Safety Assessment, GlaxoSmithKline, Research Triangle Park, NC, United States.
authors.forename: H Roger
authors.initials: HR
authors.lastname: Brown
authors.affiliation: Safety Assessment, GlaxoSmithKline, Research Triangle Park, NC, United States.
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Ambroso
authors.affiliation: Safety Assessment, GlaxoSmithKline, Research Triangle Park, NC, United States.
authors.forename: J Gregory
authors.initials: JG
authors.lastname: Falls
authors.affiliation: Gastroenterology, Duke University Medical Center and Durham Veterans Administration Medical Center, Durham, NC, United States. Electronic address: Christine.Hunt@va.gov.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Hunt
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects; D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data*; D019980:Amoxicillin-Potassium Clavulanate Combination / Q000009:adverse effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D057225:Data Mining; D016208:Databases, Factual; D004347:Drug Interactions; D007538:Isoniazid / Q000009:adverse effects; D014635:Valproic Acid / Q000009:adverse effects; D014944:World Health Organization
chemical_list: D000082:Acetaminophen; D014635:Valproic Acid; D019980:Amoxicillin-Potassium Clavulanate Combination; D007538:Isoniazid
keywords: Concomitant medications; Drug-induced liver injury; Hepatotoxicity; Quantitative signal detection methods; Spontaneous adverse event reporting system