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.

Review article: drug‐induced liver injury in the context of nonalcoholic fatty liver disease – a physiopathological and clinical integrated view

“…300 Polypharmacy represents a challenge to identify drug toxicity, since comedications were found to modify the mechanisms of DILI; certain combinations may decrease or increase the risk of hepatotoxicity, thus making it difficult to identify the causative agent. 301 Beyond this confounding factor, a number of drugs have been suggested to induce DILI more often in obese individuals, including volatile halogenated anaesthetics, acetaminophen, losartan, ticlopidine, omeprazole, and MTX. 5,102,118,130,284,302,303 Some of these drugs may be more hepatotoxic in the obesity context due to the increased activity of several CYPs that can metabolise de original drug to more toxic metabolites, such as CYP1A2, CYP2C9, CYP2D6, and CYP2E1.…”

PharmGKB summary

“…It is also worth noting that INH is rarely administered alone and some of the toxic effects seen in patients treated with INH may be due to, or exacerbated by, drug-drug interactions [7, 12, 13, 49–54]. …”

Liver Injury due to Amoxicillin vs. Amoxicillin/Clavulanate: A Subgroup Analysis of a Drug-Induced Liver Injury Case-Control Study in Italy

“…According to Yazici et al [27], the risk of death among users of co-amoxiclav increases with the use of concomitant hepatotoxic medications and they suggest that these patients may have concomitant diseases with less ability to recover from a severe DILI compared to healthier patients, or even that the occurrence of drug- drug interactions between amoxiclav and other hepatotoxic agents may result in a more serious liver injury. In their recent paper Suzuki et al [28] analyzed the reporting frequency of liver events of four drugs (one of them was co-amoxiclav) in the presence of co-reported medications on the basis of the WHO global individual case safety report database (VigiBase™); they showed that co-reported drugs were associated with changes in the frequency of hepatic ADR reporting of drugs usually associated with hepatotoxicity, suggesting that co-medications could modify drug hepatic safety.…”