Instead, researchers have used the number of published case reports of medication hepatotoxicity listed on the U.S. National Institutes of Health LiverTox website to create categories of likelihood for medications to cause severe ALI (Category A [well-known cause], ≥50 cases; Category B [highly likely], 12-49 cases; Category C [probable], 4-11 cases; and category D [possible], 1-3 cases), according to a report in the Journal of the American Medical Association Internal Medicine.
“However,” wrote University of Pennsylvania Perelman School of Medicine–led researchers, “cases of drug-induced ALI are frequently underreported. Moreover, categorizing hepatotoxic drugs using case reports does not consider the number of individuals exposed and may not accurately reflect incidence of severe ALI.”
The study team sought to find what the most hepatotoxic medications are based on real-world rates of severe ALI and how do these rates compare with hepatotoxicity categorization based on published case reports.
To do that, the researchers conducted a series of cohort studies among about 7.9 million people without liver or biliary disease who initiated any of 194 suspected hepatotoxic medications in the outpatient setting from 2000 to 2021. They determined that 17 medications had rates of severe ALI at 5.0 or more events per 10,000 person-years, representing the most potentially hepatotoxic medications. Yet, 11 of those medications (64%) were not included in the highest hepatotoxicity category by case reports.
“Because case reports of medication hepatotoxicity do not consider the number of persons exposed, safety signals derived from case reports should be investigated using epidemiologic data,” the authors advised.
The cohort studies used data from the U.S. Department of Veterans Affairs on patients who initiated a suspected hepatotoxic medication in the outpatient setting between October 1, 2000, and September 30, 2021. Data were analyzed from June 2020 to November 2023. The mostly male cohort (92.5%) had a mean age of 64.4 years.
The main outcomes were defined as hospitalization for severe ALI, defined by either inpatient: 1) alanine aminotransferase level greater than 120 U/L plus total bilirubin level greater than 2.0 mg/dL, or 2) international normalized ratio of 1.5 or higher plus total bilirubin level greater than 2.0 mg/dL recorded within the first 2 days of admission.
The results indicated that incidence rates of severe ALI ranged from 0 events per 10,000 person-years (candesartan, minocycline) to 86.4 events per 10,000 person-years (stavudine).
The study reported that seven medications (stavudine, erlotinib, lenalidomide or thalidomide, chlorpromazine, metronidazole, prochlorperazine, and isoniazid) led to rates of 10.0 or more events per 10,000 person-years, and 10 medications (moxifloxacin, azathioprine, levofloxacin, clarithromycin, ketoconazole, fluconazole, captopril, amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and ciprofloxacin) had rates between 5.0 and 9.9 events per 10,000 person-years.
“Of these 17 medications with the highest observed rates of severe ALI, 11 (64%) were not included in the highest hepatotoxicity category when based on case reports,” the researchers emphasized, adding, “In this study, incidence rates of severe ALI using real-world data identified the most potentially hepatotoxic medications and can serve as a tool to investigate hepatotoxicity safety signals obtained from case reports. Case report counts did not accurately reflect the observed rates of severe ALI after medication initiation.”
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