The existence of a relationship between increased serum alanine aminotransferase levels detected in premarketing clinical trials and postmarketing published hepatotoxicity case reports

Aliment Pharmacol Ther 31, 1337–1345 Summary Background Drug-induced liver injury (DILI) profile in most drugs’ available information is based on both the incidence of alanine aminotansferase (ALT) elevations in clinical trials and published case reports. Aim To assess the relationship between ALT elevations in clinical trials and the number of published case reports in the postmarketing setting. Methods Hepatotoxic drugs were identified from product labelling and classified in high-medium risk (Black Box Warning or Precautions section) or low risk (a statement in the Adverse Reactions section). Incidence of ALT elevations (≥3 × ULN) for drug (ID) and placebo (IC) treated patients in premarketing clinical trials and DILI published case reports were retrieved from product labelling and MEDLINE. Results The median IC was 10/1000. The high-medium-risk drugs’ median ID was significantly higher compared with low-risk drugs (17/1000 vs. 10/1000; P = 0.046). Chi-squared test, absolute difference and odds ratio comparing ID and IC identified 35%, 51% and 77% of high-medium-risk drugs respectively. Less number of case reports were associated with low- than high-medium-risk drugs (1 vs. 7; P = 0.001). A high odds ratio in clinical trials (ID vs. IC) was the strongest predictor of published DILI case reports. Conclusion A relationship between increased ALT incidence in premarketing clinical trials and postmarketing published case reports exists.