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

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 (> or = 3 x ULN) for drug (I(D)) and placebo (I(C)) treated patients in premarketing clinical trials and DILI published case reports were retrieved from product labelling and MEDLINE. RESULTS: The median I(C) was 10/1000. The high-medium-risk drugs' median I(D) 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 I(D) and I(C) 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 (I(D) vs. I(C)) 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.