Existence of a relationship between increased serum alanine aminotransferase levels (ALT) detected in premarketing clinical trials and postmarketing published hepatotoxicity case-reports

Lucia Llanos (1) , Rocio Moreu (1) , Teresa Ortin (1) , Ana Peiro (1, 2) , Sonia Pascual (3, 4) , Pablo Bellot (3) , Claudia Barquero (3) , Ruben Frances (4) , José Such (4, 5) , Miguel Pérez-Mateo (3) , Jose F Horga (1, 2) , Pedro Zapater (1, 2, 4)

1 Clinical Pharmacology Section
2 Instituto de Bioingeniería
3 Liver Unit
4 CIBERehd - Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas
5 Liver Unit

Background: Drug-induced Liver Injury (DILI) profile in most drugs' available information is based on both the incidence of 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 clasified in High-medium risk (Black Box Warning or Precautions section) or low risk (a statement in the Adverse Reactions section). Incidence of ALT elevations (≥3xULN) for drug (ID) and placebo (IP) treated patients in premarketing clinical trials and DILI published case-reports were retrieved from product labelling and Medline. Results: Median IP was 10/1000. High-medium risk drugs median ID was significantly higher compared to low risk drugs (17/1000 vs 10/1000; p=0.046). Chi-square test, absolute difference and Odds Ratio comparing ID and IP 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 (1vs7; p=0.001). High Odds Ratio in clinical trials (ID vs IP) 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.

Mots clés: Medicine

Lucia Llanos, Rocio Moreu, Teresa Ortin, Ana Peiro, Sonia Pascual, et al.. Existence of a relationship between increased serum alanine aminotransferase levels (ALT) detected in premarketing clinical trials and postmarketing published hepatotoxicity case-reports. Alimentary Pharmacology and Therapeutics, 2010, 31 (12), pp.1337. ⟨10.1111/j.1365-2036.2010.04298.x⟩. ⟨hal-00552548⟩