Liver safety issues affect patients and may result in compound termination during drug development or drug withdrawal postmarketing. While liver chemistries are monitored to protect patient safety, the frequency and timing of monitoring is largely empirically determined.Objective:
To determine the optimal timing of liver chemistry monitoring in phase I–III drug development.Setting:
Liver chemistries and safety were analysed from six GlaxoSmithKline (GSK) clinical development programmes discontinued with liver safety issues, marketed products and five products withdrawn from the market because of liver safety issues.Methods of assessment:
Retrospective analysis of the temporal appearance, incidence, form of liver injury and severity of liver chemistry elevations and adverse outcomes observed with medication use.Results:
In the phase I–III clinical studies, all six GSK compounds exhibited hepatocellular injury and/or jaundice in the first treatment month. Alanine aminotransferase (ALT) ≥3 × the upper limit of normal occurred within the first 2 weeks to 4 months in 2–50% of treated subjects. By contrast, drugs withdrawn from the market exhibited a more severe pattern of injury with a lower incidence of liver chemistry elevations observed after 3 days to >24 months of treatment.Conclusions:
Liver chemistry monitoring appears to be most productive in the first few months of drug initiation. Evaluating the incidence of liver chemistry elevations proactively identifies whether there is a compound liver safety signal that requires further assessment.