Elevation of Liver Enzymes in Multiple Dose Trials During Placebo Treatment: Are They Predictable?

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Abstract
The present study examined the increase in transaminases, especially in ALT in young healthy males during placebo treatment in phase I multiple dose trials. The primary objective was to investigate whether volunteers showing increasing ALT levels also present characteristic patterns of demographic data, laboratory parameters, and vital signs. The secondary objective was to determine whether there is a possibility to predict increases of ALT during a trial by analyzing demographic data and baseline levels of routine safety laboratory parameters and vital signs. In a meta‐analysis of 13 placebo‐controlled multiple dose phase I studies, volunteers showing elevations of ALT during placebo treatment were compared with those presenting no clinically significant changes of ALT levels. Demographic data as well as routine safety laboratory values and vital signs measured at screening and on the first day of the in‐house stay were subject to the analysis. Using Wilcoxon's rank sum test, significant differences between ALT‐susceptibles and ALT‐nonsusceptibles were found for baseline values (mean values of screening and the first day of the in‐house stay) of ALT, γGT, AST/ALT, and AST/γGT. Differences found for the screening values of the heart rate were statistically rather than clinically significant. Cut‐off values were found for baseline levels of ALT and AST/ALT ratio. Their use resulted in a sensitivity of 73% and a specificity of 74% with regard to predictability of ALT levels increasing during the trial.