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Metabolites in Safety Testing: Issues and Approaches to the Safety Evaluation of Human Metabolites in a Drug that is Extensively Metabolized

Patrizia Griffini, Alexander D. James, Andrew D. Roberts and Mario Pellegatti

In 2008 the Food and Drug Administration (FDA) modified its standard for evaluating toxicity of drug metabolites defining metabolites of concern as those that are detected circulating at more than 10% of the systemic exposure level of the parent compound at steady state. GSK1018921, a novel glycine transporter 1 inhibitor, was extensively metabolized in humans, with parent compound accounting for 12% and 1% of circulating drug related material after single and repeat dose, respectively. Since the parent was present at low relative concentrations, all fifteen metabolites detected in human plasma, met the 10% metabolites in safety testing (MIST) criterion, and therefore might require extensive quantification and further evaluation. At least thirteen metabolites warranted non-clinical characterization since they were either observed at significantly greater levels in humans than in preclinical species or they were not detected in animals. However the application of alternative strategies to 2008 FDA MIST guidance, such as those suggested by scientific literature and by the recent revision of the International Conference of Harmonisation (ICH) M3 guidance which recommended providing safety coverage for metabolites greater than 10% of total drug related material, allowed us to focus on one metabolite for additional safety evaluation.