Metabolites in Safety Testing: Issues and Approaches to the Safety Evaluation of Human Metabolites in a Drug that is Extensively Metabolized
- *Corresponding Author:
- Dr. Mario Pellegatti
Drug Metabolism and Pharmacokinetics Department
GlaxoSmithKline, Via Fleming 2, 37135 Verona, Italy
Tel: (+39) 045- 8218403
Fax: (+39) 045-9218061
E-mail: [email protected]
Received Date:October 18, 2010; Accepted Date: October 21, 2010; Published Date: October 21, 2010
Citation: Griffini P, James AD, Roberts AD, Pellegatti M (2010) Metabolites in Safety Testing: Issues and Approaches to the Safety Evaluation of Human Metabolites in a Drug that is Extensively Metabolized. J Drug Metab Toxicol 1:102. doi: 10.4172/2157-7609.1000102
Copyright: © 2010 Griffini P, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.