Page - (000102) - in Biomedical Chemistry: Current Trends and Developments

time curve must be fully characterized and all metabolites must be fully resolved, identified and quantified, demanding analytical techniques with enough sensitivity and selectivity to quantify the small amounts present in biological samples. Indeed, regulatory guidance documents have highlighted not only the importance of the identification and structure elucidation of drug metabolites, but also their early quantification in clinical development in order to address three important requirements: determination of whether metabolites contribute significantly to the overall pharmacology of a drug; assessment of safety coverage of metabolites and understanding the DDI potential of the drug and its metabolites (FDA, 2008b; 2012; Zhu, 2009; Frederick, 2010; EMA, 2012). The general key factors to be considered for these metabolites are relative quantity (major or minor metabolites), pharmacological activity, likelihood to be formed via reactive intermediates and whether they result from phase I or phase II metabolic reactions. Thus, the FDA guidance on Safety Testing of Drug Metabolites (FDA, 2008b) defines a major metabolite as that which AUC value is higher than 10% of the AUC of the parent drug at steady-state conditions. The DDI guidance also proposes that human metabolites present at ≥ 25% of the parent drug’s exposure (given by AUC) should be investigated in vitro for their DDI potential (EMA, 2012; FDA, 2012). Considering Table 2.1.1, the pharmacokinetic analysis in phase II clinical trials is employed to assess the dose/exposure response and dose ranging studies are carried out to establish the effective doses for phase III clinical trials. On the other hand, phase III clinical trials can involve up to several thousands of patients to create an adequate database for assessing the efficacy and safety profile of a compound and to enable accurate drug labeling. Pharmacokinetic analysis is particularized for special sub-populations, including patients with impaired renal or hepatic functions (EMA, 2004a, 2005) as well as pediatric and elderly populations (EMA, 2004b). Hundreds of sites around the world participate in the study to get a large and diverse group of patients, implying a vast number of samples to be handled and analyzed.