Page - (000101) - in Biomedical Chemistry: Current Trends and Developments

findings to assess the relevance of these results on human clinical safety. Toxicokinetics is thus recognized as an integral part of non- clinical testing programs that enhances the value of the toxicological data generated, not only to understand the toxicity results but also to predict the risk and safety in humans. Together with bioavailability evaluation, metabolite profile determination and plasma drug levels associated with toxicity, toxicokinetics determines the choice of the no observed adverse effect level, which is essential to define the human equivalent dose and the maximum recommended starting dose in first- in-human clinical trials (FDA, 2005). At non-clinical development, disposition studies are also performed using radiolabeled compounds administered to animals to provide useful mass balance data, first-pass metabolism from vascular and portal vein cannulation animal models, biliary excretion conducted on bile-duct cannulated animals and tissue distribution, where the organs can be removed and drug quantified in order to evaluate whether drug accumulation may be involved. In all these studies, identification and quantification of drug (radiolabeled or otherwise) and main metabolites is required, implying the application of bioanalytical techniques adequately developed and validated for that purpose. Clinical development initiates with the first administration of the drug to humans and all the stages are strictly based on specific guidelines from the International Conference on Harmonisation (ICH), European Medicines Agency (EMA) and FDA (ICH, 1997; EMA, 1998 2008; FDA, 2008a; Milton, 2009). The main goal of phase I clinical trials is to investigate whether the compound is safe and well tolerated in humans (Table 2.1.1). Pharmacokinetic properties must also be evaluated and the development of the drug can be stopped if its elimination half-life is found to be too short, too long or if it has poor bioavailability. Phase I clinical trials usually start with single sub- therapeutic dose studies which are escalated gradually followed by multiple dose studies and if the drug is not well tolerated, it is dropped from development. These closely-monitored trials help define the safe dosing range and whether the compound should move on to further development phases (Duff, 2007). Thus, from the pharmacokinetic point of view, absorption and elimination phases of the plasma concentration-