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With lead compounds identified, multiparametric compound optimization efforts continue with increased stringency for target affinity, target selectivity, and in vitro absorption, distribution, metabolism, and excretion (ADME) properties, to move compounds from leads to clinical candidates. In this lead-optimization stage of drug discovery, evaluation of in vitro parameters continues, and these are augmented with a focus on in vivo properties of the compound(s). In vitro assays of hepatic metabolism are augmented with in vivo studies of pharmacokinetics (PK) and metabolite profiling in rodent and non-rodent species. As compound quality improves, appropriate animal models of in vivo efficacy are established and used to compare compounds for in vivo efficacy, PK, and safety. The goal of these lead-optimization activities is to identify compounds of sufficient quality to be used in clinical studies. The successful completion of lead-optimization studies, resulting in clinical development candidates, marks the formal conclusion of drug discovery efforts and the beginning of preclinical development studies.