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The in vitro metabolism and in vivo pharmacokinetic (PK) properties of DNDI-VL-2098, a potential oral agent for Visceral Leishmaniasis (VL) were studied and used to predict its human pharmacokinetics. DNDI-VL-2098 showed a low solubility (10μM) and was highly permeable (>200nm/s) in the Caco-2 model. It was stable in vitro in liver microsomes and hepatocytes and no metabolite was detectable in circulating plasma from dosed animals suggesting very slow, if any, metabolism of the compound. DNDI-VL-2098 was moderate to highly bound to plasma proteins across the species tested (94–98%). DNDI-VL-2098 showed satisfactory PK properties in mouse, hamster, rat and dog with a low blood clearance (

Discovering a new drug is a complex but sequential process from discovery to preclinical development, followed with clinical drug development. It has been estimated that ∼ 87% of the phase III failures are accounted for either due to lack of efficacy (66%) or due to safety issues (21%). Majority of these failures are for compounds targeted for novel mechanisms of actions with unmet medical need, in particular, oncology and neurodegenerative disorders. Some of the reasons for these failures can be attributed to lack of appropriate preclinical animal models, biomarkers/surrogate markers, and effective pharmacokinetic (PK)–pharmacodynamic (PD) evaluation during early drug discovery. Translational research that integrates computer-aided drug design (CADD), PK, PD, drug metabolism (DM), and drug transport along with biomarkers and humanized animal models are instrumental in making informed decisions from early drug discovery through clinical development. The ability to correlate drug effect through modeling and simulations starts from early drug discovery and preclinical evaluation, including use of novel biomarkers. Such models validate the PK and PD relationships and provide a basis for their applications and guide the Phase I through Phase III clinical trials more effectively, minimizing the late stage failures. Thus, PK–PD evaluation has become an integral part of drug discovery and provides valuable insights to aid in optimizing the next steps for drug development. This chapter is focused on translational drug discovery research with particular emphasis on selective utilization of CADD; absorption, distribution, metabolism, and excretion; toxicology; PK; and PD evaluations, which identify potential liabilities early so as to minimize late-stage failures during drug development. This chapter also provides a brief overview on means and measures that can be adopted to integrate early drug discovery research along with efficacy and safety biomarkers for meaningful transition to drug development. Keywords: drug discovery; integration; computational modeling; pharmacokinetics/ADME; pharmacodynamics; toxicology; biomarkers

Definitive plasma protein binding (PB) studies in drug development are routinely conducted with radiolabeled material, where the radiochemical purity limits quantitative PB measurement. Recent and emerging regulatory guidances increasingly expect quantitative determination of the fraction unbound (Fu) for key decision making. In the present study, PB of 11 structurally- and therapeutically-diverse drugs spanning the full range of plasma binding was determined by equilibrium dialysis of non-radiolabeled compound and was validated against the respective definitive values obtained by accepted radiolabeled protocols. The extent of plasma binding was in agreement with the radiolabeled studies; however, the methodology reported herein enables reliable quantification of Fu values for highly-bound drugs and is not limited by the radiochemical purity. In order to meet the rigor of a development study, equilibrium dialysis of unlabeled drug must be supported by an appropriately validated bioanalytical method along with studies to determine compound solubility and stability in matrix and dialysis buffer, nonspecific binding to the dialysis device, and ability to achieve equilibrium in the absence of protein. The presented methodology establishes an experimental protocol for definitive PB measurement, which enables quantitative determination of low Fu values, necessary for navigation of new regulatory guidances in clinical drug development.