Drug Discovery Today  Volume 18, Numbers 1–2  January 2013 REVIEWS A modern in vivo pharmacokinetic paradigm: combining snapshot, rapid and full PK approaches to optimize and expedite early drug discovery Chun Li, Bo Liu, Jonathan Chang, Todd Groessl, Matthew Zimmerman, You-Qun He, John Isbell and Tove Tuntland Department of Metabolism and Pharmacokinetics, Genomics Institute of the Novartis Research Foundation, Novartis Institute of Biomedical Research, San Diego, CA, USA Successful drug discovery relies on the selection of drug candidates with good in vivo pharmacokinetic (PK) properties as well as appropriate preclinical efficacy and safety profiles. In vivo PK profiling is often a bottleneck in the discovery process. In this review, we focus on the tiered in vivo PK approaches implemented at the Genomics Institute of the Novartis Research Foundation (GNF), which includes snapshot PK, rapid PK and full PK studies. These in vivo PK approaches are well integrated within discovery research, allow tremendous flexibility and are highly efficient in supporting the diverse needs and increasing demand for in vivo profiling. The tiered in vivo PK studies expedite compound profiling and help guide the selection of more desirable compounds into efficacy models and for progression into development. High-throughput in vitro absorption, distribution, metabolism and elimination (ADME) assays have been implemented in early drug discovery to identify and eliminate compounds with poor drug- like properties and to promote potential pharmaceutical candi- dates for more labor-intensive in vivo PK profiling [1–5]. Data from in vitro ADME assays often contribute to the understanding of underlying mechanisms of drug absorption and disposition, which have proven invaluable to establish structure–activity rela- tionships (SAR) that guide new chemical synthesis. However, despite the advances in the in vitro technologies and in silico approaches [6–9] for prediction of in vivo PK parameters, the predictive power of these approaches is not always reliable and accurate. Complete reliance on in vitro assays in the absence of an in vitro–in vivo correlation (IVIVC) can sometimes mislead or slow down the pace of a drug discovery program [10,11]. The PK profile of a compound is governed by many physicochemical and che- mical properties of the molecule, such as its lipophilicity, solubi- lity, permeability and metabolic stability. The processes by which a compound is absorbed, distributed, metabolized and eliminated in vivo through an intact animal or human are often far more com- plex than in isolated in vitro systems. It is essential to have in vivo testing and confirmations of in vitro ADME results in early drug discovery and, therefore, there is always a continuous demand for in vivo PK studies. In vivo rodent PK studies are crucial to ensure compounds have appropriate PK properties to be evaluated in preclinical pharma- cology and safety studies. In addition, characterization of in vivo PK of new chemical entities provides insight into complex in vivo biological systems and correlates drug concentration at the site of action with pharmacological response. Despite their important role in drug discovery, most in vivo animal PK studies are still conducted in a traditional, low-throughput manner in many pharmaceutical companies and, therefore, remain the bottlenecks of discovery projects. In this review, we present three tiered in vivo rodent PK approaches that are highly efficient in supporting early drug dis- covery research. The study designs, strategies and applications of each of the tiered assays are discussed and compared with other commonly used in vivo rodent PK approaches in the pharmaceutical industry. These tiered in vivo rodent PK approaches span from the simple and abbreviated study design of ‘snapshot’ PK [12], to the more labor-intensive intravenous/per oral (IV/PO) PK study designs, such as ‘rapid PK’ and the conventional ‘full PK’. Depending on the needs and stage of a specific project, different study designs can be Reviews  POST SCREEN Corresponding author: Tuntland, T. (ttuntland@gnf.org) 1359-6446/06/$ - see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2012.09.004 www.drugdiscoverytoday.com 71