Pharm Dev Regul 2003; 1 (2): 117-132 REVIEW ARTICLE 1175-9046/03/0002-0117/$30.00/0  Adis Data Information BV 2003. All rights reserved. Applied Pharmacokinetics in Drug Development An Overview of Drug Discovery Gary W. Caldwell, Zhengyin Yan, John A. Masucci, William Hageman, Gregory Leo and David M. Ritchie Drug Discovery Department, Johnson & Johnson Pharmaceutical Research & Development L.L.C., Spring House, Pennsylvania, USA Contents Abstract ............................................................................................................... 117 1. Drug Development Process .......................................................................................... 118 1.1 Analyses of Success Rates of Pharmaceutical Drug Development ................................................... 119 1.2 Recent Strategies to Improve Success Rates of New Chemical Entities ............................................... 120 2. Overview of Pharmacokinetics ....................................................................................... 121 2.1 Oral Bioavailability .............................................................................................. 122 2.2 Half-Life ........................................................................................................ 122 2.3 Absorption ..................................................................................................... 123 2.4 Elimination and Clearance ...................................................................................... 124 2.5 Volume of Distribution ........................................................................................... 124 3. Preclinical Activities in Drug Discovery ................................................................................. 125 3.1 Drug Lead Stage (Early Drug Discovery) ........................................................................... 125 3.2 Drug Optimization Stage ........................................................................................ 127 3.3 Final Selection Stage (Late Drug Discovery) ........................................................................ 127 4. Conclusion ......................................................................................................... 128 The process of discovering, developing, and marketing new drugs has changed considerably in the last Abstract decade; however, the cost associated with this process remains staggeringly high. Although there are many reasons for this high cost, one reason appears to be the continuing high attrition rates of drugs during costly early- and late-stage human clinical trials. To address this problem, drug discovery organizations are striving to rapidly identify high-potential drug candidates and eliminate as early as possible those with inferior potency, poor pharmacokinetic properties, and toxicity problems, so that these deficient drug candidates do not incur the high costs of clinical trials. During the last 5 years, a decision-making go/no-go strategy has been introduced into the drug discovery process, using pharmacokinetic principles to minimize the risks and maximize the benefits of selecting superior drug candidates. Pharmacological deficiencies are related in part to pharmacokinetic properties. To understand this process, a brief review of pharmacokinetic properties including oral bioavailability, half-life, absorption, clearance, and volume of distribution is presented. We examine in vitro – in vivo (human) and/or in vivo (animals) – in vivo (human) correlations for several of these pharmacokinetic properties, followed by a discussion of how this preclinical information is collected and used in drug discovery at the various stages to select drug candidates. Finally, we summarize how these methods are used to make go/no-go decisions in each step of the drug discovery process. Pharmaceutical companies are continually reinventing their tion, compound screening, chemical synthesis, molecular biology, organizational structure, investing in new technologies, and pharmacology, and computer-aided drug design. Drug discovery changing their scientific cultures in order to maintain returns on and development organizations have embraced new technologies, research investments. The process of discovering, developing, and such as analytical instrumentation, chemistry and biology robotic marketing new drugs has changed considerably in the last decade systems, computerized data handling systems, and computational with advances in technologies and new strategies in target selec- and simulation software. Combinatorial chemistry techniques,