Pharmacokinetics than drug discovery

Figure 21.1. Attrition during drug development. Compounds failing to make it through drug development due to pharmacokinetic-related issues reduced from approximately 40% in 1990 to less than 10% in 2000. In part, this can be explained by pulling forward the evaluation of metabolic stability, CYP inhibition, plasma protein binding, and pharmacokinetics into drug discovery. (Reprinted with permission from Nat. Rev. Drug Discovery 2004, 3, 711-715.)...

This chapter will review some of the important methods for carrying out in vivo absorption and bioavailability studies, as well as attempt to provide an overview of how the information may be used in the drug discovery process. The chapter is aimed at medicinal chemists and thus will focus on the use of animals in discovery phase absorption, distribution, metabolism, and excretion/pharmacokinetic (ADME/PK) studies, rather than the design of studies that are for regulatory submission, or part of a development safety package. 

The drug discovery and development processes are time consuming and costly endeavors. It has been reported that on average it takes 10 to 15 years and costs more than 800 million to bring a molecule from discovery to market.12 Compounds fail for various reasons. One that accounts for a reported 40% of failures in clinical trials is poor pharmacokinetics.3 In an effort to improve the number of compounds that exhibit optimal absorption, distribution, metabolism, elimination (ADME), and pharmacokinetic (PK) properties and reach development, drug metabolism and pharmacokinetic scientists continually implement new technologies and compound screening approaches. 

The traditional role of preclinical drug metabolism in pharmaceutical research has been to define absorption, distribution, metabolism, and excretion (ADME) of potential drug compounds for regulatory fiUngs. This role has expanded over the past 5 years to include support of early drug discovery. Consequently, the number of compounds whose ADME characteristics need to be defined has expanded the work now encompasses thousands of compounds annually rather than the traditional tens of compounds. At the same time, the focus has evolved from merely defining a compound s own fate in the body to include the identification of potential liabiUties, such as parameters that Unfit in vivo pharmacokinetics (PK). 

---