ADME-PK Screening

The effort was very successful and the results were documented by Kola and Landis1 who stated that the situation changed and that fewer than 10% of current clinical failures arose from PK problems. Figure 7.1 portrays this shift in reasons for compound attrition. The increased emphasis on early ADME/PK screening resulted in a significant change in reasons for compound failure from Phase I to FDA approval—PK is no longer a major reason. 

It is certainly an exciting time to be a scientist involved in new drug discovery. As pharmaceutical companies continue to look for ways to efficiently screen thousands of compounds each year through various in vitro and in vivo ADME/PK screens, they face continuing pressures to obtain data more efficiently at a faster pace. The ongoing advances in the fields of HPLC and MS are helping scientists meet these demands. 

Conceptually, the strategy for ADME-PK screening in drug discovery can be compared to decathlon event as stated by Kerns and Di [21]. A specific ADME-PK screen is analogous to a specific athletic event. The overall winner is not necessarily the lead compound that exhibits the best performance in any single ADME-PK screen, but simply has adequate characteristics in all ADME-PK screens. 

So it can be generalized that a standard series of ADME-PK screening assays is assembled during the initiation of a drug discovery program. A drug candidate must... 

Table 2.2 contains a list of ADME-PK assays that are routinely used to provide information via in vitro assays, lead optimization screens, and in vivo PK studies [22], Each assay is developed and applied with the intent of providing a quick survey of ADME-PK properties. Certainly, the workflow of drug discovery activities can often be depicted in a linear, stepwise fashion according to the ADME-PK screens highlighted in Table 2.2. However, such a workflow would not take into consideration the dynamics of a drug discovery program nor would such a workflow depict the differences that exist between different programs (i.e., diabetes, cancer, cardiovascular). The fact is that the discovery process is often initially supported with a standard set of ADME-PK assays that can be viewed as somewhat compulsory and highly iterative.

Despite the extensive use of ADME-PK screens in drug discovery, there is no one correct or standardized workflow for drug discovery. Often, ADME screening strategies are dictated by specific needs of the discovery program (i.e., therapeutic area, competitive landscape), recent precedent (i.e., success, failure), and/or the chemistry and disposition of a series of lead compounds. 

FIGURE 2.6 The ADME-PK screening data that are obtained in drug discovery and used to determine dosing regimen (i.e., how much and how long ). A combination of assays associated with physicochemical properties (absorption, clearance, and volume of distribution) and PK properties (bioavailability and half life) are used to evaluate each drug candidate. (Courtesy of Milestone Development Services, Newtown, PA. With permission.)... 

Accurate and timely answers to the iterative questions what do I have and how much is there are paramount to the success of a drug discovery program. The bottom-line is that the pharmaceutical industry prefers analysis formats for ADME-PK screening that can generate information quickly to make fast... 

Drug discovery Purification and characterization of combinatorial libraries and lead compounds, ADME/PK screening HPLC MS, MS/MS, PDA, ELSD... 

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