The Future of ADME in Drug Design and Development

Abstract

ADME (absorption, distribution, metabolism and excretion) are the descriptive terms applied to the multiple and complex processes that govern drug distribution. DMPK (drug metabolism and pharmacokinetics) is the scientific discipline that has evolved to provide the qualitative and quantitative study of these processes throughout the drug discovery and development lifecycle and, as such, is very much a cradle to grave discipline. Successful drug discovery and development requires an integrated clinical focus from the outset. Once a compound enters drug development it cannot be re-engineered or modified. It therefore falls to the Medicinal Chemist, with one eye steadfastly fixed on the clinical prize, to design, select and progress only those compounds that have the correct biological profile and physicochemical properties for clinical evaluation. Fulfilling a critical role in supporting the selection of potent, selective leads that retain the appropriate physicochemical properties to ensure distribution from the site of administration to the site action, DMPK bridges the gap between the disciplines of biology and chemistry, thereby enabling and maintaining a clinical focus in the early discovery phase. Accordingly, a fundamental understanding of this scientific discipline is essential for any Medicinal Chemist working in the field of drug discovery. DMPK is, by necessity, a broad and multifaceted science and a wide variety of in vitro and in vivo assays are used to triage and select compounds for progression. However, no one assay has the power to improve all the odds for overall success and therefore data integration and contextualisation are now emerging as key areas of growth and scientific development. This chapter highlights the pivotal role of ADME in early drug discovery including basic principles, the consideration of “free” drug concentrations with respect to drug absorption, drug–drug interactions and concentrations at the target site of action. The evolving sciences of early and earlier human pharmacokinetic predictions aligned with estimates of clinical therapeutic dose are introduced and the concept of a more systems-based approach is advocated.