ADME drug safety

An ability to communicate with scientists in both ADME, drug safety, computational chemistry, discovery chemistry, discovery biology, biostatistics, and information technology groups. 

Following an introduction to the necessities of filtering and risk assessment of potential new drug molecules before entering lead optimization, the equally important aspects of pharmacokinetic (ADME) and safety (toxicity) profiling are covered in separate parts. 

The fully automated computational procedure is a valuable ne v tool in virtual screening and in early ADME-Tox, vhere drug safety and metabolic profile patterns must be evaluated in order to enhance and streamline the process of developing neiv drug candidates. 

In vivo Animal Models Used for ADME Studies in Support of Drug Safety Evaluation 552... 

More recently, the bottleneck of drug research has shifted from hit-and-lead discovery to lead optimization, and more specifically to PK lead optimization. Some major reasons are (i) the imperative to reduce as much as feasible the extremely costly rate of attrition prevailing in preclinical and clinical phases, and (ii) more stringent concerns for safety. The testing of ADME properties is now done much earlier, i.e. before a decision is taken to evaluate a compound in the clinic. 

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. 

Although prediction of ADME/PK in man may be the primary purpose for the pre-clinical studies, it is also important that potential new drugs have acceptable properties in toxicology species. Without these it can be very difficult to generate adequate safety margins to allow studies in man to start. It is also likely that the development safety assessment program will be difficult and hence slow. 

Because DMPK properties vary among different species, in vitro human and animal data and in vivo animal data cannot always be extrapolated to human in vivo responses. The three main reasons that drugs fail during clinical trials are (1) lack of efficacy, (2) unacceptable adverse effects, and (3) unfavorable ADME properties. Hence, clinical development is necessary to establish solid experiment-based human exposure and safety data through both short- and long-term monitoring. 

PD studies allow us to understand the potency, effectiveness, therapeutic index, and safety margins of drugs. PK information on ADME provides us with an understanding of how drugs are transported, diffused into the bloodstream, and become available to the cells and act on the target sites. 

The drug is administered to a small group of healthy volunteers with the objective of determining the processes of absorption, distribution, metabolism, and excretion (ADME) and the pharmacokinetic effects. Escalating doses are compared to choose one suitable for both safety and efficacy. 

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