De-Risking Drug Discovery with ADDME — Avoiding Drug Development Mistakes Early

Abstract

The advent of early Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) screening has increased the elimination rate of weak drug candidates early in the drug-discovery process, and decreased the proportion of compounds failing in clinical trials for ADMET reasons. This paper reviews the history of ADMET screening and why it has become so important in drug discovery and development. Assays that have been developed in response to specific needs, and improvements in technology that result in higher throughput and greater accuracy of prediction of human mechanisms of toxicity, are discussed. The paper concludes with the authors’ forecast of new models that will better predict human efficacy and toxicity.

Drug-Like Property Profiling of Novel Neuroprotective Compounds to Treat Acute Ischemic Stroke: Guidelines to Develop Pleiotropic Molecules

“…Thus, this data set clearly shows that even with this rational approach, basic chemical characteristics are not effective predictors of “efficacy”. On the basis of neuroprotective activity in 2 assays, the 10 new compounds were further screened for drug-like properties using a series of in vitro assays for ADME(29), toxicity(28, 29) and BBB penetration(24–26, 79, 84). …”

“…With the huge number of therapy failures that have been documented in the literature(13–19), it has been recommended that researchers provide substantial rationale and efficacy data to justify the development of novel drug classes (15, 20–23) and de-risk (reduce the risk of) drug development to enhance the possibility of success in randomized and blinded clinical trials. Moreover, since measuring Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) parameters during the early phases of drug development can be done economically(24, 25) and with great utility toward the development of both translational and clinical programs, preclinical development plans should incorporate ADMET measures (24–31). …”

KCN1, a Novel Synthetic Sulfonamide Anticancer Agent: In Vitro and In Vivo Anti-Pancreatic Cancer Activities and Preclinical Pharmacology

“…Because the distribution and disposition of an agent within the body is vital for determining its efficacy and toxicity, early pharmacokinetic studies are of great importance for drug development [32], [33]. Such studies can provide information about the most effective route and frequency of administration, as well as an indication of how effective the agent will be against tumors at different sites within the body.…”

“…Such studies can provide information about the most effective route and frequency of administration, as well as an indication of how effective the agent will be against tumors at different sites within the body. They may also indicate possible sites of drug accumulation and/or toxicity [32], [33]. In the present study, we attempted to characterize the pharmacological properties of KCN1 in preclinical setting, with regard to its plasma stability, plasma protein binding, bioavailability, and distribution following systemic administration to mice.…”

In Vitro Models of the Liver: Disease Modeling, Drug Discovery and Clinical Applications

“…In the discovery and preclinical development stages of drug development, candidates are identified by correlating drug responses in cell cultures and preclinical animal models-usually one rodent and one non-rodent species (10). Screening for absorption, distribution, metabolism, excretion, and toxicity (ADMET screening, also commonly referred to as ADME or the study of drug metabolism and pharmacokinetics) optimizes preclinical testing by enabling better understanding of the pharmacokinetic and pharmacodynamic properties of drug candidates (11). Desirable drug-like properties identified by ADMET screening include adequate absorption and distribution, low metabolism, complete elimination from the body, and a minimal toxicological risk (10).…”