Review of Drug Discovery and ADMET process

Medicilon's pharmacokinetics department offers the clients a broad spectrum of high quality of services in the areas of in vitro ADME, in vivo pharmacokinetics and bioanalysis services, ranging from small molecules to large molecules, such as protein and antibody. The animal species involved in our services are non-human primate, canine, mice, rat, rabbit and hamster. Meanwhile, non-human primate experimental platform and isotope platform for protein/antibody are certified by the Shanghai Government. Email:marketing@medicilon.com.cn Web:www.medicilon.com

Pharmaceutical drug discovery is an expensive and time-consuming process. In order to have one effective and safe drug, millions of molecules are screened. A successful IND application requires that the sponsor demonstrate reasonable evidence concerning safety of the candidate molecule. This evidence is derived from a battery of in vitro assays as well as in vivo studies using animals. Animal studies often fail to predict clinical results due to inter-species differences in enzymes, transporters and biochemical pathways. Although many in vitro assays use human cells, they lack the interplay of body systems and biochemical pathways. Due to these shortcomings, both in vitro and in vivo studies often fail to predict clinical outcomes. Nearly 30% of molecules entering clinical trials fail because of insufficient safety. This inadequacy opens opportunities for new technologies that can address these issues, thereby leading to a more predictive human model. In addition, due to time-consuming and expensive nature of in vivo studies, improved in vitro assays that lead to reduction in animal usage present interesting opportunities. With these ideas in mind we framed the objective to summarize the in vitro ADME/T tests in order to better predict human clinical outcomes. 1. Introduction Drug Discovery Process The drug discovery process begins with first choosing a specific disease to treat. Understanding something about the biochemical pathway(s) or genetics of the disease allows researchers to focus on a specific class of enzymes or receptors potentially responsible for the disorder. After identifying and validating the target enzyme/receptor, a high-throughput screen of potentially millions of small molecules is conducted. The results of this screening allow medicinal chemists to focus only on those molecules containing certain functional groups, core structures and 3D shapes. These leads are then subjected to further biochemical and in vitro assays to eliminate molecules with potential side effects, drug-drug interactions or toxicity. A select few candidates are pursued further during the lead optimization phase. Herein, medicinal chemists fine tune the reactivity and structure of these ligands. These leads are again tested using both in vitro and in vivo methods. This cycle of chemical fine tuning and biological testing is repeated several times until the most likely molecule to succeed in clinical trials has been synthesized and characterized as best as possible. The optimized molecule is then chosen to be subjected to more extensive studies for IND filing; meanwhile, the scale-up process synthesis is executed. This assessment involves bioanalytical quantification of metabolites, plasma concentration measurements, regular vet assessments, and ultimately necropsy of several organs. These more extensive in vivo ADME/T studies are then used to estimate the PK/PD parameters in humans and also provide guidance for physicians in clinical trials. 2. Drug Failure: Fail Early, Fail Cheap The discovery and development of a new pharmaceutical drug requires more than a billion dollars and can take 12 years of research effort (Adams and Brantner 2010; DiMasi, Hansen, and Grabowski 2003). The drug discovery and development process can be divided into four distinct phases: early discovery, late discovery, preclinical, (Fig.1) and finally the clinical trials. Although there are several factors that contribute to attrition, two major reasons are efficacy and toxicity. It has been estimated that only 1 of 10,000 chemicals that enter the discovery process ever reaches the market. This is not hard to imagine when one considers that 40% of NCEs that begin preclinical safety studies in animals will fail due to toxicity, and that 89% of NCEs that enter clinical trials will fail. The greatest cost in terms of time occurs in early and late discovery, which can require 6 to 8 years of research effort. In comparison, the highest cost in terms of dollars occurs in the preclinical and clinical studies (DiMasi, Hansen, and Grabowski 2003; Kletter et al. 2013; McCarter et al. 2013). The ability to identify and reduce risk early can significantly improve the process of drug development by improving efficiency and improving the probability of success. The new paradigm in drug discovery should include a robust means of identifying issues related to toxicity early in the discovery process where the cost of dropping a molecule is less than in later phases. 3. Preclinical ADME/T Testing As discussed above, every potential drug molecule needs to be tested for ADME/T properties. In this section, we briefly describe the commonly performed in vitro and in vivo ADME/T studies. 3.1. In vitro Assays ADME/T studies are done throughout the drug discovery and development process (Guttendorf) . They can be done in preclinical studies leading up to an IND or be assessed in humans during clinical trials to file an NDA (Guttendorf). In vitro ADME studies are typically conducted at the same stage as in vivo PK studies to facilitate selection of drug candidates with the best safety and pharmacological profile while understanding the mechanisms behind their activity (Steinmetz and Spack 2009).