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The Why and How of Absorption, Distribution, Metabolism, Excretion, and Toxicity Research☆ H van de Waterbeemd, Consultant in Small Molecule Drug Discovery, Saint André, France B Testa, Pharmacy Dept, Lausanne University Hospital, Lausanne, Switzerland ã 2013 Elsevier Inc. All rights reserved. Evolving Paradigm in Drug R&D The Increasing Role of ADME-Tox in Pharmaceutical R&D Issues in ADMET Transporters Metabolite identification Drug-drug interactions Toxicology and safety prediction Technological Issues In vitro screening In silico ADME Simulations: PBPK and PK/PD Conclusion References Nomenclature ADMET CYP DDI DMPK EMEA FDA IT Absorption, distribution, metabolism, excretion and toxicity Cytochrome P450 Drug-drug interaction Drug metabolism and pharmacokinetics European Agency for the Evaluation of Medicinal Products Food and Drug Administration (USA) Information technology 1 2 3 3 3 3 4 4 4 4 4 5 5 NCE PAMPA PBPK PD P-gp PK QSAR R&D New chemical entity Parallel artificial membrane permeability assay Physiologically-based pharmacokinetics Pharmacodynamics P-glycoprotein Pharmacokinetics Quantitative structure-activity relationship Research and development Evolving Paradigm in Drug R&D Not very long ago, pharmacokinetics, drug metabolism and toxicology of selected clinical candidates were studied mainly during preclinical and clinical development. In those days the mission of medicinal chemistry was to discover and supply very potent compounds, with less interest being given to their behavior in the body. However, the R&D paradigm in the pharmaceutical industry has undergone dramatic changes since the 1970’s and particularly since the mid-1990’s. High-throughput biological assays were developed which have enabled large series of compounds to be screened. This was driven by the increasing sizes of proprietary depositories and the availability of new reagents and detection technologies. Simultaneously, medicinal chemists have developed new synthetic strategies such as combinatorial chemistry and parallel synthesis. The number of compounds synthesized increased dramatically. In addition, specialized biotech companies as well as universities began offering compound collections and focused libraries. As a result, much attention is currently being paid to the design and/or purchase criteria of lead- and drug-like compounds.1–3 Increasingly this includes considerations on ADME-related physicochemical properties as well as to ADME properties themselves. The concept of property-based design,4 in addition to structure-based design where target structures are available, is now commonly used to address ADME issues as early as possible. Thus the former traditional in vivo animal ADME evaluation could no longer cope with the demand and in vitro ADME screens became widely used. Despite rapid advances in the use of automation and robotics to increase the throughput of the in vitro ADME assays,5 screening all available compounds was not necessarily the most efficient and cost-effective strategy. It thus became reasonable and even essential to develop in silico tools to predict and simulate various physicochemical and ADME properties and to balance these in decision making processes together with combined in vivo and in vitro approaches (in combo). ☆ Change History: June 2013. H van de Waterbeemd updated the references, deleted figure 3b, deleted the ‘Concept of the Volume’ section and replaced it with a conclusion. Reference Module in Chemistry, Molecular Sciences and Chemical Engineering http://dx.doi.org/10.1016/B978-0-12-409547-2.02586-5 1 2 The Why and How of Absorption, Distribution, Metabolism, Excretion, and Toxicity Research Figure 1 The two basic modes of interaction between bioactive agents and biological systems, namely pharmacodynamic events (activity and toxicity) and pharmacokinetic events (ADME) (Reproduced with modifications from Testa, B.; Vistoli, G.; Pedretti, A., Chem. Biodiv. 2005, 2, 1411–1427 with the kind permission of the copyright owner, Verlag Helvetica Chimica Acta in Zurich). Rigorous analyses of the root causes of attrition during development revealed that lack of efficacy, toxicity, as well as inappropriate absorption, distribution, metabolism, and excretion (ADME) are among the major determinants of the failure of candidates.6,7 Lack of efficacy, in addition to insufficient response of the target, may of course be caused by poor absorption, inadequate distribution and/or rapid metabolism, leading to too low drug concentrations at the target site.8 And since toxicity is also a major factor of attrition, the development of compounds is often halted even before a detailed human pharmacokinetics or efficacy study can be performed. Hence, the real impact of ADMET processes remains somewhat hidden in (incomplete) attrition data. During the 1990’s, it became good practice to collect ADME and toxicity data during the drug discovery stage in order to use them in decision making to select the best clinical candidates.9,10Today, the drug discovery process has also become strongly dependent on departments providing data, guidance and insight on issues of drug metabolism and pharmacokinetics (DMPK), toxicology and safety. Yet the success of this move to early involvement of DMPK has been questioned. According to some practitioners the main contribution of a discovery (research) department of drug metabolism and pharmacokinetics has been to enable the design of pharmacokinetically adequate rather than optimal compounds and thus to make it possible to work on difficult targets.11 Yet despite all preclinical efforts there will always remain an essential need for extensive clinical pharmacokinetics to lay the ground for safe prescription once the drug is on the market.11 A bird’s-eye view allows the above historical summary to be summarized in two statements. First and in a more industrial perspective, it is now entirely clear that ADMET profiling must be initiated as early as possible in the discovery process, using highthroughput and in silico methods characterized by the best possible balance between good relevance to clinical properties on the one hand, and high speed, efficiency and capacity on the other hand. Second and in a more fundamental perspective, it took decades for pharmacologists and biologists to realize that there is an unseverable relation between pharmacodynamic effects (what the drug does to the organism) and pharmacokinetic effects (what the organism does to the drug) (Figure 1).12–14 For much more than a century, these two components of the interaction between drug and organism were investigated separately and in complete ignorance of any influence the other component might have. The importance now given to early ADME screening is a belated recognition the interdependence of pharmacodynamic and pharmacokinetic effects. Indeed, the influence of pharmacokinetic effects on a drug’s actions is common knowledge, be it in the duration and intensity of these actions, or even in their nature when active metabolites are produced. As for the changes in its disposition that result directly from a drug’s pharmacodynamic effects, these may be due to modifications in blood flow, gastrointestinal transit time or enzyme responses, to name a few. The Increasing Role of ADME-Tox in Pharmaceutical R&D ADME studies aim at obtaining an early estimate of human pharmacokinetic and metabolic profiles.15 But drug behavior in the body is a highly complex process involving numerous components, as presented in very simplified form in Figure 2.16 This diversity and complexity is reflected in the ADMET studies themselves, which include absorption, bioavailability, clearance and its mechanism, volume of distribution, plasma half-life, involvement of major metabolizing enzymes, nature and level of metabolites, dose estimates, dose intervals, potential for drug-drug interactions, etc.17,18 Early toxicology and safety studies should weed out compounds before they enter lengthy and costly clinical trials. As a result of the recent withdrawal of a number of marketed drugs, more pressure is now put on pharmaceutical companies by regulatory agencies such as the FDA and the EMEA, on safety evaluations including pharmacological and toxicological safety. Investigation of the potential to cause QT prolongation is now routine. However, the interpretation of data in not straightforward, since many marketed drugs can prolong the QT interval.19 The increased role of early and preclinical ADME and safety/tox studies has led to an important growth of the supporting departments and a considerable development of various technologies to address the key issues. A short overview of hot issues is The Why and How of Absorption, Distribution, Metabolism, Excretion, and Toxicity Research 3 Figure 2 A schematic description of the major processes of drug disposition, showing absorption (passive and active), distribution (passive including binding, and active including efflux), metabolism (¼ biotransformation), and excretion (passive and active including efflux). Elimination is not indicated explicitly, since metabolism is chemical elimination and excretion is physical elimination (Reproduced from. Van de Waterbeemd, H.; Testa, B., The Why and How of Absorption, Distribution, Metabolism, Excretion, and Toxicity Research. In Comprehensive Medicinal Chemistry II; Taylor, J.B. and Triggle, D.J. Ed.; Elsevier: Oxford, 2007, Vol.5, Chapter 5.01; pp. 1–9) given below,20 where we highlight first important challenges in investigating the disposition of new chemical entities (NCEs) and candidates, followed by some technological issues. Issues in ADMET Transporters Transporter proteins constitute a significant fraction of membrane-bound proteins. They are typically expressed in all organs involved in the uptake, distribution and elimination of drugs, including the gastrointestinal tract, the blood–brain barrier, the liver and the kidneys.21 There is hope that in the near future we might get experimental 3D structures of the key transporters. Interaction of drugs with transporters can alter their behavior in membrane transport, which may result in e.g. active uptake, efflux and rapid elimination. In other words, the pharmacokinetics of a drug may be influenced by transporters. Apart from a metabolic component (see subsection Drug-drug interactions), drug-drug and drug-nutrient interactions may involve transporters.22,23 But while the basic knowledge on transporters is rapidly growing, their real clinical significance remains open to debate.24 A number of P-glycoprotein (P-gp) assays have been developed, as well as some double- and triple-transfected assays. More transporter assays will soon be available. The challenge will be to translate the flood of experimental data into relevant information for drug design projects. Metabolite identification With increasing resolution of mass spectrometry and NMR, it is now feasible to detect minute amounts of metabolites.25,26 Debate is ongoing to define major vs. minor metabolites.27 Some metabolites might be pharmacologically active and contribute to the overall PK. Reactive metabolites28,29 might bind to proteins and cause idiosyncratic reactions.30 The challenge remains to detect these as early as possible. It has been suggested that time-dependent inhibition should be in standard in vitro screening protocols.31 Good progress has been made in metabolite prediction.32,33 Drug-drug interactions Regulatory authorities require information to be submitted on the potential for interactions to cause adverse effects. With the availability of in vitro systems this aspect is therefore often considered at early stages of discovery, including hit evaluation. Oxidative metabolism by cytochromes P450 (CYPs) is the major route of elimination of most drugs. Since CYPs are also able to metabolize multiple substrates, their inhibition is the major focus of drug-drug interaction (DDI) studies. Thus, CYP3A4 is not only 4 The Why and How of Absorption, Distribution, Metabolism, Excretion, and Toxicity Research the most abundant hepatic CYP, but is also present in the gut wall and is responsible for the metabolism of 50-60% of all drugs. This enzyme is therefore highly susceptible to both reversible and irreversible (mechanism-based) inhibition.34Most CYP3A4 substrates or inhibitors are also P-glycoprotein substrates or inhibitors. It is believed that CYP3A4 and P-gp in the gastrointestinal tract work in concert to limit uptake of xenobiotics including drugs.35 Current inhibition studies are based on Ki and IC50? values,36 but more quantitative approaches would be a benefit.37 Great progress has been made in the reliable simulation of DDIs, even taking into account variability in the population.38 A further question is how metabolites contribute to DDIs; a better understanding of allosteric kinetics of CYPs is also needed.39 Although clinically somewhat less important than enzyme inhibition, enzyme induction is also an unescapable issue and adequate protocols are being developed for its characterization. It remains to be agreed when to carry out such assays or screens during the discovery process.31 Toxicology and safety prediction Drug safety is a great concern to patients, medical professionals and regulatory bodies. As a result, early toxicity predictions and safety estimates are receiving ever increasing attention in all drug discovery programs.40 Simple in vitro screening assays for, e.g. hERG and other cardiac ion channels, genetic toxicology, and cytotoxicity now are routinely added to the growing battery of biology, ADME and tox/safety screens. Despite encouraging progress,41 in silico predictive toxicology is still in its infancy,42 but gets funding from e.g. EU Framework projects to underline its importance. A promising tool is the integration of ADME, tox and pharmacology data to predict side-effects, as in the BioPrint approach.43 Technological Issues In vitro screening Based on the experience gained with pharmacodynamic high-throughput screening, many in vitro ADME screens can now run in medium or high-throughput modes using automation, robotics and miniaturisation.44–46 Physicochemical properties are now recognized to play a key role in modulating DMPK properties,4,47–49 and their assessment and understanding are therefore receiving greater attention.50 Due to the nature of many high-throughput physicochemistry and ADME assays, the typical analytical endpoint is often LC-MS. Cell-based assays such as the Caco-2 screen for permeability/absorption are quite expensive due to considerable reagent costs, particularly when run in screening mode with many compounds. The trend is to investigate in either cheaper in vitro alternatives such as PAMPA (parallel artificial membrane permeability assay) method or to move to in silico approaches. A proper synergistic hybrid combination of in vitro and in silico methods,51 which has been called the in combo approach,52 may be the most cost-effective approach to ADME screening in drug discovery. In silico ADME Prediction and simulation of various ADME properties is considerable cheaper than in vitro screening. Therefore great efforts have been made to turn all available data into predictive computational models using quantitative structure-activity relationship (QSAR) methods and molecular modeling.52–58 In vitro data are now generated for many ADME and physicochemical endpoints and can be used to build more robust models. Model updating will need to be automated and fitted in the data generation cycle.59 There is a need for both local (project-specific) as well as global (general, encompassing a wide range of chemotypes) models. Unfortunately, there is still a paucity of human in vivo data, and thus models based upon these will needed to be handled with care. Of course interindividual variability within the population is another key factor to take into account for human predictions. Predictions will be ranges rather than hard numbers. Many drug companies have web-based cheminformatics and ADME predictions deployed via their intranet giving the medicinal chemist easy access to “web screening”.60 For the development of potential drugs, predictions may contribute to high-throughput pharmaceutics and rational drug delivery.61 Simulations: PBPK and PK/PD Physiologically-based pharmacokinetic (PBPK) models rely on principles well known in chemical engineering and describe the human or animal body as a series of pipes and tanks.62,63 Convenient softwares are now available and make PBPK modeling more accessible to drug discovery and development to predict various PK parameters and concentration-time profiles in the body. Population variability64 and specific groups such as children and elderly can also be taken into account. The more experimental data are available, the better the simulations, making these approaches of interest in drug discovery and clinical development. Some commercial programs have put considerable effort in simulating the absorption process, which is of interest in optimizing pharmaceutical formulations. Pharmacokinetic/pharmacokinetic (PK/PD) modelling links dose-concentration relationships (PK) to concentration-effect relationships (PD). This approach helps to simulate the time course of drug effects depending on the dose regimen.65 Specialized softwares and a better understanding of the applications may help to speed up clinical development. As a whole the pharmaceutical industry is still far behind in using prediction, modeling and simulation as compared to engineeringbased industries such as car and airplane manufacturers. Often resources still remain allocated to producing experimental data rather than developing the information technology (IT) tools to move toward in silico pharma, in other words toward web screening rather than wet screening and to a “will do” rather than a “can do” attitude.66 The Why and How of Absorption, Distribution, Metabolism, Excretion, and Toxicity Research 5 Figure 3 The major steps in drug R&D, showing target validation, discovery and development, followed by the clinical phases and the post marketing phase. Note the overlaps, since many knowledge-expanding investigations are carried out after the next phases have begun, e.g. in vivo research in animals continues during the clinical phases, and clinical studies continue post-marketing for confirmatory and indication-enlarging purposes. Preclinical R&D has two objective, activity and ADMET. These translate as efficacy and tolerance in the early clinical phases, to merge subsequently into the global objective of utility. Conclusion ADME-Tox issues were far from the forefront in the early days of drug discovery and development. Innumerable and fast developments since three decades or more have completely changed the picture, with activity/efficacy assessment running in parallel with ADMET/tolerance assessment, both lines merging in the global paradigm of ‘utility’ (Figure 3). In this view, pharmacodynamics (i.e., activity) is obviously the prime object of study, but it is so markedly influenced by pharmacokinetic events (Figure 1) that drawing a separation line becomes a challenge. This is why both lines of inquiry must run together, a further condition of success being for research directors and supervisors to share full information with high intensity and great constancy. This is particularly true for medicinal chemists, who find themselves in progressing in close collaboration with pharmacologists, biologists, biochemists, bioanalysts, physicochemists, computer scientists and other experts. 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