Combinatorial Chemistry & High Throughput Screening, 2005, 8, 89-98 89 The Role of In Vitro ADME Assays in Antimalarial Drug Discovery and Development Todd W. Shearer*, Kirsten S. Smith, Damaris Diaz, Constance Asher and Julio Ramirez Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, Maryland 20910, USA Abstract: The high level of attrition of drugs in clinical development has led pharmaceutical companies to increase the efficiency of their lead identification and development through techniques such as combinatorial chemistry and high-throughput (HTP) screening. Since the major reasons for clinical drug candidate failure other than efficacy are pharmacokinetics and toxicity, attention has been focused on assessing properties such as metabolic stability, drug-drug interactions (DDI), and absorption earlier in the drug discovery process. Animal studies are simply too labor-intensive and expensive to use for evaluating every hit, so it has been necessary to develop and implement higher throughput in vitro ADME screens to manage the large number of compounds of interest. The antimalarial drug development program at the Walter Reed Army Institute of Research, Division of Experimental Therapeutics (WRAIR/ET) has adopted this paradigm in its search for a long-term prophylactic for the prevention of malaria. The overarching goal of this program is to develop new, long half-life, orally bioavailable compounds with potent intrinsic activity against liver- and blood-stage parasites. From the WRAIR HTP antimalarial screen, numerous compounds are regularly identified with potent activity. These hits are now immediately evaluated using a panel of in vitro ADME screens to identify and predict compounds that will meet our specific treatment criteria. In this review, the WRAIR ADME screening program for antimalarial drugs is described as well as how we have implemented it to predict the ADME properties of small molecule for the identification of promising drug candidates. Keywords: ADME, antimalarial drugs, metabolism, mass spectrometry, drug-drug interactions, permeability, modeling. INTRODUCTION related to the desired indication must be considered. For instance: What is the goal of the antimalarial drug program? Will the drug be a treatment, prophylactic, or both? What is the intended route of administration? What is the potency of the compound? What are the potential toxicities associated with the compound? Once the desired indication is defined, selected candidates must then be evaluated for properties that are appropriate to the indication such as half-life, membrane permeability, and mechanisms of elimination. Traditionally, these properties have been evaluated in labor- and resource- intensive animal studies. With the implementation of rapid synthetic processes and high-throughput (HTP) screening systems, however, it is now implausible for even the most highly-funded pharmaceutical companies to conduct animal studies on the number of active compounds being identified. Although animal studies will continue to be required for pre- clinical development for the foreseeable future, several pharmaceutical organizations have implemented a battery of in silico and in vitro test systems to screen out and prioritize compounds based on desirable pharmaceutical properties. To be effective, these screening systems are placed early in pre- clinical development in order to limit the number of compounds requiring expensive evaluations in animal models and to provide a rational approach to lead optimization. The cost of drug discovery and development has reached exorbitant levels and is currently estimated to be greater than 800 million dollars per drug entity reaching the market [Discovery.com, FDA.com]. The majority of this cost is incurred during the clinical phase of drug development. Having a compound fail in the later stages of clinical development or, even worse, after release into the market can be devastatingly expensive even to the largest pharmaceutical organizations. In addition to toxicity, one of the primary reasons for the clinical failure of a compound is a poor pharmacokinetic profile [1, 2]. The pharmacokinetic properties of a compound are the summation of its absorption (A), distribution (D), metabolism (M), and excretion (E) characteristics, collectively described as ADME. Pharmaceutical development of small molecules for the treatment of disease must carefully consider the pharmacokinetic properties of each compound prior to pursuing it as a drug candidate. Antimalarial drug candidates are no exception. Although small molecules that exhibit potent antimalarial properties are regularly discovered in various screening programs, most of these compounds will never reach clinical use, primarily because of poor pharmacokinetic and/or toxicity profiles. Before pharmacokinetic studies are undertaken, several factors Development of antimalarial compounds, particularly for prophylaxis, requires that a number of ADME considerations be met. First and foremost, administration of antimalarial compounds for treatment (with the exception of severe malaria) or prophylaxis must be for the most part through a “user friendly” route. Thus, priority must be given to develop drugs that can be administered through an oral or *Address correspondence to this author at the Alcon Laboratories, 6201, South Freeway, M/S R9-13, Fort Worth, TX 76134, USA; Tel: 301-319- 9668; Fax: 301-319-9449; E-mail: todd.shearer@na.amedd.army.mil 1386-2073/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd.