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The discovery of novel therapies for a disease often begins with identifying the cellular and biochemical target whose malfunction is implicated in the initiation or progression of the disease. Because abnormally high or low activity of proteins (receptors, enzymes, or transporters) or of the genes that code for these proteins is the underlying cause of most diseases, therapeutic intervention requires modulation of the target protein or gene activity by chemical agents. Identifying the chemical agents that can modulate activities of specific proteins or genes with a high degree of selectivity and potency through rational design or high throughput screening with combinatorial libraries has become a less daunting task in the past two decades. This is because most proteins can be readily expressed, isolated, and structurally characterized, their functional activity can be assessed using systems, and vast numbers of compounds can be synthesized using combinatorial approaches as potential modulators of their expression or functional activity. However, it is important to recognize that the therapeutic efficacy of these agents in humans can only by achieved if sufficiently high concentration of these compounds can be attained and maintained at the target site. This requires that the compound has appropriate physicochemical properties so that (i) it can be absorbed effectively from the site of administration (e.g. gastrointestinal tract for orally administered compounds), (ii) it escapes extensive metabolism in the liver and other extrahepatic tissues, (iii) it is distributed sufficiently in the target tissue, and (iv) it is not excreted too rapidly via the renal or the hepatobiliary clearance mechanisms.

During the drug discovery process an average of five to ten thousand compounds are evaluated to identify the small subset of structures with appropriate properties to become a drug. A potential drug is distinguished from a potent agonist /antagonist based on multiple factors affecting safety, exposure and marketability including target selectivity, chemical stability, physical chemical properties, and drug metabolism properties. From the drug metabolism standpoint unfavorable pharmacokinetics is one of the primary barriers to overcome in drug discovery. In the case of most CNS drugs, this is further complicated by the requirement for the compound to traverse the blood-brain barrier in order for it to be efficacious. Thus, for CNS drugs, a compound must balance chemical properties conferring good CNS penetration, favorable metabolic characteristics, and good oral absorption in addition to high potency against the target activity.

Adverse drug reactions continue to pose a major impediment to drug development, and the clinical management of marketed products. These are typically divided into acute, dose dependent reactions (Type A), and reactions that may occur in only a small percentage of patients, where the frequency of occurrence in the population is not dependent on dose (Type B), although more complex classifications have also been proposed, (). According to a recent PhRMA review, the most frequently encountered toxicities in pre clinical drug development are hepatotoxicity and dermal reactions (). Hepatotoxicity may take many forms (), so implying drug metabolism generally would be presumptive, but as the major organ responsible for the metabolism of drugs it seems clear that metabolism is important in many cases. Type A reactions generally may be mediated through parent compound or metabolites, and the role of chemically reactive metabolites has been well recognized (). Type B reactions, also referred to as idiosyncratic or hypersensitivity reactions, have been the subject of extensive reviews in recent years (, ). These are generally believed to be immune mediated, and are not predictable from pre clinical animal studies, thus they may not be identified until late clinical stages, or post marketing. Type B reactions have been reported to constitute 25% of all clinical adverse events (). While direct T cell stimulation has been proposed as a possible mechanism (), bioactivation to reactive metabolites that covalently bind to proteins is still believed to be a key event in the origin of most Type B reactions, and is the basis of the Hapten hypothesis ().

Efficacy and safety are the two key elements in the drug discovery and development processes. The primary goal for pharmaceutical research companies is to identify and manufacture therapeutic agents that are safe and efficacious for patients. In principle, benefits versus risks have to be considered for target patient populations. The risks are relatively high in life threatening diseases, e.g. cancer, compared to general areas, e.g. inflammation. Pharmacology, medicinal chemistry, pharmaceutical sciences, safety assessment, drug metabolism and pharmacokinetics (DMPK), clinical research, etc. are the essential multidisciplinary R&D functions assembled within the pharmaceutical R&D engine to accomplish the aforementioned mission. Pharmacokinetics (PK) is generally viewed as the universal biomarker which reflects the processes of how a drug molecule is absorbed (e.g. ka), distributed (e.g. Vd) in the body, and cleared from the body through metabolism and excretion. The area under the drug plasma concentration versus time curve (AUC) provides an indirect assessment of the exposure level and duration of action of the therapeutic agent at the site of action (e.g. synovial fluid, tumor, brain). An ideal drug candidate should possess a plasma drug level which is above the therapeutic concentration (i.e. efficacious) and below the toxic concentration (i.e. safe). In general, the therapeutic index is calculated by dividing the plasma exposure at the NO (toxic) Effect Level (NOEL), or NO Adverse Effect Level (NOAEL), by the minimum plasma concentration required for efficacy (e.g. EC50) and the safety margin is calculated by dividing NOEL (or NOAEL) plasma concentration by the maximum plasma drug concentration (Cmax) achieved at an efficacious dose.

At this symposium, as in much of the literature over the last 5-10 years, there has been continued discussion regarding ways to reduce drug candidate attrition during the more costly drug development phases. Much of this discussion has revolved around the recognized importance of selecting drug candidates that have “drug-like” properties, i.e. physical, chemical and structural properties that appear to differentiate nondrug and drug molecules (; ; ). As a result, there has been a conscious effort made to move from highly potent ligands toward a molecule that has “drug-like” properties, presumably with a lower risk to attrit during development. In an effort to address these properties sooner, preclinical groups such as pharmaceutics, metabolism and toxicology have been brought into the drug candidate selection process.

Pharmaceutical formulations containing natural and/or synthetic lipids are an accepted strategy for potentially improving the oral bioavailability and systemic exposure of poorly water soluble, highly lipophilic drug candidates. For example, lipid-based formulations are commercially available for various drugs including cyclosporine, saquinavir, ritonavir, dutasteride and amprenavir. Consequently, lipid-based systems are often considered when needing to increase drug exposure during pre-clinical drug development.

Early in the drug development process, studies are often run to help select molecules with appropriate ADME characteristics, generate data in efficacy models, and evaluate toxicity. Poor exposure can lead to highly variable data, and/or ambiguous study results. Use of resource and scarce API for uninterpretable study outcomes is highly inefficient, and based on poor data, a compound may be given an undeservedly low priority. Because exposure is such a critical factor for compound evaluation during lead optimization, the formulation of the compound can be a key component of the drug selection process.

A successful drug must combine both potency and drug-like properties. Traditionally, pharmaceutical companies have focused on activity optimization, based on and biological assays. Nowadays, many of the pharmaceutical property assays are implemented early in drug discovery, so that properties can be optimized in parallel with activity (; ; ; ).

Design of successful drug development candidates requires balancing a number of different characteristics simultaneously including intrinsic activity, biopharmaceutical properties, synthesis, stability, and many others. Independently, each of these can be considered a barrier to drug performance or development success (). Among the most important of these processes determining performance are absorption, distribution, metabolism and excretion, collectively referred to as ADME. The structure and physicochemical characteristics of the drug are important determinants of these processes, as are the characteristics of the physiological mechanisms. Further complicating the issue is the interrelationship of many of these processes, frequently in antagonistic ways. Increasing solute lipophilicity, for example, can decrease aqueous solubility, which frequently compromises oral absorption. Also, it can increase metabolic clearance, thus making difficult sustaining the pharmacologically relevant systemic exposure. In contrast, permeability, in many cases, increases with increasing lipophilicity, favoring absorption (; ). The actual result will be determined by the relative contributions of these two competing phenomena.

My colleagues in this workshop have commented on what is meant by the terms “drug-like” or “drugable” properties. Clearly, most companies prefer to develop drugs that do not require heroic interventions to achieve drug delivery, pharmacokinetic (PK) and pharmacodynamic (PD) goals. Thus a drug should have adequate water solubility to facilitate dissolution if administered orally and superior solubility if a parenteral solution dosage form is required. The drug should have the ability to cross biological membranes either via passive permeation or via a carrier-mediated process. If it is unable to do so, absorption from the gastrointestinal tract (GIT) may be limited and access to intracellular sites a challenge. For passive permeation, having lipophilic properties is ideal, thus this property can conflict with the goal of adequate water solubility. The drug must have adequate chemical stability in its desired dosage forms, once in solution and adequate metabolic stability so that it does not undergo excessive presystemic clearance and has a reasonable residence time. The drug should have properties such as taste, odor, etc. that allow for ease of formulation and it would be ideal if the drug had greater affinity for the activity receptor site than for sites and receptors that could lead to toxic outcomes.