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Most medicines are administered orally, since this route offers the greatest convenience to patients undergoing chronic treatment, and because stable and readily manufactured oral products are routinely possible. During the drug discovery process, a typical requirement that must be met by a candidate compound intended to be developed into an orally administered drug is the achievement of adequate systemic exposure (plasma or blood concentrations or area under the plasma or blood concentration versus time curve) after oral dosing in animal models. If a compound is poorly absorbed and plasma concentrations are low following an oral dose, the beneficial pharmacologic effects of the new chemical entity may not be realized, even if the compound has potent effects on the pharmacologic target in vitro. It is important to attain sufficient systemic absorption not only to elicit the desired pharmacologic effect, but there are also very important clinical and economic reasons to maximize oral bioavailability. When oral bioavailability is low, plasma concentrations have greater intersubject variability. This was clearly demonstrated in a review of clinical data for 100 drugs for which there was a significant inverse relationship between the extent of oral bioavailability and the intersubject variability (%CV) in bioavailability. 1 When the intersubject variability in bioavailability is increased, there is poorer control of drug effects, both desired and undesired effects. Conversely, consistent and predictable dose versus exposure versus effect properties may provide a therapeutic advantage for one drug over another used for a particular indication. Another practical disadvantage of low oral bioavailability is that much of the drug material that never reaches the systemic circulation is wasted, a certain economic disadvantage for costly drug substances. And if a drug is poorly bioavailable due to extensive presystemic metabolism, the pharmacologic and side effects of the metabolites that are formed must be considered. These are the reasons for striving to achieve maximum oral bioavailability in drug discovery and development.
Analyses of the properties of lead compounds and newly introduced drugs produced by various pharmaceutical companies have shown that both molecular weight (MW) and lipophilicity have gradually increased over the last several decades. 3 and 4 It is therefore increasingly common for compounds with good in vitro activity identified as leads, to also have poor water solubility. It was estimated that at one pharmaceutical company 40% of new compounds had water solubility ≤50 μg/mL, and 30% had solubility ≤5 μg/mL. 5 Poor water solubility can certainly limit oral absorption, especially if little consideration is given to the formulation. It is increasingly important in drug discovery and candidate selection to address the oral delivery of poorly water soluble compounds, including evaluation of the influence of formulation on bioavailability. In this article, the topic of formulating discovery stage compounds, particularly poorly water soluble compounds, is discussed. An overview is given of the options available for selection of dosing vehicles and potentially bioavailability-enabling formulations.