The Impact of Dosing Interval in a Novel Tandem Oral Dosing Strategy: Enhancing the Exposure of Low Solubility Drug Candidates in a Preclinical Setting

摘要

In drug discovery, time and resource constraints necessitate increasingly early decision making to accelerate or stop preclinical programs. Early discovery drug candidates may be potent inhibitors of new targets, but all too often exhibit poor pharmaceutical or pharmacokinetic properties that limit thein vivoexposure. Low solubility of a drug candidate often leads to poor oral bioavailability and poor dose linearity. This issue is more significant for efficacy and target safety studies where high drug exposures are desired. When solubility issues are confronted, enabling formulations are often required to improve the exposure. However, this approach often requires a substantial and lengthy investment to develop the formulation. Previously, we introduced a gastrointestinal (GI) transit time-based novel oral tandem dosing strategy that enhancedin vivoexposures in rats. In this study, a refined time interval versus dose theory was tested. The resultingin vivoexposures based on altering frequency and doses were compared, and significant impacts were found.