Better solubility will allow for faster absorption of drug, less will remain in the GI, and drug overlap will no longer be an issue. Figure 8 The 200mg/kg X3 Tandem dose predicted (2.5hr) versus obtained exposures from 1, 1.5, and 2.5hrs interval. Figure 9 The 200mg/kg X3 Tandem Dose Wagner-Nelson Plot (presented as mean values). The above data strongly support the tandem dose approach to increase exposure while minimizing compound usage. The present work supports the transit time theory in rats. We have also demonstrated Inhibitors,research,lifescience,medical that the ideal interval is dose Sepantronium Bromide nmr dependent. In summary, significantly improved exposures were obtained

by using the tandem dose with the appropriate interval. A simple calculation of dose efficiency Inhibitors,research,lifescience,medical was performed based on using 40% less drug (600mg/kg versus 1000mg/kg) and doubling the exposure. This tandem dose has improved the dose efficiency by approximately 300% for Compound 1. This conservative calculation was done by assuming a linear increase of both Cmax and AUC from 1000 to 2000mg/Kg doses for both compounds. This assumption is an overestimation since exposure increases of Compound

1 (s.i.d) were proven nonlinear beyond 300mg/Kg (and the actual nonlinear dose could be lower than Inhibitors,research,lifescience,medical 300mg/Kg). Thus, the true efficiency could be much higher. This novel tandem dose oral delivery approach using an optimized dosing interval achieves significantly higher in vivo exposure using less drug and requires no additional resources. It

is simple, cost effective, and well tolerated by animals and should be further utilized in industry. Regular b.i.d. or t.i.d. doses take up to Inhibitors,research,lifescience,medical 12 or 16 hours to administer. Depending on the dose, a simple X3 tandem dose can be administered within 2–5hrs (1 to 2.5hr interval). This easily fits into the traditional work day, and no additional staff or overtime is necessary. In theory, the tandem dose is not limited to three doses per day; a fourth dose can be given to further boost the exposure if needed without Inhibitors,research,lifescience,medical altering first the normal eight-hour work day [12]. Our current investigation of dosing interval further refines the tandem dosing strategy. This improved strategy can positively impact the preclinical oral delivery of low solubility compounds. 4. Conclusion In our research, we utilized this novel tandem dose strategy in rat and assessed the impact of dosing intervals on exposure. We successfully demonstrated that by using the tandem dose strategy with the appropriate dosing interval, significantly higher in vivo exposure can be reached without extraresources and investments. This method is well tolerated by the animal and achieves increased exposure with less drugs dosed. This novel approach allows the preclinical researcher to quickly evaluate the in vivo efficacy and safety of a new target.