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Purpose The challenge of developing poorly soluble drugs continues to grow as more and more new chemical entities (NCEs) are poorly soluble. Formulation strategies often rely on maintaining a supersaturated state for poorly soluble drugs. A large portion of modern patients are medicated to reduce stomach acidity, and Drug–Drug Interactions (DDI) with Acid Reducing Agents (ARAs) an dramatically increase pharmacokinetic variability and decrease bioavailability—especially for weak bases. This study valuated pH-shift flux measurements as in vivo predictive tool for DDI assessment.