Assessing and mitigating pH-mediated DDI risks in drug development - formulation approaches and clinical...

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Drug Development and Regulatory Science

Background:

• pH-mediated drug-drug interactions (DDI) are prevalent, particularly for weak base compounds with pH-dependent solubility.
• The US FDA has issued guidance for evaluating pH-mediated DDI, but standardized testing practices are lacking in academia and industry.

Purpose of the Study:

• To review and propose improved strategies for assessing and mitigating pH-mediated drug-drug interactions (DDI).
• To provide a comprehensive overview of biorelevant dissolution testing, preclinical and clinical study requirements, and physiologically-based biopharmaceutics modeling (PBBM) for acid-reducing agent (ARA)-DDI assessment.

Main Methods:

• Biorelevant dissolution testing methods.
• Preclinical and clinical study designs for DDI evaluation.
• Physiologically-based biopharmaceutics modeling (PBBM) approaches.
• Development of an improved decision tree for pH-mediated DDI assessment.

Main Results:

• Biopredictive methods and PBBM approaches demonstrate accurate prediction of ARA-DDI.
• These modeling approaches can decrease drug development burden, inform clinical trial design, and potentially lead to waiving clinical studies.
• Formulation strategies and careful clinical design can mitigate pH-mediated DDI.

Conclusions:

• Accurate prediction of ARA-DDI using biopredictive and PBBM methods offers significant advantages in drug development.
• Mitigation strategies, including formulation and clinical design, can reduce the need for extensive clinical studies and label restrictions.
• An improved decision tree and discussed mitigation strategies aim to streamline the assessment and management of pH-mediated DDI, ultimately benefiting patients.