Drug-drug interaction assessments of clinical transporter inhibition: Learnings from the Transporter Working Group of the International Consortium for Innovation and Quality in Pharmaceutical Development.

The International Consortium for Innovation and Quality for Pharmaceutical Development Transporter Working Group analyzed survey results submitted by 17 member companies describing in vitro and in vivo data for drug-drug interactions (DDI) based on drug transporter inhibition. Trends for in vitro-in vivo correlation and impact of physicochemical properties on potential for clinical inhibition were explored for intestinal (P-glycoprotein/breast cancer resistance protein), hepatic (organic anion transporting polypeptide [OATP]1Bs), and renal (organic cation transporter 2/organic anion transporter/multidrug and toxin extrusion proteins) drug transporters. The dataset comprised 58 clinical inhibition studies involving 42 compounds as DDI perpetrators, balanced across Biopharmaceutics Classification System/Biopharmaceutical Drug Disposition Classification System classes and therapeutic areas. Studies were often triggered by in vitro data indicating potential clinical DDI risk or based on anticipated comedications. Overall findings suggest that the magnitude of transporter-mediated drug interactions was relatively low for the majority of the studies (<2-fold increase in exposures). Larger area under the curve, C, or renal clearance changes in the presence of inhibitors were often seen with compounds that inhibited more than 1 pathways. Interactions >2-fold were only reported for statin probe substrates with OATP1B, breast cancer resistance protein, and/or CYP3A4 inhibitors. Consistent with previous reports, low false negative and high false positive rates were observed when applying static cutoff criteria suggested by regulatory agencies for both P-glycoprotein and OATPs. Lastly, the physicochemical analyses demonstrated that clinical inhibitors of P-glycoprotein and breast cancer resistance protein tended to be more lipophilic than noninhibitors (median log D, 2.9 vs 1.7), and OATP1B1/1B3 inhibitors also tended to have higher molecular weights (median, 700 vs 530 Da). This work highlights current strategies for identifying transporter-mediated DDI risks and the need to incorporate additional approaches, such as biomarker profiling and predictive modeling, for nuanced insights. SIGNIFICANCE STATEMENT: A diverse dataset comprising 58 clinical studies evaluating transporter inhibition showed that inhibitors of P-glycoprotein, breast cancer resistance protein, and organic anion transporting polypeptide-1B transporters tend to be more lipophilic and larger than noninhibitors. Greater than 2-fold interactions were generally observed with substrates involving multipathway inhibitors of organic anion transporting polypeptide-1B, breast cancer resistance protein, and/or CYP3A. Low false negative and high false positive rates were observed when applying the static cutoff values in the regulatory guidance, indicating adequacy of static approach with a role for additional approaches such as modeling or biomarkers for nuanced insights.