Clinical Significance of Drug–Drug Interaction Studies During Therapeutic Peptide Drug Development: Follow‐Up Investigation of Therapeutic Peptides Approved Between 2021 and 2024

ABSTRACT The risk of clinically relevant drug–drug interactions (DDIs) for therapeutic peptides remains unclear, mandating a comprehensive analysis for this modality. In our prior study, we analyzed DDIs for 31 peptide drugs approved between January 2008 and August 2021. Here, we analyze DDI data for an additional nine peptide drugs (trofinetide, nirmatrelvir, danicopan, odevixibat, rezafungin, motixafortide, zilucoplan, vosoritide, and tirzepatide) approved from September 2021 to September 2024, focusing on in vitro and clinical DDI data for metabolism‐ and transporter‐based interactions. All nine peptides investigated CYP inhibition in human liver microsomes (HLMs), with low risk identified for larger peptides (> 2 kDa). Likewise, all nine peptides assessed CYP induction in human hepatocytes, with one peptide showing a risk in vitro (danicopan). Phenotyping investigations varied from standard studies (e.g., HLMs with selective CYP inhibitors) to submission packages without classical phenotyping studies. All nine peptides included information related to in vitro transporter properties, but the level of detail varied between submitted packages. Clinical studies investigating metabolism‐ or transporter‐mediated DDIs were performed for four peptides (all < 2 kDa). Area under the curve changes attributed to the peptide drug were < 2.3 fold. Our expanded dataset now includes 40 therapeutic peptides approved since 2008, providing a unique resource for drug developers. The findings reinforce our previous conclusions regarding the low likelihood of DDIs for larger peptides and a higher risk for smaller peptides with xenobiotic structural properties. This collective data will be invaluable in developing clear and meaningful DDI guidelines for therapeutic peptides.