Subcutaneous catabolism of peptide therapeutics: bioanalytical approaches and ADME considerations

Many peptide drugs such as insulin and glucagon-like peptide (GLP-1) analogues are successfully administered subcutaneously (SC). Following SC injection, peptides may undergo catabolism in the SC compartment before entering systemic circulation, which could compromise their bioavailability and in turn affect their efficacy.This review will discuss how both technology and strategy have evolved over the past years to further elucidate peptide SC catabolism.Modern bioanalytical technologies (particularly liquid chromatography-high-resolution mass spectrometry) and bioinformatics platforms for data mining has prompted the development of in silico, in vitro and in vivo tools for characterising peptide SC catabolism to rapidly address proteolytic liabilities and, ultimately, guide the design of peptides with improved SC bioavailability.More predictive models able to recapitulate the interplay between SC catabolism and other factors driving SC absorption are highly desirable to improve in vitro/in vivo correlations.We envision the routine incorporation of in vitro and in vivo SC catabolism studies in ADME screening funnels to develop more effective peptide drugs for SC delivery.