Impact of injection sites on clinical pharmacokinetics of subcutaneously administered peptides and proteins.

For most approved subcutaneously (SC) administered drug products in the US, the recommended injection sites (i.e., abdomen, thigh, and upper arm) are usually based on experience from phase 3 trials. Relative bioavailability data directly comparing the pharmacokinetics (PK) of different SC injection sites are often not available and the underlying mechanisms that may affect SC absorption have not been systematically investigated. In this study, we surveyed clinical PK data (AUC, C, and T) for SC administered drug products including therapeutic proteins and peptides based on literature and FDA database. The PK data after abdominal injection was used as a reference to determine the relative bioavailability of SC injections to the arm and thigh. The survey retrieved 19 immunoglobulin G (IgGs), 18 peptides/small proteins (molecular weight < 16 kDa), and 8 non-IgG proteins that had available clinical PK data from multiple SC injection sites. Among these, 5 (26%) IgGs, 9 (50%) peptides/small proteins, and 3 (38%) non-IgG proteins, exhibited injection site-dependent PK (i.e. PK differed by injection sites). Correlation analyses revealed that the PK of peptides/small proteins undergoing rapid SC absorption (T ≤ 2 h), elimination (CL/F ≥ 39 L/h) or low plasma protein binding were more sensitive to injection sites. Similarly, non-IgG proteins (molecular weight ≥ 16 kDa) with high CL/F and low T are associated with high risk of injection site-dependent SC absorption. IgGs with T < 15 days or T < 5 days are more likely to show injection site-dependent SC absorption. Positive charge of the drug molecule (isoelectric point ≥8) may reduce SC absorption from all three injection sites but is not associated with high risk of injection site-dependent SC absorption. In summary, the results suggested that regional differences in pre-systemic catabolism and local SC blood flow potentially contribute injection site-dependent SC absorption of peptides/small proteins while local lymphatic flow and FcRn binding likely contribute to site-dependent SC absorption of IgGs.