AIM: The majority of the subcutaneously injected monoclonal antibodies already on the market achieve 50-65% bioavailability, yet the fate of the portion that is lost remains unknown. This consistently incomplete systemic absorption affects the efficacy, safety and overall cost of the drug product. There are many potential factors that might influence the absorption, such as charge, hydrophobicity, formulation variables and the depth and volume of the injection. MATERIALS & METHODS: To explore the possibility that the charge of the injected protein and/or formulation components is partially responsible for drug retention at the subcutaneous site, an ex vivo study, where the monoclonal antibodies were exposed to homogenized rat subcutaneous tissue, was performed. RESULTS & CONCLUSION: It was found that positively charged monoclonal antibodies bind to subcutaneous tissue in a manner that is dependent on ionic strength and pH, suggesting the electrostatic nature of the interaction. As expected, saturation of both nonspecific and electrostatic subcutaneous binding sites was observed after incubation with highly concentrated monoclonal antibody solutions. Additionally, it was demonstrated using model proteins that electrostatic effects of buffer components depend on ionic strength of ions bearing opposite charge rather than total ionic strength of the solution. These results suggest that electrostatic interactions may play a role in absorption processes of positively charged therapeutic proteins after subcutaneous administration.
AIM: The majority of the subcutaneously injected monoclonal antibodies already on the market achieve 50-65% bioavailability, yet the fate of the portion that is lost remains unknown. This consistently incomplete systemic absorption affects the efficacy, safety and overall cost of the drug product. There are many potential factors that might influence the absorption, such as charge, hydrophobicity, formulation variables and the depth and volume of the injection. MATERIALS & METHODS: To explore the possibility that the charge of the injected protein and/or formulation components is partially responsible for drug retention at the subcutaneous site, an ex vivo study, where the monoclonal antibodies were exposed to homogenized rat subcutaneous tissue, was performed. RESULTS & CONCLUSION: It was found that positively charged monoclonal antibodies bind to subcutaneous tissue in a manner that is dependent on ionic strength and pH, suggesting the electrostatic nature of the interaction. As expected, saturation of both nonspecific and electrostatic subcutaneous binding sites was observed after incubation with highly concentrated monoclonal antibody solutions. Additionally, it was demonstrated using model proteins that electrostatic effects of buffer components depend on ionic strength of ions bearing opposite charge rather than total ionic strength of the solution. These results suggest that electrostatic interactions may play a role in absorption processes of positively charged therapeutic proteins after subcutaneous administration.
Authors: Daniela Bumbaca Yadav; Vikas K Sharma; Charles Andrew Boswell; Isidro Hotzel; Devin Tesar; Yonglei Shang; Yong Ying; Saloumeh K Fischer; Jane L Grogan; Eugene Y Chiang; Konnie Urban; Sheila Ulufatu; Leslie A Khawli; Saileta Prabhu; Sean Joseph; Robert F Kelley Journal: J Biol Chem Date: 2015-10-21 Impact factor: 5.157
Authors: Joannes A A Reijers; Martijn J C Dane; Anton Jan van Zonneveld; Jacobus Burggraaf; Matthijs Moerland Journal: Eur J Drug Metab Pharmacokinet Date: 2018-02 Impact factor: 2.441
Authors: D S Collins; L C Kourtis; N R Thyagarajapuram; R Sirkar; S Kapur; M W Harrison; D J Bryan; G B Jones; J M Wright Journal: Pharm Res Date: 2017-07-13 Impact factor: 4.200
Authors: M Borte; G Kriván; B Derfalvi; L Maródi; T Harrer; S Jolles; C Bourgeois; W Engl; H Leibl; B McCoy; D Gelmont; L Yel Journal: Clin Exp Immunol Date: 2016-10-18 Impact factor: 4.330