Anatomical, physiological, and experimental factors affecting the bioavailability of sc-administered large biotherapeutics.

Subcutaneous route of administration is highly desirable for protein therapeutics. It improves patient compliance and quality of life (McDonald TA, Zepeda ML, Tomlinson MJ, Bee WH, Ivens IA. 2010. Curr Opin Mol Ther 12(4):461-470; Dychter SS, Gold DA, Haller MF. 2012. J Infus Nurs 35(3):154-160), while reducing healthcare cost (Dychter SS, Gold DA, Haller MF. 2012. J Infus Nurs 35(3):154-160). Recent evidence also suggests that sc administration of protein therapeutics can increase tolerability to some treatments such as intravenous immunoglobulin therapy by administering it subcutaneously (subcutaneous immunoglobulin therapy SCIG), which will reduce fluctuation in plasma drug concentration (Kobrynski L. 2012. Biologics 6:277-287). Furthermore, sc administration may reduce the risk of systemic infections associated with i.v. infusion (McDonald TA, Zepeda ML, Tomlinson MJ, Bee WH, Ivens IA. 2010. Curr Opin Mol Ther 12(4):461-470; Dychter SS, Gold DA, Haller MF. 2012. J Infus Nurs 35(3):154-160). This route, however, has its challenges, especially for large multidomain proteins. Poor bioavailability and poor scalability from preclinical models are often cited. This commentary will discuss barriers to sc absorption as well as physiological and experimental factors that could affect pharmacokinetics of subcutaneously administered large protein therapeutics in preclinical models. A mechanistic pharmacokinetic model is proposed as a potential tool to address the issue of scalability of sc pharmacokinetic from preclinical models to humans.