Anatomical, Physiological, and Experimental Factors Affecting the Bioavailability of sc-Administered Large Biotherapeutics

Abstract

Subcutaneous route of administration is highly desirable for protein therapeutics. It improves patient compliance and quality of life1,2, while reducing healthcare cost2. Recent evidence also suggests that sc administration of protein therapeutics can increase tolerability to some treatments such as intravenous immunoglobulin therapy (IVIG) by administering it subcutaneously (subcutaneous immunoglobulin therapy SCIG), which will reduce fluctuation in plasma drug concentration3. Furthermore, sc administration may reduce the risk of systemic infections associated with iv infusion1,2. This route, however, has its challenges especially for large multi-domain 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

A Population Pharmacokinetic-Pharmacodynamic Model of Pegfilgrastim

“…The dose-dependency in T max can be understood both from the zero-order absorption process as well as the saturable elimination. Mechanistic models accounting for distribution of drug to lymph before reaching plasma can be used to describe absorption of subcutaneously administered large molecules but require extensive data in the absorption phase for parameter estimation (30).…”

Pharmacokinetics and Tolerability of a Dual Variable Domain Immunoglobulin ABT‐981 Against IL‐1α and IL‐1β in Healthy Subjects and Patients With Osteoarthritis of the Knee

“…Subcutaneously administered biologics may enter the bloodstream by a combination of processes that includes direct entry to the blood at the postcapillary bed or through the basal membrane of blood vesicles, uptake into the lymphatic system, and, in the case of IgG-type molecules, FcRn-mediated transport across epithelial cells. 23 Increases in protein size can reduce the rate of transport for direct entry to the blood and, to a lesser extent, lymphatic entry. With a molecular weight of 197 kDa, ABT-981 is 31% larger than an IgG molecule, 15 but absorption of Ig-type molecules may be more influenced by FcRn binding kinetics than size.…”

Characterization and Interspecies Scaling of rhTNF-α Pharmacokinetics with Minimal Physiologically Based Pharmacokinetic Models

“…In addition, this model is not able to address the structural and physiologic differences of skin between species, as well as the use of unrealistic large injection volumes in experimental animals, which further hinder reliable scale-up of absorption in man (McDonald et al, 2010). A physiologic model accounting for these unaddressed issues has been proposed in theory (Fathallah and Balu-Iyer, 2015). However, more sophisticated animal studies and experimental data are required to allow application of such complicated models.…”