Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities

Abstract

Subcutaneous delivery of biotherapeutics has become a valuable alternative to intravenous administration across many disease areas. Although the pharmacokinetic profiles of subcutaneous and intravenous formulations differ, subcutaneous administration has proven effective, safe, well-tolerated, generally preferred by patients and healthcare providers and to result in reduced drug delivery-related healthcare costs and resource use. The aim of this article is to discuss the differences between subcutaneous and intravenous dosing from both health-economic and scientific perspectives. The article covers different indications, treatment settings, administration volumes, and injection devices. We focus on biotherapeutics in rheumatoid arthritis (RA), immunoglobulin-replacement therapy in primary immunodeficiency (PI), beta interferons in multiple sclerosis (MS), and monoclonal antibodies (mAbs) in oncology. While most subcutaneous biotherapeutics in RA, PI, and MS are self-administered at home, mAbs for oncology are still only approved for administration in a healthcare setting. Beside concerns around the safety of biotherapeutics in oncology, a key challenge for self-administration in this area is that doses and dosing volumes can be comparatively large; however, this difficulty has recently been overcome to some extent by the development of high-concentration solutions, the use of infusion pumps, and the coadministration of the dispersion enhancer hyaluronidase. Furthermore, given the increasing number of biotherapeutics being considered for combination therapy and the high dosing complexity associated with these, especially when administered intravenously, subcutaneous delivery of fixed-dose combinations might be an alternative that will diminish these burdens on healthcare systems.

Comparison of pharmacokinetics, safety and tolerability of secukinumab administered subcutaneously using different delivery systems in healthy volunteers and in psoriasis patients

“…Label text for the anti‐IL‐17A antibody, ixekizumab, states that “in studies of subjects with plaque psoriasis, ixekizumab bioavailability ranged from 60 to 81% following s.c. injection. Administration of ixekizumab via injection in the thigh achieved a higher bioavailability relative to that achieved using other injection sites including the arm and abdomen.” For secukinumab we seem to have a similar observation, which is also confirmed for other investigated monoclonal antibodies such as bococizumab, golimumab and mepolizumab; s.c. administration in the thigh consistently resulted in higher serum exposure compared to injections in the abdomen region . It is well acknowledged that the incomplete absorption of protein drugs, with absolute bioavailabilities ranging from 20 to 100%, is likely to be due to protein degradation in the region of the s.c. injection site as well as in lymphatic vessels during transport.…”

“…20 For secukinumab we seem to have a similar observation, which is also confirmed for other investigated monoclonal antibodies such as bococizumab, golimumab and mepolizumab; s.c. administration in the thigh consistently resulted in higher serum exposure compared to injections in the abdomen region. [21][22][23][24] It is well acknowledged that the incomplete absorption of protein drugs, with absolute bioavailabilities ranging from 20 to 100%, is likely to be due to protein degradation in the region of the s.c. injection site as well as in lymphatic vessels during transport. It might be speculated that degree of protein degradation, transport time in lymphatic vessels and the protecting role of FcRn during transport differ to some extent between abdominal and thigh injection.…”

In Vivo Delivery of Nucleic Acid-Encoded Monoclonal Antibodies

“…IV delivery frequently requires hours of clinical monitoring and may involve post-infusion monitoring for allergic or anaphylactic reactions, further increasing the medical personnel required and costs of administration. Subcutaneous (SC) delivery has advantages for lower dose antibody delivery, including being less invasive and the possibility for self-administration in several indications, such as rheumatoid arthritis, primary immunodeficiencies, and multiple sclerosis [10,11]. Drug autoinjectors have greatly improved the uptake and convenience of SC delivery, also regulating dosing.…”

Tumescent Injections in Subcutaneous Pig Tissue Disperse Fluids Volumetrically and Maintain Elevated Local Concentrations of Additives for Several Hours, Suggesting a Treatment for Drug Resistant Wounds

“…Similar infusion rates are used when administering biotherapeutics or antibiotics subcutaneously (but not tumescently) as an alternative to the intravenous (IV) route [14]. As the non-tumescent subcutaneous route is used as an alternative for systemic delivery, research on it has focused on the altered pharmacokinetics, pharmacodynamics, and bioavailability [15][16][17][18][19][20][21][22][23][24], not on its potential for localized treatment. Tumescent infusions are done 10-100× faster, with total volumes ranging between 0.1-2 L, depending on the surface area to be covered.…”