In terms of pharmacokinetics, IV appear to be superior to SC injections
due to faster absorption, higher bioavailability, short time to reach
maximum serum concentration (Tmax) and similar
elimination half-life (Table 1) (Matucci, Vultaggio, & Danesi, 2018).
Subcutaneous route results in slow absorption, with a slow increase in
plasma concentration and delayed time of Tmax, ranging
from 1.7 to 13.5 days (Ortega, Yancey, & Cozens, 2014; Ryman &
Meibohm, 2017; Zhao et al., 2013). The longer Tmaxassociated with slow lymphatic uptake is due to the limited flow rate of
1-2 mg kg-1h-1 in the thoracic duct
(Zhao, Ren, & Wang, 2012). While the SC route offers more convenience
to patients compared to IV administration, it was reported that SC
administration resulted in higher risk of immunogenicity (Hamuro et al.,
2017). This observation was investigated by comparing the immunogenicity
profiles of marketed mAbs by monitoring the formation and persistence of
anti-drug antibody (ADA) events with either SD- or IV-formulations
(Hamuro et al., 2017). ADA events can potentially impact the
pharmacokinetics of the product by increasing or decreasing drug
clearance or affecting its pharmacodynamics and efficacy. Tocilizumab
(Actemra®), a humanized mAb against interleukin 6 receptor (IL-6R) for
the treatment of rheumatoid arthritis (RA) was studied by IV and SC RoA
in a phase 3 study in a Japanese cohort. After 24 weeks of treatment,
ADAs were detected in 3.5% and 0% of patients for SC or IV
administration, respectively. Trastuzumab (Herceptin®), a humanized IgG1
mAb against HER2 was first approved for IV injections and became the
standard treatment for patients with HER2-positive breast cancer. A SC
formulation was offered as a fixed-dose alternative to the
weight-adjusted IV-formulated product, and a 2-fold increase in ADA
incidence was observed for SC (14.6%) compared to IV (7.6%) route.
Rituximab (MabThera®), an anti-CD20 chimeric IgG1 approved for
non-Hodgkin’s lymphoma, has a similar SC formulation to trastuzumab, but
no difference in ADA incidence was reported between SC and IV routes
(Hamuro et al., 2017). Further examples comparing IV and SC routes for
therapeutic mAbs are described in literature (Blair & Duggan, 2018;
Matucci et al., 2018). Additional examples of dosing and administration
methods of FDA-approved mAbs are listed in Table 2. Despite the majority
of therapeutic mAbs being administered through IV or SC routes, early
drug development programs are still exploring novel delivery systems for
biopharmaceuticals. Examples of these delivery systems are ones that can
pass the intestinal tract without being digested, or administration
through pulmonary or nasal routes (Anselmo, Gokarn, & Mitragotri, 2019;
Bequignon et al., 2019; Kumar et al., 2018; Mitragotri et al., 2014).
Table 2 : Characteristics (route of administration, mode of
delivery and dose strength) of several therapeutic mAbs approved by the
FDA. Abbreviations: RoA : route of administration,IV : intravenous, SC : subcutaneous, IVP :
intravenous pyelogram, PFS : pre-filled syringe, AI :
autoinjector. Information gathered from MedScape (2020).