Subcutaneous Administration ofBiotherapeutics: AnOverview
ofCurrent Challenges andOpportunities
BeateBittner1· WolfgangRichter2· JohannesSchmidt1
© The Author(s) 2018
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 admin-
istration 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 scle-
rosis (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.
* Beate Bittner
1 Product Optimization, Global Product Strategy,
F. Hoﬀmann-La Roche Ltd, Grenzacher Strasse 124,
2 Roche Pharmaceutical Research andEarly Development,
Pharmaceutical Sciences, Roche Innovation Center Basel,
F. Hoﬀmann-La Roche Ltd, Grenzacher Strasse 124,
Complex and invasive intravenous administration of
biotherapeutics, typically conducted in clinic, contributes
to the pressure on healthcare systems. Subcutaneous
administration has been shown to be a safe and eﬃca-
cious dosing alternative that is generally valued by both
patients and healthcare professionals.
The development of ﬁxed-dose subcutaneous formula-
tions that are delivered independent of patient body
weight, technologies that facilitate the injection of dos-
ing volumes > 5ml, and devices that allow self-admin-
istration outside of the hospital setting have all markedly
contributed to shifting care to the home setting.
Many biotherapeutics are being investigated for com-
bination therapy; subcutaneous administration could
further simplify drug delivery with the development of
ﬁxed-dose combinations or ready-to-use devices that
deliver two or more biotherapeutics via one single sub-
B.Bittner et al.
in self-injection; it has been shown that coadministration of
the dispersion enhancer hyaluronidase facilitates spreading
of an injected volume in the subcutaneous interstitial space
and, therefore, enables injection of a larger volume at an
individualized rate at the patient’s preferred injection site
(e.g. thigh, abdomen, or upper arm) . Moreover, infusion
pumps can complement these eﬀorts by helping overcome
the back pressure generated by subcutaneous tissue during
Another important aspect in the development of subcu-
taneous administration is the integration of a ﬁxed dosing
regimen, i.e. patients receive the same dose independent of
body size. This type of dosing regimen has a number of
advantages over body weight- or body surface area-adjusted
dosing; a ﬁxed dose is less complicated as dose calculations
are not necessary, which reduces the potential for dosing
errors. Furthermore, population pharmacokinetic (PopPK)
modeling using data from clinical trials of various biothera-
peutics has conﬁrmed that ﬁxed dosing of mAbs could be
feasible for the majority of molecules assessed, without
impairing the safety and eﬃcacy of the treatment [20–23].
The aim of this review is to provide an overview of the
current status and recent advances in subcutaneous dosing
of biotherapeutics compared with intravenous administration
in key disease areas. We discuss the impact of subcutane-
ous biotherapeutic administration on the healthcare system,
describe the subcutaneous formulations and administration
approaches to overcome issues with high-volume formula-
tions, and describe pharmacokinetic considerations when
Fig. 1 Overview of methodologies that can facilitate subcutaneous
administration of high-dose biotherapeutics. These diﬀerent tech-
niques can be used alone or in combination
When the ﬁrst subcutaneous monoclonal antibodies (mAbs)
in oncology were developed as an alternative to intravenous
infusions , this delivery approach for biotherapeutics was
already established in several disease areas, including dia-
betes, rheumatoid arthritis (RA), multiple sclerosis (MS),
and primary immunodeﬁciency (PI). The access required
for intravenous infusions, the standard administration route
for biologic drugs in oncology, involves invasive procedures
that can be inconvenient and painful and a drain on the time
and resources of patients, healthcare professionals (HCPs),
and the healthcare system in general [2–4].
After subcutaneous formulations of trastuzumab and
rituximab were introduced in Europe in 2013 and 2014,
respectively, it became evident that a change from intrave-
nous infusions to subcutaneous bolus injections in oncol-
ogy not only reduced the drug administration burden on
the healthcare system but was also generally preferred by
patients and HCPs [5–8]. This positive impact led to intensi-
ﬁed research aiming to understand the processes behind the
absorption of biotherapeutics via interstitial tissue and the
impact of changes in the pharmacokinetic proﬁle on eﬃcacy,
safety, immunogenicity, and tolerability [9–12].
Subcutaneous medications for diabetes, RA, MS, or PI
can be administered in the home by patients or caregiv-
ers, but biotherapeutics for cancer treatment are yet to be
approved for administration outside a designated health-
care setting. However, given the beneﬁcial impact of home
administration on costs and resources [13, 14], eﬀorts are
ongoing to assess the feasibility of HCPs administering
trastuzumab subcutaneously in the home environment. This
change is expected to improve patient quality of life (QoL)
and provide support to patients who live far from a hospital
or have diﬃculty traveling. As initial data have been promis-
ing, with the safety proﬁle of home-administration consistent
with that in a hospital setting , it has been proposed that,
with appropriate training, patients may administer doses at
home in the future .
A number of formulation challenges remain to be over-
come before home-administration of subcutaneous biothera-
peutics can become a reality. Even if a biotherapeutic has
been shown to be safe and well-tolerated, home-administra-
tion in a life-threatening disease carries the risk of under-
or over-dosing. This is particularly true for high-volume
dosing solutions, which can be challenging for patients
and caregivers. Therefore, scientists have been focusing
on ways to further optimize subcutaneous applications of
high-dose biotherapeutics (Fig.1). Signiﬁcant progress has
been made towards the development of high-concentration
formulations  to reduce the overall volume of a subcu-
taneous medication. Other work has aimed at improvements
Subcutaneous Administration of Biotherapeutics
switching from intravenous to subcutaneous formulations.
We also discuss the potential of subcutaneous administration
in the context of the increasing number of biotherapeutics
being considered for combination therapy .
2 Recent Advances inSubcutaneous
This section provides an overview of the major subcutane-
ous biotherapeutic originator formulations deployed in RA,
PI, and MS, and the mAbs in oncology approved by the
European Medicines Agency (EMA) and/or the US FDA.
Indications have been selected to cover diﬀerent administra-
tion settings, dosing volumes, and injection devices.
RA is a chronic inﬂammatory autoimmune disease inﬂu-
enced by both genetic and environmental factors that causes
inﬂammation and deformity of the joints . Other auto-
immune diseases, such as juvenile RA, psoriatic arthritis,
ankylosing spondylitis, plaque psoriasis, Crohn’s disease,
or ulcerative colitis, are treated by a range of similar and
overlapping drug classes. Most common treatments include
nonsteroidal anti-inﬂammatory drugs, oral immunosuppres-
sants, disease-modifying antirheumatic drugs, and biologics
. Most biotherapeutics approved for autoimmune dis-
eases are available in a subcutaneous formulation that can
be self-administered at home with a preﬁlled syringe, a pen
injector, or an autoinjector. Currently, the majority of bio-
logic treatments in RA are tumor necrosis factor (TNF)-α
inhibitors. Among these, etanercept (Enbrel), adalimumab
(Humira), and certolizumab pegol (Cimzia) are available
only as subcutaneous formulations. Golimumab (Simponi)
oﬀers both intravenous and subcutaneous dosing alterna-
tives, and inﬂiximab (Remicade) is the sole anti-TNFα with
only an intravenous formulation on the market. Approved
non-anti-TNFα biologics include the B-cell-depleting ther-
apy rituximab (Rituxan/MabThera), with an intravenous
formulation, and the selective co-stimulating modulator
abatacept (Orencia), with both subcutaneous and intravenous
formulations. The interleukin (IL)-6 receptor antagonist
(anti-IL-6R) tocilizumab (Actemra) is available for intrave-
nous and subcutaneous administration, and the anti-IL-6R
sarilumab (Kevzara) and the IL-1 receptor antagonist (anti-
IL-1) anakinra (Kineret) can only be administered subcuta-
PI is a collection of disorders in which part of the immune
system is either missing or does not function normally; treat-
ment includes immunoglobulin-replacement therapy deliv-
ered either intravenously or subcutaneously . Unlike
in RA, subcutaneous dosing volumes in PI treatment are
typically > 10ml. The ﬁrst subcutaneous immunoglobulin
(Vivaglobin) was licensed for self-administration in the
USA in 2006 . Since then, many more products have
been approved by the EMA or the FDA for subcutaneous
self-administration, typically using an infusion pump or
syringe driver pump. Hizentra, Vivaglobin, and HyQvia
are only available for subcutaneous delivery, but other PI
products can be purchased for intravenous or intramuscular
Table 1 Biologic treatments for subcutaneous administration in rheumatoid arthritis [64, 65]
TNF tumor necrosis factor, IL interleukin, qXw once every X weeks, qXd once every X days, qXm once every X months
a Only a subcutaneous formulation marketed
b Both subcutaneous and intravenous formulations marketed
Molecule Brand name (originator) Dosing frequency Injection volume Device
Etanercept Enbrel (Amgen)aq1w or twice weekly 0.5–1ml Preﬁlled syringe, vial, preﬁlled pen/
autoinjector, preﬁlled cartridge for
Adalimumab Humira (AbbVie)aq2w 0.4–0.8ml Preﬁlled syringe, vial, preﬁlled pen
Certolizumab pegol Cimzia (UCB - Euronext and BEL20)aq2w and q4w 1 ml Preﬁlled syringe, vial, preﬁlled pen
Golimumab Simponi (Janssen)bq1m 0.5–1ml Preﬁlled syringe, preﬁlled pen/auto-
Tocilizumab Actemra (Roche)bq1w and q2w 0.9 ml Preﬁlled syringe, preﬁlled pen
Sarilumab Kevzara (Sanoﬁ-Aventis)aq2w 1.14 ml Preﬁlled syringe, preﬁlled pen
Anakinra Kineret (Swedish Orphan Biovitrum
q1d or q2d 0.67ml Preﬁlled syringe
Selective co-stimulating modulator
Abatacept Orencia (Bristol-Myers Squibb)bq1w 1ml Preﬁlled syringe, preﬁlled pen/auto-
B.Bittner et al.
use. The dosing frequency of the subcutaneous immuno-
globulin formulations typically ranges between once weekly
and once monthly and varies depending on the treatment
cycle. The dose may need to be individualized according to
pharmacokinetic and clinical response. Maximum volumes
per injection site are either not speciﬁed in the label or are
between 15 (Subcuvia) and 50 ml (Hizentra). Hyqvia is the
only immunoglobulin administered following subcutaneous
pre-injection of the dispersion enhancer recombinant human
hyaluronidase (rHuPH20, Sect.4), and the maximum vol-
ume is 600ml per site for patients weighing ≥ 40kg and up
to 300ml per site for patients weighing < 40kg [64, 65]. In
other disease conditions, approved treatments with immu-
noglobulins are typically for intravenous application and not
approved for self-administration. These indications include
chronic lymphocytic leukemia, chronic demyelinating poly-
radiculoneuropathy, idiopathic thrombocytopenic purpura,
or multifocal motor neuropathy formulations .
MS is a demyelinating disease that damages the nerve
cells, resulting in a wide range of symptoms . Currently,
ﬁve beta interferon disease-modifying biotherapeutics are on
the market for relapsing-remitting MS. The ﬁrst approved
beta interferon (Avonex) was made available as an intramus-
cular formulation for weekly administration. However, the
newer formulations are approved for subcutaneous admin-
istration in the home setting, with dosing frequencies rang-
ing from once every other day (Betaseron) to once every
2weeks (Plegridy). The immunomodulator glatiramer ace-
tate (Copaxone) is also available as a subcutaneous formula-
tion, with administration once daily or three times weekly.
Given the low injection volume of 0.5–1ml, all these treat-
ments can be self-administered using a preﬁlled syringe, an
injection pen, or an autoinjector (Table2).
The mode of action for most mAbs in the treatment of
cancer is either to attach and/or block antigens on cancer
cells or to interfere with antigen action on other non-
cancerous cells or free-floating proteins. Other mAbs can
boost the immune response by targeting so-called immune
system checkpoints . While most mAbs on the mar-
ket for cancer treatment are administered intravenously,
subcutaneous dosing alternatives have recently been
developed, for example, trastuzumab (Herceptin) for the
treatment of human epidermal growth factor receptor 2
(HER2)-positive breast cancer and rituximab (MabThera/
Rituxan Hycela) for non-Hodgkin’s lymphoma (NHL)
[32, 33]. These two subcutaneous fixed-dose formula-
tions have the same dosing frequency as the approved
bodyweight- or body surface area-adjusted intravenous
preparations (Table3). For trastuzumab, a subcutaneous
dose is given every 3weeks, and the rituximab dosing
frequency depends on the type of follicular lymphoma
and treatment setting and, therefore, ranges between every
3weeks and every 3months. Subcutaneous trastuzumab
and rituximab are not approved for home- or self-admin-
istration and are dosed manually by an HCP using a vial
and handheld syringe in a hospital, physician’s office, or
infusion center [32, 33].
Daratumumab (Darzalex) is another mAb being devel-
oped for subcutaneous administration. Daratumumab binds
to cluster of diﬀerentiation (CD)-38 overexpressed on multi-
ple myeloma cells and is already marketed for the treatment
of multiple myeloma with an intravenous formulation and a
weight-adjusted dosing regimen . The novel subcutane-
ous formulation with a ﬁxed-dose regimen has reached phase
III clinical development [35, 36].
3 The Health‑Economic Impact
Of the approved subcutaneous biotherapeutics described,
immunoglobulins for replacement therapy in PI and mAbs
for the treatment of cancer are deployed as high-volume
Table 2 Beta interferons and glatiramer acetate for subcutaneous administration in multiple sclerosis [64, 65]
qXd once every X days, qXw once every Xweeks
a Preﬁlled diluent syringe with vial
Molecule Brand name (originator) Dosing frequency Injection volume Device
Interferon beta-1b Betaseron/Betaferon (Bayer) q2d 0.25–1ml Preﬁlled syringea, vial, autoinjector
Extavia (Novartis) q2d 0.25–1ml Preﬁlled syringea, vial, autoinjector
Peg-interferon beta-1a Plegridy (Biogen) q2w 0.5ml Preﬁlled syringe, preﬁlled pen/auto-
Interferon beta-1a Rebif (EMD Serono/Pﬁzer) Three times per week 0.2–0.5ml Preﬁlled syringe, preﬁlled pen/auto-
injector, electronic injection system
Glatiramer acetate Copaxone (Teva) q1d or three times per week 1ml Preﬁlled syringe, pen/autoinjector
Subcutaneous Administration of Biotherapeutics
injections (usually > 5ml). In this section, we discuss the
impact of high-volume subcutaneous administration on
patients and HCP preferences and on healthcare costs and
resources. Observations from an examination of the avail-
able data for trastuzumab and rituximab, which are both
approved only for administration in a designated healthcare
setting, as well as for immunoglobulins that can be self-
administered in the home setting, are highlighted. Overall,
data support that subcutaneous administration is simpler
than intravenous infusions, can reduce drug delivery-related
healthcare costs and resources, and is largely preferred by
both patients and HCPs.
Changing the trastuzumab administration route from
intravenous to subcutaneous led to several modifica-
tions to the treatment regimen, including a move from a
bodyweight-adjusted treatment (including the removal of
the loading dose) to a ﬁxed-dose regimen. A ﬁxed-dose
treatment regimen refers to a single consistent dose given
to all patients in all treatment cycles. The subcutaneous
dosing alternative presents a number of advantages over
intravenous dosing, including hospital and clinical cost
savings, reduced time and resource use, increased ﬂex-
ibility in appointment scheduling, and reduced capacity
bottlenecks and nursing overtime [5, 37, 38].
Evidence that subcutaneous dosing reduced overall
administration time was initially gained from the pivotal
registration study, HannaH, which investigated subcutane-
ous compared with intravenous trastuzumab administration
. This was a phase III, randomized, open-label study
in patients with HER2-positive breast cancer in the (neo)
adjuvant setting. Patients were randomized to receive a
loading dose of intravenous trastuzumab 8mg/kg followed
every 3weeks by a maintenance dose of 6mg/kg (n = 299)
or a ﬁxed dose of subcutaneous trastuzumab 600mg every
3weeks (n = 297). HannaH demonstrated that the duration
of subcutaneous injections was generally between 1 and
5min (average 3.3min) compared with 30–90min for
intravenous administration .
In the subsequent PrefHer study, patients with HER2-
positive early breast cancer were randomly allocated to
either receive four cycles of subcutaneous trastuzumab fol-
lowed by four cycles of intravenous trastuzumab (n = 245)
or vice versa (n = 243) . The respective doses and dos-
ing regimens were the same as in the HannaH study. A
time and motion assessment demonstrated that, per ses-
sion, subcutaneous administration using a handheld
syringe saved a mean of 55min (range 40–81; p < 0.0001)
of patient chair time (time between entry and exit of infu-
sion chair) versus intravenous dosing. Moreover, the active
HCP time, deﬁned as time actively dedicated by any staﬀ
member to prespeciﬁed tasks, was reduced by a mean
17min (range 5–28; p < 0.0001) .
These reductions in administration time were reﬂected
in reduced costs, as reported by a PrefHer TaM substudy
conducted in the UK from February 2012 to February 2013.
This study was a noninterventional, prospective, multicentre,
descriptive research study that assessed the cost of HCP time
and consumables used in trastuzumab subcutaneous versus
intravenous administration. A total of 24 patient episodes
were recorded (12 subcutaneous, 12 intravenous). The mean
cost of HCP time, including drug preparation and adminis-
tration, reduced from approximately £132.00 for intravenous
to £32.00 for subcutaneous dosing. The cost of consuma-
bles was also lower for subcutaneous administration, aver-
aging approximately £1.20 versus £12.90 for intravenous.
Total cost savings with SC administration (versus IV) were
£111.81 per patient episode (95% conﬁdence interval (CI) of
this diﬀerence 100.44–123.56; p < 0.001) . The authors
concluded that, over a full course of treatment (18 cycles),
subcutaneous administration of trastuzumab represented sav-
ings of approximately £2012.00 per patient compared with
intravenous administration .
An independent observational, non-interventional, pro-
spective, monocentric time, motion and cost assessment study
in Belgium reported similar outcomes. A total of 130 patient
episodes were recorded (65 intravenous, 65 subcutaneous)
Table 3 Monoclonal antibodies for subcutaneous administration in oncology [64, 65]
CD cluster of diﬀerentiation, HER human epidermal growth factor receptor, mAb monoclonal antibody, qXw once every X weeks, qXm once
every X months
a Subcutaneous and intravenous formulation marketed
b Subcutaneous formulation contains recombinant human hyaluronidase (rHuPH20)
c Depending on the type of follicular lymphoma
Molecule Brand name (originator) Dosing frequency Injection volume Device
Trastuzumab Herceptin (Roche)a,b q3w 5 ml Vial and syringe
Rituximab MabThera/Rituxan Hycela
q3w–q3mc11.7–13.4ml Vial and syringe
B.Bittner et al.
from October 2015 until November 2016. The doses and dos-
ing regimens were the same as in the HannaH study, and 18
administrations were considered one treatment cycle (1year).
The study demonstrated that patients receiving intravenous
trastuzumab spent more time in the daycare oncology unit
[mean 172.7min (min 84, max 320, SD 53.6)] than those
receiving subcutaneous treatment [mean 50.2min (min 5,
max 166, SD 33.3)]. Compared with intravenous dosing,
subcutaneous administration resulted in a reduction in mean
active HCP time: 13.9min (95% CI 12.6–15.1) compared
with 67.6min (95% CI 64.6–70.7) for intravenous admin-
istration. In addition, intravenous administration required
additional HCP time for treatment preparation in the hos-
pital pharmacy [9.8min (min 5.2, max 16.4, SD 2.6)]. The
mean cost of HCP time per patient episode was €7.9 (95% CI
7.1–8.6) and €37.4 (95% CI 34.8–39.9) for subcutaneous and
intravenous trastuzumab, respectively. The mean overall cost
was €10.6 (95% CI 9.8–11.3) for subcutaneous administra-
tion and €224.48 (95% CI 221.93–227.03) for intravenous
administration. The authors concluded that, in the base-case
scenario, subcutaneous administration of trastuzumab led to
a total cost saving of €212.93 per administration or €3832.74
per treatment cycle . Signiﬁcant cost savings were also
seen in various other countries [7, 8, 44–47].
In the international PrefHer study, 415/467 patients
preferred subcutaneous over intravenous dosing (88.9%;
95% CI 85.7–91.6; p < 0.0001; two-sided test against null
hypothesis of 65% subcutaneous preference); 45/467 pre-
ferred intravenous (9.6%; 95% CI 7–13); and 7/467 indicated
no preference (1.5%; 95% CI 1–3) . The most common
reasons for the preference were time saved and reduced pain/
discomfort. The perceived qualitative impact of replacing
intravenous with subcutaneous trastuzumab was assessed
in a survey with HCPs from 17 centers participating in the
PrefHer study. Respondents were asked to indicate their
level of agreement with several statements on a scale of 1–7
(where 1 was strongly disagree and 7 was strongly agree).
The strongest agreements were observed for the following
statements: “Due to the ready-to-use, ﬁxed dose of subcu-
taneous trastuzumab formulations, potential dosing errors
would be avoided” (6.2); “Due to the ready-to-use, ﬁxed
dose of subcutaneous trastuzumab formulations, there would
be less drug wastage” (6.1); and “Staﬀ would have increased
availability for other tasks in the pharmacy” (5.9). In total,
235 HCPs participated in the preference questionnaire: 181
(77.0%; 95% CI 71.1–82.2) were more satisﬁed with sub-
cutaneous administration, 7 (3.0%; 95% CI 1.2–6.0) were
more satisﬁed with intravenous; and 47 (20.0%; 95% CI
15.1–25.7) indicated no preference for either route .
The increasing use of the mAb rituximab in thetreat-
ment of hematological malignancies in both induction and
maintenance settings has placed a major burden on infusion
services, resulting in long waiting times for eligible patients
. Development of subcutaneous rituximab has reduced
infusion time from at least 90min with intravenous rituxi-
mab to just 6–8min . This has helped alleviate the bur-
den on overall healthcare resources due to the high number
of patients treated with rituximab. Similar to trastuzumab,
the conversion from intravenous to subcutaneous adminis-
tration included a change from body surface area-adjusted
dosing to a subcutaneous ﬁxed dose. In cycle 1 of both dos-
ing regimens, rituximab is still administered intravenously
in a body surface area-adjusted manner.
The multinational, multicentre, non-interventional TaM
study  was conducted to assess the time actively spent
by HCPs and patients during drug administration (chair
time). For subcutaneous rituximab, data were collected as
part of the MabCute study (actual enrolment 694 patients)
both for induction and subsequent maintenance treatment in
relapsed–refractory indolent NHL (iNHL). Patients received
induction therapy consisting of rituximab every 3–4weeks
for 8 cycles (intravenous 375mg/m2 in cycle 1 then subcu-
taneous 1400mg in cycles 2–8) and 6–8 cycles of stand-
ard chemotherapy. Patients who experienced a complete or
partial response continued into standard maintenance treat-
ment (subcutaneous rituximab 1400mg every 8weeks for
24months). The MabCute data for rituximab intravenous
dosing were collected at the same time in the same cent-
ers in the real-world setting in patients with either relapsed/
refractory iNHL or previously untreated iNHL. The data
revealed a reduction in active HCP time and mean patient
chair time of 32% (35.0min for intravenous versus 23.7min
for subcutaneous;p < 0.0001) and 74% (262.1min for intra-
venous, including 180.9min infusion versus 67.3min for
subcutaneous, including 8.3min for subcutaneous injection
administration), respectively. It was concluded that these
time savings could increase the eﬃciency of the day oncol-
ogy units, and the time freed with the use of subcutaneous
dosing could be deployed on other activities, increasing the
number of available appointments, and/or reducing waiting
lists. Similar conclusions were also drawn from other time
and motion and cost-eﬀectiveness studies [51–54].
Patient preferences were assessed in the PrefMab study.
In this randomized, open-label, crossover, phase IIIb study,
patients with diﬀuse large B-cell lymphoma or follicular
lymphoma received 8 cycles of rituximab according to
two schedules. In arm A, 372 patients received 1 cycle of
intravenous rituximab 375mg/m2 and 3 cycles of subcu-
taneous rituximab 1400mg, then 4 cycles of intravenous
rituximab 375mg/m2; in arm B, 371 patients received 4
cycles of intravenous rituximab 375mg/m2, then 4cycles
of subcutaneous rituximab 1400mg. Alongside rituximab,
both arms received 6–8 cycles of chemotherapy. A patient
preference questionnaire was completed post-rituximab
administration by 620 and 591 patients at cycle 6 and cycle
8 of therapy, respectively. The majority of patients preferred
Subcutaneous Administration of Biotherapeutics
subcutaneous over intravenous rituximab therapy, regard-
less of whether they received subcutaneous rituximab during
the ﬁrst or second part of the study; 79–81% expressed an
overall preference for subcutaneous administration at cycle
6 and 77–84% at cycle 8. The most common reasons for the
preference were less time required in the clinic and increased
comfort with subcutaneous administration .
For patients with immunodeﬁciency who receive life-
long immunoglobulin-replacement therapy, improved QoL
through home-administration appears to be the most sig-
niﬁcant driver for moving from an intravenous to a subcuta-
neous dosing alternative, as subcutaneous immunoglobulin
(SCIG) facilitates home-administration . A variety of
intravenous immunoglobulin (IVIG) and SCIG treatments
are on the market (Sect.2). Subcutaneous formulations
typically have a higher dosing frequency than intravenous
formulations, mainly due to challenges inherent to the
high-volume doses required. A systematic review of stud-
ies comparing the eﬃcacy and safety of IVIG and SCIG
was conducted based on data from 1028 eligible patients
receiving immunoglobulin replacement (67.7% were adults,
56.3% had a diagnosis of common variable immunodeﬁ-
ciency). The meta-analysis was performed using a random-
eﬀects method for immunoglobulin trough levels (odds
ratio (OR) 1.00, range 0.84–1.15; p < 0.01), infection rates
(OR 0.59, range 0.36–0.97; p = 0.04), and adverse events
(OR 0.09, range 0.07–0.11; p < 0.001), which showed a sig-
niﬁcant preference for SCIG over IVIG. Moreover, SCIG
resulted in better health-related QoL and faster functional
recovery with less time oﬀ work .
A cost-minimization analysis of SCIG (IgPro20, Hizen-
tra) compared with IVIG was conducted from September
2010 to November 2011 as part of a prospective, multicen-
tre, open-label, single-arm study. After a screening period,
24 Japanese patients with PI entered an IVIG treatment
period with threeplanned infusions every 3 or 4weeks, fol-
lowed by a 12-week SCIG wash-in and wash-out period,
and a 12-week SCIG efficacy period. The difference in
medical costs and productivity loss from changes in hos-
pital frequency, as well as the impact on QoL between the
two routes of administration, was evaluated. Subcutaneous
dosing markedly reduced hospital-related absenteeism, with
the number of patients and caregivers not absent from work
or housework duties and with no reduction in working time
increasing from four (17.4%) at week 1 to nine (39.1%) at
week 24. Productivity loss was reduced by 60% from base-
line at weeks 12 and 24, which resulted in a reduction in
costs of ¥10,875 per patient per month at weeks 12 and 24.
The Life Quality Index scores included areas such as treat-
ment interferences with daily activities, treatment-related
problems (such as convenience or painfulness of infusions),
convenience of the setting in which the treatment was
conducted, and costs of therapy and transportation to the
location of therapy. Index scores for all domains were higher
with SCIG than with IVIG .
An evidence-based review of 25 randomized and non-
randomized trials as well as health-economic assessments
comparing SCIG versus IVIG substitution therapy in
patients with immunodeﬁciency showed that improvements
in QoL with SCIG were mainly related to home therapy. It
was found that the main advantage from an economical point
of view lies in fewer days of school or work absence .
4 The Complexities andImprovements
Hyaluronan (hyaluronic acid) and collagen ﬁbers are the
main components in the extracellular matrix in subcutane-
ous connective tissue. Hyaluronan provides a barrier against
the spreading of injected ﬂuids . Therefore, the subcu-
taneous administration of larger volumes at a single injec-
tion site could cause diﬃculties for the administering HCP,
patient, and/or caregiver. As splitting dosing volumes that
exceed 20 ml for administration at diﬀerent injection sites
can result in reduced patient convenience and less reproduc-
ible serum levels, the focus of this section is on eﬀorts made
to optimize products to facilitate subcutaneous administra-
tion of high-volume biotherapeutics (Fig.1). These eﬀorts
aim to further reduce dosing complexity in the hospital set-
ting but also potentially provide a platform for home- or
self-administration. Speciﬁcally, the development of high-
concentration formulations, the use of infusion pumps, as
well co-dosing of the dispersion enhancer hyaluronidase
have all been shown to largely facilitate the subcutaneous
administration of biotherapeutics.
The preparation of biologics solutions at a concentration
of > 100mg/ml is generally feasible today, which is a
major step towards reducing the dosing volume. However,
the development of such high-concentration dosing solutions
remains a challenge for many reasons, including the high
viscosities involved, limitations in protein solubility, protein
degradation and aggregation, protein stability in long-term
storage, and the diﬃculty of achieving mAb concentrations
> 500mg/ml .
Attempts have been made to further overcome the obsta-
cles to large-volume subcutaneous injections, and signiﬁcant
experience is available from work in the ﬁeld of immuno-
globulin-replacement therapy. Subcutaneous infusion of a
high-volume solution of immune human serum globulin
was ﬁrst reported in 1952, when a subcutaneous infusion of
20ml was administered to an 8-year-old patient with agam-
These days, infusion pump-facilitated subcutaneous
administration of high-volume immunoglobulins is an
B.Bittner et al.
established dosing alternative to intravenous infusions, oﬀer-
ing the possibility of home- andself-administration, and is
generally preferred by patients and caregivers. However,
as some patients report local pain, itching, erythema, and
induration at the injection site with subcutaneous infusions,
such doses are typically given more frequently in smaller
individual doses than intravenous infusions (weekly or every
2weeks subcutaneously versus monthly intravenously).
While infusion pump-facilitated high-volume subcu-
taneous infusions (3–20ml, typically administered over
5–20min) are a safe, eﬀective, and convenient alternative
to invasive and lengthy intravenous infusions, some patients
still prefer the convenience of the so-called rapid push sub-
cutaneous administration. Here, a syringe and butterﬂy nee-
dle are used to deliver the dosing solution over short inter-
vals (e.g. in < 5min) according to an individual patient’s
comfort level .
Subcutaneous infusion of larger volumes can be further
facilitated using rHuPH20. This enzyme supports dispersion
of a subcutaneously injected volume by temporarily depo-
lymerizing the polysaccharide hyaluronic acid in the intercel-
lular ground substance of connective tissue . rHuPH20
(Hylenex) is FDA approved as an adjuvant to increase the
absorption and dispersion of other injected drugs by hypoder-
moclysis (interstitial infusion), and as an adjunct in subcutane-
ous urography for improving resorption of radiopaque agents
. The safety proﬁle of rHuPH20 supporting the registration
of Hylenex has been studied in rodents and non-human pri-
mates. Intravenous doses from 38 to 12,000units/kg in rhesus
primates and 10,500units/kg in rodents have been generally
well-tolerated. In primates, rHuPH20 has been shown to be
well-tolerated at 45,000units per subcutaneous injection and
4500units per periocular injection. A comprehensive overview
on the nonclinical safety and mode of action of rHuPH20 has
been published .
rHuPH20 is commercially available in HyQvia, an SCIG
approved by both the EMA and the FDA for the treatment of
PI and hypogammaglobulinemia . HyQvia comprises one
vial containing hyaluronidase and a second vial containing
human immunoglobulin. To ensure optimal depolymerization
of hyaluronic acid in the interstitial space, the two compo-
nents are administered sequentially through the same needle,
with rHuPH20 introduced ﬁrst, followed by the immunoglob-
ulin. In a recent study in patients with PI, rHuPH20-facilitated
immunoglobulin (IGHy) administered subcutaneously was
largely preferred over SCIG without pre-injection of hya-
luronidase. Of the 69 patients who completed a satisfaction
survey at the ﬁnish of immunoglobulin treatment, 28 received
IVIG then SCIG before receiving IGHy, and 41 received
IVIG before receiving IGHy; 65.9 and 75.0%, respectively,
preferred the IGHy . Subcutaneous co-formulations with
rHuPH20 were approved for the mAbs trastuzumab and ritux-
imab for use in the treatment of HER2-positive breast cancer
and lymphoma, respectively . Contrasting with HyQvia,
rHuPH20 is co-formulated with the subcutaneous active bio-
therapeutic, omitting the need for pre-injection of the enzyme
(sequential administration) [32, 33].
Today, particularly in the area of oncology treatment, a
large number of intravenous biologics are reaching the mar-
ket. In parallel, the already high pressure on healthcare budgets
and resources is expected to continue to increase. Intravenous
infusion represents a key drug-delivery challenge because of
its invasive nature, the need for administration in a controlled
healthcare setting, and expanding costs. It is therefore expected
that companies will continue to consider developing subcu-
taneous dosing alternatives for intravenous biotherapeutics.
Inspired by the beneﬁts of subcutaneous dosing to patients
and the overall healthcare system, signiﬁcant research is being
conducted with a focus on further facilitating subcutaneous
injections, such as enhancements in infusion-rate-dependent
tolerability, improvements in infusion pump technology, and
novel drug-delivery devices [67–69].
5 Pharmacokinetic Dierences Between
Administration andPotential Impact
This section is primarily based on available clinical data.
Nonclinical data are described only where human data on
a speciﬁc topic are lacking. A review article detailing the
nonclinical evidence for subcutaneous administration of bio-
therapeutics has been published .
5.1 General Dierences intheIntravenous Versus
Subcutaneous Pharmacokinetic Proles
Potential diﬀerences in the safety, immunogenicity, and eﬃ-
cacy of subcutaneous versus intravenous administration are
best visualized by comparing the pharmacokinetic proﬁles
of a therapeutic protein that can be administered via either
route. A biotherapeutic intravenous infusion or injection
directly into the bloodstream usually results in immediate
maximum serum concentrations (Cmax), whereas the phar-
macokinetic proﬁle of subcutaneously injected therapeutic
proteins is typically characterized by a slow absorption
rate from the subcutaneous extracellular matrix with Cmax
levels below those achieved with intravenous dosing. This
absorption pattern of macromolecules into the blood is a
consequence of their limited permeability across the vas-
cular endothelia; therefore, the lymphatics provide an alter-
native absorption pathway into the circulation system [70,
71]. However, absorption via the lymphatics has also been
Subcutaneous Administration of Biotherapeutics
described as a barrier for complete uptake of subcutane-
ously injected molecules. Other factors that can contribute to
incomplete bioavailability of subcutaneously injected mol-
ecules can include the composition, volume, pH, and viscos-
ity of the dosing formulation; interactions with interstitial
glycosaminoglycans and proteins; and enzymatic degrada-
tion [70, 72, 73].
5.2 Pharmacokinetic Considerations
Formulations forwhich Intravenous Treatments
are Already Approved
Traditionally, mAb treatments in oncology were developed
for intravenous infusion based on a bodyweight- or body
surface area-adjusted dosing regimen that aimed to correct
potential interpatient variability and drug distribution and
elimination issues .
Generally, when developing a subcutaneous dosing alter-
native for a molecule that is already on the market or in late-
stage development with an intravenous bodyweight- or body
surface area-adjusted regimen, a change to a ﬁxed dose or
dose bands for predeﬁned weight categories could be con-
sidered. A ﬁxed dose would require less complex handling,
avoid the need for dose calculations, and reduce the poten-
tial for dosing errors. A regimen that needs to consider a
patient’s bodyweight or size can be challenging, especially
when thesubcutaneous formulationis considered to facili-
tate home- or patient self-administration and requires a
ready-to-use injection device.
Today, based on emerging knowledge about the phar-
macokinetics of mAbs, considerable pharmacokinetic/
pharmacodynamic data from clinical studies, and exten-
sive PopPK modeling, there is evidence that ﬁxed dosing
of mAbs could generally be justiﬁed without impairing the
safety and eﬃcacy of the treatment [20, 23]. Wang etal.
 used data from mAb studies published in peer-reviewed
journals to evaluate body size-based dosing and ﬁxed dos-
ing for 12 mAbs in terms of their population and individual
performance in adult patients. They found that the diﬀerent
dosing approaches performed similarly across the mAbs
investigated. Body size-adjusted administration resulted in
lower pharmacokinetic variability for ﬁve mAbs, whereas
the pharmacokinetic variability of the other seven mAbs
was lower with a ﬁxed dosing approach. The average vari-
ability in area under the plasma concentration–time curve
(AUC) and Cmax of all 12 mAbs was similar following the
two dosing approaches (AUC 42.4 versus 44.2%, Cmax 30.1
and 30.3% by ﬁxed dosing and bodyweight/body surface
area-based dosing, respectively). The authors recommended
that ﬁxed dosing should be the preferred approach in adult
ﬁrst-in-human studies because of the advantages in ease of
dose preparation, reduced costs, and reduced chances of dos-
ing errors .
Moreover, as described by Hendrikx etal. , mAbs
typically distribute within the blood plasma and extracellular
ﬂuids only, which increase less than proportionally with an
increase in bodyweight. Depending on the mAb, intracel-
lular degradation after binding to the target can be the pri-
mary route of elimination and is notaﬀected by body size.
Therefore, administering mAbs with a ﬁxed dose represents
a valuable treatment alternative to weight- and body surface
Generally, whether a dosing approach is acceptable
depends on the width of the targeted range of exposure, and
the therapeutic index must be large enough to accommodate
the exposure diﬀerences introduced by ﬂat dosing across the
body weight ranges.
When developing the subcutaneous formulation for
trastuzumab and rituximab, the change from intravenous
to subcutaneous administration included a switch from
weight- and body surface area-adjusted dosing to a ﬁxed
dose [21, 39, 74]. The selection of a subcutaneous ﬁxed
dose was based on a pharmacokinetic bridging approach
assuming that a subcutaneous dose achieving serum
trough concentrations (Ctrough) non-inferior to those with
intravenous dosing would achieve comparable saturation
of target receptors and result in noninferior eﬃcacy [32,
33]. Previous comparisons of diﬀerent dosing regimens
[75, 76] revealed that trastuzumab or rituximab Cmax did
not correlate with clinical eﬃcacy. Therefore, despite the
lower Cmax after subcutaneous administration, the risk of
underexposing patients with the novel subcutaneous dos-
ing regimen was considered low.
The intravenous and subcutaneous dosing regimens for
trastuzumab and rituximab have been described previously
[21, 39, 74]. Subcutaneous trastuzumab is administered with
a ﬁxed subcutaneous dose from cycle 1 onwards, omitting
the need for a loading dose. Subcutaneous rituximab still
requires a ﬁrst body surface area-adjusted intravenous dose.
For both mAbs, the dosing frequency is the same as with
the respective intravenous dosing schedules. The pivotal
phase III studies used a noninferiority design to compare
the pharmacokinetics, eﬃcacy, and safety of the ﬁxed subcu-
taneous versus intravenous regimens. The trastuzumab Han-
naH study was a randomized, open-label study in the (neo)
adjuvant setting in patients with HER2-positive, operable,
locally advanced, or inﬂammatory breast cancer (see Sect.3
for more details on trial design). The coprimary endpoints
were Ctrough at pre-dose cycle 8 before surgery and patho-
logic complete response (pCR) . The rituximab Sabrina
study was a randomized, open-label study in patients with
previously untreated grade 1–3a, CD20-positive follicular
lymphoma. The primary endpoint for stage I was Ctrough at
pre-dose cycle 8, and the primary endpoint for stage II was
B.Bittner et al.
overall response at the end of induction [21, 74]. Patients
were randomly assigned (205:205) to intravenous rituxi-
mab 375 mg/m2or subcutaneous rituximab 1400mg plus
In both the HannaH and the Sabrina studies, subcutane-
ous administration of trastuzumab and rituximab resulted in
noninferior Ctrough and eﬃcacy to intravenous dosing and a
similar safety proﬁle [21, 39, 74]. In HannaH, the geometric
mean ratio of Ctrough subcutaneous to Ctrough intravenous was
1.33 (90% CI 1.24–1.44), and 40.7% (95% CI 34.7–46.9)
of the intravenous group and 45.4% (95% CI 39.2–51.7)
of the subcutaneous group achieved a pCR. The diﬀerence
between groups in pCR was 4.7% (95% CI − 4.0 to 13.4).
In Sabrina, the geometric mean ratio of Ctrough subcutane-
ous to Ctrough intravenous was 1.5 (90% CI 1.3–1.7). Over-
all response at the end of induction was 84.9% (95% CI
79.2–89.5) in the intravenous group and 84.4% (78.7–89.1)
in the subcutaneous group. The ﬁxed-dose regimens for
trastuzumab and rituximab were further supported by expo-
sure–response analyses of response and grade ≥ 3 adverse
events, which did not identify a statistically meaningful
impact of bodyweight or body surface area, respectively,
nor of exposure or route of administration of the respective
mAbs [21, 74].
It is of note that while the pharmacokinetic-non-inferi-
ority clinical bridging approach was successful for rituxi-
mab and trastuzumab, the situation can be diﬀerent for other
mAbs in other indications, especially when Cmax is expected
to contribute to eﬃcacy.
5.3 Impact ofSubcutaneous Administration
While the abovementioned studies demonstrated that Cmax
did not contribute to the eﬃcacy of trastuzumab and rituxi-
mab, the question remains as to whether the lower Cmax with
subcutaneous administration results in fewer hypersensitiv-
ity and infusion-related reactions (IRRs) than intravenous
administration, where higher maximum serum levels are
The underlying mechanism of immune reactions to mAb
infusions remains unclear. These reaction symptoms can be
characterized by ﬂushing, rash, fever, rigors, chills, dyspnea,
mild, and/or severe hypotension with(out) bronchospasms,
cardiac dysfunction, and/or anaphylaxis. For mAbs, such
reactions are typically mild to moderate and occur predom-
inantly during the ﬁrst infusion . In clinical practice,
one way to reduce the extent and rate of hypersensitivity
and IRRs is to continue dosing at a slower intravenous infu-
sion rate [77, 78]. From a pharmacokinetic perspective, this
slowing of the intravenous infusion rate results in a slower
increase of mAb serum levels, similar to what is achieved
with subcutaneous dosing. Importantly, although serum drug
levels will still be lower with subcutaneous administration
than those achieved with slower intravenous infusion, the
principle of lowering mAb serum concentrations in both
dosing strategies is the same. It has, therefore, been pro-
posed that when Cmax-related adverse reactions are observed
during intravenous infusion, a change to subcutaneous dos-
ing may be advantageous for the patient .
Alemtuzumab (Campath-H1) is an example of an mAb
with marked IRRs during the ﬁrst intravenous infusion. The
biotherapeutic is directed against CD52 cells and is approved
for the intravenous treatment of chronic lymphocytic leu-
kemia. Small pilot studies using subcutaneous infusion
reported that immediate ﬂu-like toxicities associated with
intravenous treatment were less severe when using the sub-
cutaneous route of administration . Furthermore, acute
subcutaneous IRRs, such as rigor, rash or urticaria, nausea,
hypotension, or bronchospasm, were rare or absent in con-
trast to the observations previously made for intravenous
Recently, published data on the tolerability of ﬁrst-dose
subcutaneous administration for daratumumab have become
available. Daratumumab is an mAb approved for the intra-
venous treatment of multiple myeloma, and in clinical trials
(monotherapy and combination treatments; n = 820) intra-
venous dosing was associated with IRRs in 46% of patients
with the ﬁrst infusion, 2% with the second infusion, and 3%
with subsequent infusions. With the ﬁrst intravenous infu-
sion, 4–9% of patients had grade 3 events, and with second
or subsequent infusions < 1% of patients had grade 3 events.
Median time to onset of a reaction was 1.4h . An open-
label, multicentre, dose-escalation phase Ib study assessing
the safety, pharmacokinetics, and eﬃcacy of subcutaneous
daratumumab 1200mg (n = 8) and 1800mg (n = 33) found
lower rates of IRRs with daratumumab. IRRs were reported
in 9 of 41 patients (22%) and were mostly grade 1/2 in sever-
ity; these included chills, fever, rigors, vomiting, itching,
edema of the tongue, noncardiac chest pain, and wheezing.
All IRRs developed during or within 6h of the ﬁrst subcu-
taneous infusion. No IRRs were reported with subsequent
Overall, while there is a trend towards a reduction in rate
and severity of IRRs with the subcutaneous route for the
above examples, data are currently still limited, and head-
to-head clinical studies with diﬀerent mAbs are required to
further investigate thetopic.
5.4 Impact ofSubcutaneous Administration
ofBiotherapeutics onAntidrug Antibodies
Following subcutaneous injection, molecules reach the sys-
temic circulation via either the blood capillaries or the lym-
phatic system. Unlike small molecules, biotherapeutics with
Subcutaneous Administration of Biotherapeutics
molecular weights of > 20kDa exhibit limited transport into
the blood capillaries and cross into the circulation system
predominantly via the lymphatics [10, 71]. This increased
exposure to the lymphatic system has led to the suggestion
that subcutaneous administration of biotherapeutics could be
more immunogenic than intravenous dosing, but this hypoth-
esis may not be universally valid .
In this context, not only the formation of antidrug anti-
bodies (ADAs) with the diﬀerent administration routes per
se but also their impact on the exposure, eﬃcacy, and safety
of the biotherapeutic needs to be considered. With the piv-
otal noninferiority trials for trastuzumab and rituximab,
the HannaH and Sabrina studies, respectively, two larger
head-to-head studies comparing the immunogenicity of
intravenous versus subcutaneous administration with the
same dosing regimen have become available [21, 74]. In
the HannaH study, 8.1% of patients (30/296) treated with
intravenous trastuzumab and 15.9% of patients (47/295)
receiving subcutaneous trastuzumab developed antibodies
against trastuzumab . Trastuzumab pharmacokinet-
ics and pCR rates within each treatment arm were similar
regardless of trastuzumab–ADA status or treatment cycle.
Likewise, the incidence of administration-related reactions
was not statistically diﬀerent independent of the ADA status
. In the Sabrina study, which was performed in a CD20-
positive follicular lymphoma treatment setting, the incidence
of treatment-induced/enhanced anti-rituximab ADAs in the
subcutaneous group was low and similar to that observed
in the intravenous group (2% (4/205) versus 1% (2/205),
respectively) . In patients testing positive for rituximab
ADAs, no impact on B-cell depletion, eﬃcacy, pharmacoki-
netics, or safety was found . A lack of impact of ADAs
on eﬃcacy, safety, or pharmacokinetics was also described
for abatacept or tocilizumab in RA [85, 86]. However, these
data cannot be directly compared with the HannaH and Sab-
rina studies, as the intravenous and subcutaneous treatments
were given at diﬀerent dosing frequencies.
A recent review looking into the subcutaneous admin-
istration route and its impact on immunogenicity for thera-
peutic proteins highlighted the importance of further clinical
research in the ﬁeld, with the aim to understand key factors
that are likely to contribute to the immunogenicity in addi-
tion to the route of administration. Namely, the composition
of the drug delivery formulation, the indication and disease
state of the patient population, the mode of action of the
molecule, diﬀerences in the dose and dosing frequency, or
concomitant medications that could modulate the immune
system should all be considered .
In addition, as many of the biologic therapeutics given
subcutaneously today are immunosuppressive drugs, such
as rituximab, tocilizumab, abatacept, or golimumab, a key
question that needs to be answered in future trials is whether
therapeutic proteins intended to stimulate the immune
response can be administered subcutaneously without trig-
gering signiﬁcant ADA formation, and whether these ADAs
would, in turn, impact the pharmacokinetics, eﬃcacy, or
safety compared with intravenous administration.
5.5 Impact ofSubcutaneous Administration
A drawback of subcutaneous administration of biotherapeu-
tics is the incomplete bioavailability of the injected mol-
ecule, which can range widely from 50 to 80% for mAbs
and even more for other biotherapeutics. The underlying
presystemic catabolism at the subcutaneous administration
site or in the lymphatic system is still poorly understood
with respect to both the involved enzymes and their transla-
tion across species. For mAbs, subcutaneous bioavailability
appears to be inversely correlated with clearance after intra-
venous dosing, so that mAbs with a lower intravenous clear-
ance exhibit higher subcutaneous bioavailability . This
correlation may be due to the involvement of hematopoietic
cells (e.g. macrophages or dendritic cells) in both subcutane-
ous ﬁrst-pass clearance and systemic clearance after intra-
venous dosing . Richter and Jacobsen  have only
recently reviewed the current understanding and knowledge
of this area, so we do not discuss it further.
As incomplete bioavailability typically results in the need
for a higher dose for subcutaneous infusions than for intrave-
nous infusions, costs of goods can be higher for subcutane-
ous formulations. In an attempt to increase the subcutaneous
bioavailability of a biotherapeutic, subcutaneous infusions
can be coadministered (or produced as coformulations) with
the dispersion-enhancer hyaluronidase (discussed in detail in
Sect.4), an enzyme that facilitates spreading of an injected
ﬂuid in the subcutaneous tissue . This increased disper-
sion in the interstitial tissue can result in a higher bioavail-
ability of a co-injected molecule. Initial evidence support-
ing this hypothesis was found in a rat study on the absolute
intradermal bioavailability for peg-interferon alfa-2b and the
therapeutic antibody inﬂiximab. Bioavailability was calcu-
lated to increase from 61 to 108% and from 59 to 94%, with
and without co-injecting with hyaluronidase, respectively.
In addition, the time to reach Cmax (Tmax) was lower for both
molecules in the presence of hyaluronidase, indicating a
faster absorption into the circulation system in the presence
of the hyaluronidase (Tmax of inﬂiximab decreased from 48
to 18.7h) . The impact of hyaluronidase on the fraction
absorbed is likely to depend on the molecule coadministered.
In a study with trastuzumab with and without hyaluroni-
dase using the mini-pig model, the fraction absorbed from
compartmental pharmacokinetic analysis was similar across
formulations and estimated to be 85%. Comparable to what
was observed for intradermal peg-interferon alfa-2b and inf-
liximab in the rat, subcutaneous trastuzumab absorption was
B.Bittner et al.
more rapid from the hyaluronidase-containing formulation
than from the control without hyaluronidase (average ﬁrst-
order absorption rate constants were 0.828 and 0.166/day,
Limited clinical data on the impact of hyaluronidase on
bioavailability are available for SCIG in the treatment of PI.
Hyaluronidase-facilitated subcutaneous administration did
improve the bioavailability by approximately 20% as com-
pared with subcutaneous administration in the absence of
the enzyme . The authors reported that, when investigat-
ing the AUC, normalized by dose per kilogram, for IGHy
compared with IGSC alone from a prior study, hyaluroni-
dase improved the bioavailability of the immunoglobulin
by approximately 20%. The ratio of AUC per dose per kilo-
gram for IGHy/IGSC was 120.4% (90% CI 115.5–125.5).
A low subcutaneous bioavailability in PI can increase the
treatment burden for patients who require lifelong replace-
ment therapy, as the resulting higher dose and larger dosing
volume may necessitate administration at multiple injection
sites, more frequent dosing, and dose adjustment to achieve
immunoglobulin serum concentrations comparable to those
with intravenous administration.
In a study of tocilizumab in healthy volunteers, coadmin-
istration of hyaluronidase resulted in a slightly increased
tocilizumab exposure, a trend towards lower pharmacoki-
netic variability, and earlier Tmax compared with admin-
istration without hyaluronidase . The earlier Tmax and
increased absorption rate following subcutaneous coadmin-
istration with hyaluronidase has been shown to increase the
absorption rate of insulin, resulting in superior glycemic
control compared with insulin alone, meaning lower insulin
requirements and reduced hypoglycemic excursions .
As understanding of the impact of the various anatomic
injection sites on subcutaneous absorption remains limited
, the injection sites for the subcutaneous formulations
of trastuzumab and rituximab are restricted to those stud-
ied in clinical trials (thigh for trastuzumab and abdomen for
rituximab) [64, 65]. Xu etal.  investigated the absolute
bioavailability of golimumab, an anti-TNFα human IgG1κ,
among three diﬀerent injection sites. Healthymale volun-
teers (n = 78) were randomly assigned to either a single dose
of golimumab 100mg via a 30-min intravenous infusion
(n = 23) or subcutaneous administration at the upper arm
(n = 18), the abdomen (n = 18), or the thigh (n = 19). The
absorption of golimumab was found to be similar independ-
ent of the injection site. The overall mean bioavailability of
subcutaneous golimumab was 51% (upper arm, mean 52.0%,
coeﬃcient of variation (CV) 23; abdomen, mean 47.0%,
CV 30; thigh, mean 54.1%, CV 34; p = 0.364). Similar ﬁnd-
ings were reported by Ortega etal. . In a randomized,
open-label, parallel-design, phase I study, 60 healthy vol-
unteers were randomly assigned (1:1:1:1 ratio) to receive a
single dose of either mepolizumab 250mg by intravenous
injection, subcutaneous injection (upper arm, abdomen, or
thigh), or intramuscular injection. The mean bioavailability
for each injection site was 64% (90% CI 55–73), 75% (90%
CI 66–86), 71% (90% CI 62–82), and 81% (90% CI 71–94)
for subcutaneous abdomen, arm, thigh, or intramuscular,
respectively. While the above studies show comparable bio-
availability independent of the anatomic site of injection,
results may diﬀer depending on the individual biotherapeu-
tic. Therefore, additional clinical evidence is required to
allow a more general conclusion on whether diﬀerent injec-
tion sites can be used for a biotherapeutic without impairing
the established eﬃcacy or safety proﬁle.
6 Conclusion andFuture Perspectives
In diseases such as diabetes, RA, or MS, subcutaneous
administration of biologics, including home- or self-admin-
istration, is already the standard of care. Treatments have
been shown to be safe and well-tolerated, the injection vol-
ume does typically not exceed 1 ml, and dosing is facilitated
with preﬁlled syringes, auto-injectors, or injection pens.
Even in immunoglobulin-replacement therapy requiring
large subcutaneous infusions, patient self-administration or
caregiver-supported subcutaneous dosing in the home set-
ting represents an established treatment modality, facilitated
using infusion pumps, the rapid-push methodology, or the
dispersion enhancer hyaluronidase (Fig.1).
Similarly, in oncology, with the introduction of subcuta-
neous versions of trastuzumab and rituximab and a number
of other molecules currently in development, subcutaneous
administration is becoming an attractive alternative to inva-
sive and time-consuming intravenous infusions. The key
question remains, to what extent will subcutaneous dosing
further complement or replace intravenous dosing in this
area? The clear health-economic beneﬁt of a change from
intravenous to subcutaneous dosing due to a reduction in
drug administration-related healthcare resources and costs
will likely foster future research on subcutaneous adminis-
tration in oncology. While subcutaneous dosing would be
expected to reduce Cmax-related side eﬀects of a biothera-
peutic compared with intravenous dosing, it still remains to
be elucidated whether this administration route is feasible
for all molecules. A molecule’s overall safety and tolerabil-
ity proﬁle and especially the impact of absorption via the
lymphatic system with subcutaneous administration on the
formation of ADAs, and their impact on eﬃcacy and safety,
needs to be the subject of research for each individual mAb.
When looking at the pharmacoeconomic benefit of
switching intravenous hospital-based to subcutaneous home-
based administration for immunoglobulins while at the same
time maintaining the clinical outcomes, a similar change
could also be considered in oncology. Patients receiving a
Subcutaneous Administration of Biotherapeutics
subcutaneous biologic as monotherapy in the maintenance/
adjuvant setting or in combination with oral chemotherapy
are particularly expected to beneﬁt from a subcutaneous dos-
ing alternative, as the change to this administration route
reduces the time required for frequent hospital visits. To
enable convenient self-administration, the products should
preferentially be delivered as ﬁxed doses, ideally in a ready-
to-use injection device.
An additional area in which subcutaneous administra-
tion could be beneﬁcial is in combination therapy, as more
biologic treatments are developed for co-dosing, requiring
relatively time-consuming sequential parenteral administra-
tion. In oncology, where patients receive multiple treatments
intravenously, the availability of a subcutaneous alternative
for one of the intravenous regimens could itself reduce treat-
ment complexity and costs. Complex dosing regimens could
be further simpliﬁed using subcutaneous ﬁxed-dose combi-
nations that contain two or more active molecules co-for-
mulated within the same formulation. An alternative would
be the development of multiple-chamber devices that either
inject the products sequentially or pre-mix them directly
before subcutaneous injection. This type of device would
allow ﬂexibility in combining diﬀerent biologics without
extensive formulation development and provide the option to
use available long-term stability data of the individual bio-
logics in the event that the same primary container is used.
Whether a biotherapeutic should be available in only a
subcutaneous formulation or whether having both the sub-
cutaneous and intravenous formulations on the market would
be preferred should be carefully evaluated. While preference
studies reveal that the majority of patients prefer subcutane-
ous over intravenous dosing, some patients do continue to
favor intravenous infusions. In addition, if a biotherapeutic
is dosed in combination with an intravenously administered
molecule, the convenience advantage of the subcutaneous
route is not as strong as with monotherapy or in combina-
tion with anorally or subcutaneouslyadministered molecule.
Moreover, especially for treatments that require immediate
absorption and high Cmax values to be eﬃcacious, intrave-
nous administration will continue to play a major role.
Compliance with Ethical Standards
Funding Support for third party medical writing assistance for this
manuscript was provided by F. Hoﬀmann La Roche Ltd.
Conflict of interest Beate Bittner, Wolfgang Richter, and Johannes
Schmidt are employees of F. Hoﬀmann La Roche and own stock in
Open Access This article is distributed under the terms of the Crea-
tive Commons Attribution-NonCommercial 4.0 International License
(http://creativecommons.org/licenses/by-nc/4.0/), which permits any
noncommercial use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the
source, provide a link to the Creative Commons license, and indicate
if changes were made.
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