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

Authors:

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.
Vol.:(0123456789)
BioDrugs
https://doi.org/10.1007/s40259-018-0295-0
REVIEW ARTICLE
Subcutaneous Administration ofBiotherapeutics: AnOverview
ofCurrent Challenges andOpportunities
BeateBittner1· WolfgangRichter2· JohannesSchmidt1
© The Author(s) 2018
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 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
beate.bittner@roche.com
1 Product Optimization, Global Product Strategy,
F. Hoffmann-La Roche Ltd, Grenzacher Strasse 124,
4070Basel, Switzerland
2 Roche Pharmaceutical Research andEarly Development,
Pharmaceutical Sciences, Roche Innovation Center Basel,
F. Hoffmann-La Roche Ltd, Grenzacher Strasse 124,
4070Basel, Switzerland
Key Points
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 > 5ml, 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-
cutaneous injection.
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) [18]. Moreover, infusion
pumps can complement these efforts by helping overcome
the back pressure generated by subcutaneous tissue during
injection [19].
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 [2023].
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
1 Introduction
When the first subcutaneous monoclonal antibodies (mAbs)
in oncology were developed as an alternative to intravenous
infusions [1], 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 [24].
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 [58]. 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 [912].
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 [15], it has been proposed that,
with appropriate training, patients may administer doses at
home in the future [16].
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 [17] 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 [24].
2 Recent Advances inSubcutaneous
Biotherapeutic Administration
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 [25]. 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
[26]. 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-
neously (Table1).
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 [27]. Unlike
in RA, subcutaneous dosing volumes in PI treatment are
typically > 10ml. The first subcutaneous immunoglobulin
(Vivaglobin) was licensed for self-administration in the
USA in 2006 [28]. 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
Anti-TNFα
Etanercept Enbrel (Amgen)aq1w or twice weekly 0.5–1ml Prefilled syringe, vial, prefilled pen/
autoinjector, prefilled cartridge for
reusable autoinjector
Adalimumab Humira (AbbVie)aq2w 0.4–0.8ml 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 0.5–1ml Prefilled syringe, prefilled pen/auto-
injector
Anti-IL-6
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
Anti-IL-1
Anakinra Kineret (Swedish Orphan Biovitrum
GmbH)a
q1d or q2d 0.67ml Prefilled syringe
Selective co-stimulating modulator
Abatacept Orencia (Bristol-Myers Squibb)bq1w 1ml Prefilled syringe, prefilled pen/auto-
injector
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 600ml per site for patients weighing ≥ 40kg and up
to 300ml per site for patients weighing < 40kg [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 [29].
MS is a demyelinating disease that damages the nerve
cells, resulting in a wide range of symptoms [30]. 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
2weeks (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 0.5–1ml, all these treat-
ments can be self-administered using a prefilled syringe, an
injection pen, or an autoinjector (Table2).
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 [31]. 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 (Table3). For trastuzumab, a subcutaneous
dose is given every 3weeks, and the rituximab dosing
frequency depends on the type of follicular lymphoma
and treatment setting and, therefore, ranges between every
3weeks and every 3months. 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 [34]. The novel subcutane-
ous formulation with a fixed-dose regimen has reached phase
III clinical development [35, 36].
3 The Health‑Economic Impact
ofHigh‑Volume Subcutaneous
Biotherapeutic Administration
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 Xweeks
a Prefilled diluent syringe with vial
Molecule Brand name (originator) Dosing frequency Injection volume Device
Interferon
Interferon beta-1b Betaseron/Betaferon (Bayer) q2d 0.25–1ml Prefilled syringea, vial, autoinjector
Extavia (Novartis) q2d 0.25–1ml Prefilled syringea, vial, autoinjector
Peg-interferon beta-1a Plegridy (Biogen) q2w 0.5ml Prefilled syringe, prefilled pen/auto-
injector
Interferon beta-1a Rebif (EMD Serono/Pfizer) Three times per week 0.2–0.5ml Prefilled syringe, prefilled pen/auto-
injector, electronic injection system
Glatiramer acetate
Glatiramer acetate Copaxone (Teva) q1d or three times per week 1ml Prefilled syringe, pen/autoinjector
Subcutaneous Administration of Biotherapeutics
injections (usually > 5ml). 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
[39]. 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 8mg/kg followed
every 3weeks by a maintenance dose of 6mg/kg (n = 299)
or a fixed dose of subcutaneous trastuzumab 600mg every
3weeks (n = 297). HannaH demonstrated that the duration
of subcutaneous injections was generally between 1 and
5min (average 3.3min) compared with 30–90min for
intravenous administration [40].
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) [5]. 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 55min (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
17min (range 5–28; p < 0.0001) [41].
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) [42]. 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 [42].
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
Anti-HER2 mAb
Trastuzumab Herceptin (Roche)a,b q3w 5 ml Vial and syringe
Anti-CD20 mAb
Rituximab MabThera/Rituxan Hycela
(Roche)a,b
q3w–q3mc11.7–13.4ml 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 (1year).
The study demonstrated that patients receiving intravenous
trastuzumab spent more time in the daycare oncology unit
[mean 172.7min (min 84, max 320, SD 53.6)] than those
receiving subcutaneous treatment [mean 50.2min (min 5,
max 166, SD 33.3)]. Compared with intravenous dosing,
subcutaneous administration resulted in a reduction in mean
active HCP time: 13.9min (95% CI 12.6–15.1) compared
with 67.6min (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 [9.8min (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 [43]. Significant cost savings were also
seen in various other countries [7, 8, 4447].
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) [5]. 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 [48].
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
[49]. Development of subcutaneous rituximab has reduced
infusion time from at least 90min with intravenous rituxi-
mab to just 6–8min [50]. 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 [8] 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 3–4weeks
for 8 cycles (intravenous 375mg/m2 in cycle 1 then subcu-
taneous 1400mg 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 1400mg every 8weeks for
24months). 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% (35.0min for intravenous versus 23.7min
for subcutaneous;p < 0.0001) and 74% (262.1min for intra-
venous, including 180.9min infusion versus 67.3min for
subcutaneous, including 8.3min 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 [5154].
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 375mg/m2 and 3 cycles of subcu-
taneous rituximab 1400mg, then 4 cycles of intravenous
rituximab 375mg/m2; in arm B, 371 patients received 4
cycles of intravenous rituximab 375mg/m2, then 4cycles
of subcutaneous rituximab 1400mg. 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 [55].
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 [56]. 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 [57].
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 threeplanned infusions every 3 or 4weeks, 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 [58].
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 [59].
4 The Complexities andImprovements
forSubcutaneous Administration
ofHigh‑Volume Biologics
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 [18]. 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 > 100mg/ml is generally feasible today[60], 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
> 500mg/ml [17].
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
20ml was administered to an 8-year-old patient with agam-
maglobulinemia [61].
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
2weeks subcutaneously versus monthly intravenously).
While infusion pump-facilitated high-volume subcu-
taneous infusions (3–20ml, typically administered over
5–20min) 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 < 5min) according to an individual patient’s
comfort level [62].
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 [63]. 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
[64]. 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 12,000units/kg in rhesus
primates and 10,500units/kg in rodents have been generally
well-tolerated. In primates, rHuPH20 has been shown to be
well-tolerated at 45,000units per subcutaneous injection and
4500units per periocular injection. A comprehensive overview
on the nonclinical safety and mode of action of rHuPH20 has
been published [18].
rHuPH20 is commercially available in HyQvia, an SCIG
approved by both the EMA and the FDA for the treatment of
PI and hypogammaglobulinemia [65]. 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 [66]. 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 [12]. 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 [6769].
5 Pharmacokinetic Dierences Between
Intravenous andSubcutaneous
Administration andPotential Impact
onSafety andEcacy
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 [10].
5.1 General Dierences intheIntravenous Versus
Subcutaneous Pharmacokinetic Proles
ofBiotherapeutics
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
fortheDevelopment ofSubcutaneous
Formulations forwhich 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 [23].
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 thesubcutaneous formulationis 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 etal.
[20] 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 [20].
Moreover, as described by Hendrikx etal. [23], 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
area-adjusted administration.
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) [39]. 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/m2or subcutaneous rituximab 1400mg plus
chemotherapy.
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 ofSubcutaneous Administration
ofBiotherapeutics onHypersensitivity
andInfusion‑Related Reactions
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
generally achieved.
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 [77]. 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 [79].
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 [80]. 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
infusions [81].
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 1.4h [65]. An open-
label, multicentre, dose-escalation phase Ib study assessing
the safety, pharmacokinetics, and efficacy of subcutaneous
daratumumab 1200mg (n = 8) and 1800mg (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 6h of the first subcu-
taneous infusion. No IRRs were reported with subsequent
infusions [82].
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 ofSubcutaneous Administration
ofBiotherapeutics onAntidrug 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 > 20kDa 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 [83].
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 [65]. 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
[84]. 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) [65]. In patients testing positive for rituximab
ADAs, no impact on B-cell depletion, efficacy, pharmacoki-
netics, or safety was found [74]. 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 [11].
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 ofSubcutaneous Administration
ofBiotherapeutics onBioavailability
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 [87]. 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 [88]. Richter and Jacobsen [10] 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 [18]. 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 18.7h) [63]. 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,
respectively) [32].
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 [89]. 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 [90]. 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 [91].
As understanding of the impact of the various anatomic
injection sites on subcutaneous absorption remains limited
[10], 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 etal. [92] 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 100mg 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 etal. [93]. 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 250mg 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 andFuture 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 anorally or subcutaneouslyadministered 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
Roche.
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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... The active substance can then be absorbed to the systemic blood circulation through either blood capillaries or via the lymphatic system (Aulton and Taylor, 2018). Many drugs traditionally administered intravenously are now replaced by the SC route, like insulin (Fry, 2012), heparin (Verstraete, 1990), immunoglobulins (Rezaei et al., 2011), and more recently oncological biologic drugs such as monoclonal antibodies (Bittner et al., 2018). Compared to the intravenous route, it is less invasive, more convenient and less painful for the patient, and the ease of administration reduces the need for involvement of healthcare systems on a frequent basis (Bittner et al., 2018). ...
... Many drugs traditionally administered intravenously are now replaced by the SC route, like insulin (Fry, 2012), heparin (Verstraete, 1990), immunoglobulins (Rezaei et al., 2011), and more recently oncological biologic drugs such as monoclonal antibodies (Bittner et al., 2018). Compared to the intravenous route, it is less invasive, more convenient and less painful for the patient, and the ease of administration reduces the need for involvement of healthcare systems on a frequent basis (Bittner et al., 2018). Reduced need for healthcare systems on a frequent basis reduce the costs of the care. ...
Article
There is a growing body of research about subcutaneously administered biologics, emphasizing the need for optimized bioavailability predictions. It is important to inform both translational and in silico models with properties of the drug products and compounds. However, the pharmaceutical, therapeutic and physicochemical properties of market authorized drug products for subcutaneous administration are currently not collated in the public domain. We provide an overview of subcutaneous administered drug products for humans and animals market authorized in EU, Canada, and the US. Data on the drug products were collected from the respective authorities, i.e. European Medicines Agency, Health Canada, and U.S. Food and Drug Administration. Physicochemical properties of active substances were gathered from DrugBank. Human drug products were often indicated for treatment of diabetes and anemia. EU veterinary drug products were often immunologicals. Canadian and US veterinary drug products often acted as antiinfectives for systemic use, on the genito-urinary system or as sex hormones. The final dataset with >1700 subcutaneous drug products is provided. In EU drug products, the majority of active substances were biologics. In the US, drug products most often contained small molecules. Solutions, emulsions and suspensions were the most common dosage forms. A minority of subcutaneous drug products were also registered for intramuscular or intravenous administration. The analysis presented here could aid further research, exploring formulation properties, prescription or sales of market authorized SC drug products and development of inclusive in silico models.
... Many RA patients who are treated with bDMARDs achieve long periods of stable low disease activity or remission [2]. However, bDMARDs may also lead to adverse events, call for self-injections, or hospital visits and are expensive [3][4][5]. Thus, tapering bDMARDs to the lowest effective dose is of great clinical interest and may support the sustainability of the healthcare system as a whole. ...
Article
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Background Biological disease-modifying anti-rheumatic drugs (bDMARDs) are effective in the treatment of rheumatoid arthritis (RA) but are expensive and increase the risk of infection. Therefore, in patients with a stable low level of disease activity or remission, tapering bDMARDs should be considered. Although tapering does not seem to affect long-term disease control, (short-lived) flares are frequent during the tapering process. We have previously developed and externally validated a dynamic flare prediction model for use as a decision aid during stepwise tapering of bDMARDs to reduce the risk of a flare during this process. Methods In this investigator-initiated, multicenter, open-label, randomized (1:1) controlled trial, we will assess the effect of incorporating flare risk predictions into a bDMARD tapering strategy. One hundred sixty RA patients treated with a bDMARD with stable low disease activity will be recruited. In the control group, the bDMARD will be tapered according to “disease activity guided dose optimization” (DGDO). In the intervention group, the bDMARD will be tapered according to a strategy that combines DGDO with the dynamic flare prediction model, where the next bDMARD tapering step is not taken in case of a high risk of flare. Patients will be randomized 1:1 to the control or intervention group. The primary outcome is the number of flares per patient (DAS28-CRP increase > 1.2, or DAS28-CRP increase > 0.6 with a current DAS28-CRP ≥ 2.9) during the 18-month follow-up period. Secondary outcomes include the number of patients with a major flare (flare duration ≥ 12 weeks), bDMARD dose reduction, adverse events, disease activity (DAS28-CRP) and patient-reported outcomes such as quality of life and functional disability. Health Care Utilization and Work Productivity will also be assessed. Discussion This will be the first clinical trial to evaluate the benefit of applying a dynamic flare prediction model as a decision aid during bDMARD tapering. Reducing the risk of flaring during tapering may enhance the safety and (cost)effectiveness of bDMARD treatment. Furthermore, this study pioneers the field of implementing predictive algorithms in clinical practice. Trial registration Dutch Trial Register number NL9798, registered 18 October 2021, https://www.trialregister.nl/trial/9798. The study has received ethical review board approval (number NL74537.041.20).
... The subcutaneous administration route is advantageous in many ways. Compared with the intravenous (IV) route, SC administration is less invasive and more convenient for the patient, and the ease of use reduces the need for involvement of healthcare professionals on a frequent basis, thereby reducing the cost of healthcare (Bittner et al., 2018). Additional advantage over oral administration is the avoidance of first pass extraction, leading to less interindividual variability and a larger fraction of the drug available in the systemic circulation (Turner and Balu-Iyer, 2018). ...
Article
Subcutaneous injection is a commonly used route of drug administration for both small molecules and biologics. To facilitate the development of new subcutaneously administered drugs, methods for prediction of drug absorption from the injection site are essential. For this purpose, in silico models have increasingly been used. This report summarize the current state of in silico models for description and prediction of subcutaneous drug absorption. Original articles on physiologically based models describing subcutaneous administration published from 2010 and onward were reviewed. Eighteen physiologically based models were identified: eleven for small molecules and seven for biologics. Most models described the PK of one drug and for one species. In models for small molecules, the subcutaneous administration site was most often described as a depot compartment with first-order absorption into the plasma or blood. Most models for biologics divided administration and organ compartments into vascular and interstitial subcompartments. Mass transfer to these compartments was frequently described with convection and diffusion, according to the one- or two-pore theory. Tremendous improvement in the quantitative aspects of subcutaneous administration and subsequent absorption of physiologically based models has occurred the last decade. However, improvements related to data translation and generalization of these models were identified.
... The 4R dose was injected s.c. in the interscapular region via a slow bolus injection. This route of administration is proposed for clinical use in humans as it simplifies drug delivery and decreases the economic burden [22]. The 4R dose was previously shown to have neuroprotective properties at 6 mg/kg in various models of neurodegenerative diseases [16,17,19]. ...
Article
Full-text available
The tobacco cembranoid (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol (4R) interacts with nicotinic acetylcholine receptors, which results in neuroprotection against organophosphate toxicity, brain ischemia, and Parkinson’s disease. The present study is a continuation of our previous research in which we applied a single dose of 4R 1 h before or 24 h after exposure to diisopropylfluorophosphate (DFP) (analog of the nerve agent sarin). The 4R dose robustly decreased neuroinflammation and neuronal death at both timepoints. Here, we investigated the toxicity of a single dose of 4R in male and female Sprague Dawley (SD) rats after a subcutaneous (s.c.) injection of 6, 24, or 98 mg/kg. Body weight was not affected by 4R during the 7-day observation period. No histopathologic changes in the organs were attributed to 4R. Minor hematological and blood composition variations were detected on Day 3 in the mid- and the high-dose males, but these were resolved by Day 8. At the area of the s.c. injection site, alopecia and dry skin were detected in both the 4R-treated males and females and in the female controls.
... Monoclonal antibodies (mAbs) are a major class of protein biotherapeutics widely used to treat a variety of diseases [1]. Owing to gastric degradation and their inherent high molecular weights, the most preferable administration route for mAb therapeutics is through subcutaneous (SC) injections [2,3]. Due to their relatively low specificity and restrictions on the injection volume for SC administration, mAbs are frequently formulated at high concentrations to achieve desired therapeutic dosages [4][5][6]. ...
Article
Full-text available
In this study, we used sodium chloride (NaCl) to extensively modulate non-specific protein-protein interactions (PPI) of a humanized anti-streptavidin monoclonal antibody class 2 molecule (ASA-IgG2). The changes in PPI with varying NaCl (CNaCl) and monoclonal antibody (mAb) concentration (CmAb) were assessed using the diffusion interaction parameter kD and second virial coefficient B22 measured from solutions with low to moderate CmAb. The effective structure factor S(q)eff measured from concentrated mAb solutions using small-angle X-ray and neutron scattering (SAXS/SANS) was also used to characterize the PPI. Our results found that the nature of net PPI changed not only with CNaCl, but also with increasing CmAb. As a result, parameters measured from dilute and concentrated mAb samples could lead to different predictions on the stability of mAb formulations. We also compared experimentally determined viscosity results with those predicted from interaction parameters, including kD and S(q)eff. The lack of a clear correlation between interaction parameters and measured viscosity values indicates that the relationship between viscosity and PPI is concentration-dependent. Collectively, the behavior of flexible mAb molecules in concentrated solutions may not be correctly predicted using models where proteins are considered to be uniform colloid particles defined by parameters derived from low CmAb.
... Arthritis Research & Therapy (2022) 24:74 Background Many rheumatoid arthritis (RA) patients who are treated with biological disease-modifying anti-rheumatic drugs (bDMARDs) achieve long periods of low disease activity or remission [1]. However, bDMARDs may also lead to adverse events, call for self-injections or hospital visits, and are expensive [2][3][4]. Thus, tapering bDMARDs to the lowest effective dose is of great clinical interest and may support the sustainability of the healthcare system as a whole. ...
Article
Full-text available
Background Biological disease-modifying antirheumatic drugs (bDMARDs) are effective in the treatment of rheumatoid arthritis. However, as bDMARDs may also lead to adverse events and are expensive, tapering them is of great clinical interest. Tapering according to disease activity-guided dose optimization (DGDO) does not seem to affect long term remission rates, but flares are frequent during this process. Our objective was to develop a model for the prediction of flares during bDMARD tapering using data from routine care and to evaluate its potential clinical impact. Methods We used a joint latent class model to repeatedly predict the probability of a flare occurring within the next 3 months. The model was developed using longitudinal data on disease activity (DAS28) and other routine care data from two clinics. Predictive accuracy was assessed in cross-validation and external validation was performed with data from the DRESS (Dose REduction Strategy of Subcutaneous tumor necrosis factor inhibitors) trial. Additionally, we simulated the reduction in number of flares and bDMARD dose when implementing the model as a decision aid during bDMARD tapering in the DRESS trial. Results Data from 279 bDMARD courses were used for model development. The final model included two latent DAS28-trajectories, bDMARD type and dose, disease duration, and seropositivity. The area under the curve of the final model was 0.76 (0.69–0.83) in cross-validation and 0.68 (0.62–0.73) in external validation. In simulation of prediction-aided decisions, the mean number of flares over 18 months decreased from 1.21 (0.99–1.43) to 0.75 (0.54–0.96). The reduction in he bDMARD dose was mostly maintained, increasing from 54 to 64% of full dose. Conclusions We developed a dynamic flare prediction model, exclusively based on data typically available in routine care. Our results show that using this model to aid decisions during bDMARD tapering may significantly reduce the number of flares while maintaining most of the bDMARD dose reduction. Trial registration The clinical impact of the prediction model is currently under investigation in the PATIO randomized controlled trial (Dutch Trial Register number NL9798).
Article
Subcutaneous infliximab recently received approval for the treatment of various immune-mediated inflammatory diseases in Europe, following pivotal clinical trials in patients with rheumatoid arthritis and inflammatory bowel disease. Subcutaneous infliximab demonstrated an improved pharmacokinetic profile compared with intravenous infliximab: the more stable exposure and increased systemic drug concentrations mean it has been cited as a biobetter. Alongside the pharmacokinetic advantages, potential benefits for efficacy, immunogenicity, and health-related quality-of-life outcomes have been suggested with subcutaneous infliximab. During the coronavirus disease 2019 pandemic, the benefits of subcutaneous over intravenous therapies became apparent: switching from intravenous to subcutaneous infliximab reduced the hospital visit-related healthcare resource burden and potential viral transmission. Clinical advantages observed in pivotal trials are also being seen in the real world. Accumulating experience from four European countries (the UK, Spain, France, and Germany) in patients with rheumatic diseases and inflammatory bowel disease supports clinical trial findings that subcutaneous infliximab is well tolerated, increases serum drug concentrations, and offers maintained or improved efficacy outcomes for patients switching from intravenous infliximab. Initial evidence is emerging with subcutaneous infliximab treatment after intravenous infliximab failure. High patient satisfaction and pharmacoeconomic benefits have also been reported with subcutaneous infliximab. Treatments aligned with patient preferences for the flexibility and convenience of at-home subcutaneous administration could boost adherence and treatment outcomes. Altogether, findings suggest that switching from intravenous to subcutaneous infliximab could be advantageous, and healthcare professionals should be prepared to discuss supporting data as part of shared decision making during patient consultations.
Article
Protein and peptide biopharmaceuticals have had a major impact on the treatment of a number of diseases. There is a growing interest in overcoming some of the challenges associated with biopharmaceuticals, such as rapid degradation in physiological fluid, using nanocarrier delivery systems. Biopharmaceutical nanoclusters (BNCs) where the therapeutic protein or peptide is clustered together to form the main constituent of the nanocarrier system have the potential to mimic the benefits of more established nanocarriers (e.g., liposomal and polymeric systems) whilst eliminating the issue of low drug loading and potential side effects from additives. These benefits would include enhanced stability, improved absorption, and increased biopharmaceutical activity. However, the successful development of BNCs is challenged by the physicochemical complexity of the protein and peptide constituents as well as the dynamics of clustering. Here, we present and discuss common methodologies for the synthesis of therapeutic protein and peptide nanoclusters, as well as review the current status of this emerging field.
Article
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In recent years, the development of self-injectable formulations has attracted much attention, and the development of formulations to control pharmacokinetics, as well as drug release and migration in the skin, has become an active research area. In the present study, the development of a lipid-based depot formulation containing leuprorelin acetate (LA) as an easily metabolizable drug in the skin was prepared with a novel non-lamellar liquid-crystal-forming lipid of mono-O-(5,9,13-trimethyl-4-tetradecenyl) glycerol ester (MGE). Small-angle X-ray scattering, cryo-transmission electron microscopy, and nuclear magnetic resonance observations showed that the MGE-containing formulations had a face-centered cubic packed micellar structure. In addition, the bioavailability (BA) of LA after subcutaneous injection was significantly improved with the MGE-containing formulation compared with the administration of LA solution. Notably, higher Cmax and faster Tmax were obtained with the MGE-containing formulation, and the BA increased with increasing MGE content in the formulation, suggesting that LA migration into the systemic circulation and its stability might be enhanced by MGE. These results may support the development of self-administered formulations of peptide drugs as well as nucleic acids, which are easily metabolized in the skin.
Article
Drug administration is an indispensable part of human life and human society. Delivery patch provides a comfortable and convenient manner to treat various diseases with minimal interference to everyday life. The passion and obsession of researchers to advance the delivery patch design has been accompanied by the vigorous development of new materials, sensors, as well as integrated circuits. A piece of slim drug delivery patch is expected to be interactive, accurate, biofriendly to human tissues, and ultimately, to effectively cure. The delicate design and the high demand of functional integration of the delivery patch can rival a precise and versatile chip in some sense. In this review we document the latest development of delivery patch and recount its sub-parts of drug carriers, motivation unit, transport devices, and feedback units. Subsequently, the application scenarios of these drug delivery patches are recorded. Finally, we discussed the challenges and prospects for the further development of drug delivery devices. We hope that this manuscript inspires and promote further development of drug delivery devices, and provide better treatment services for various diseases.
Article
PURPOSE: To evaluate the efficacy and safety of first-line, single-agent trastuzumab in women with HER2-overexpressing metastatic breast cancer. PATIENTS AND METHODS: One hundred fourteen women with HER2-overexpressing metastatic breast cancer were randomized to receive first-line treatment with trastuzumab 4 mg/kg loading dose, followed by 2 mg/kg weekly, or a higher 8 mg/kg loading dose, followed by 4 mg/kg weekly. RESULTS: The objective response rate was 26% (95% confidence interval [CI], 18.2% to 34.4%), with seven complete and 23 partial responses. Response rates in 111 assessable patients with 3+ and 2+ HER2 overexpression by immunohistochemistry (IHC) were 35% (95% CI, 24.4% to 44.7%) and none (95% CI, 0% to 15.5%), respectively. The clinical benefit rates in assessable patients with 3+ and 2+ HER2 overexpression were 48% and 7%, respectively. The response rates in 108 assessable patients with and without HER2 gene amplification by fluorescence in situ hybridization (FISH) analysis were 34% (95% CI, 23.9% to 45.7%) and 7% (95% CI, 0.8% to 22.8%), respectively. Seventeen (57%) of 30 patients with an objective response and 22 (51%) of 43 patients with clinical benefit had not experienced disease progression at follow-up at 12 months or later. The most common treatment-related adverse events were chills (25% of patients), asthenia (23%), fever (22%), pain (18%), and nausea (14%). Cardiac dysfunction occurred in two patients (2%); both had histories of cardiac disease and did not require additional intervention after discontinuation of trastuzumab. There was no clear evidence of a dose-response relationship for response, survival, or adverse events. CONCLUSION: Single-agent trastuzumab is active and well tolerated as first-line treatment of women with metastatic breast cancer with HER2 3+ overexpression by IHC or gene amplification by FISH.
Article
Introduction : Daratumumab (DARA), a human CD38 IgG1κ monoclonal antibody, has demonstrated single agent efficacy while being highly tolerable as a monotherapy, and significant efficacy in combination with standard-of-care regimens in pts with multiple myeloma (MM) who have received ≥1 prior lines of therapy (Lokhorst HM. NEJM 2015, 373(13):1207-19; Lonial S. Lancet 2016, 387:1551-60;Palumbo A. NEJM 2016, in press; Dimopoulos MA. NEJM 2016, in press). DARA is currently administered as an intravenous (IV) infusion. Subcutaneous (SC) delivery of DARA is being tested in combination with the recombinant human hyaluronidase enzyme (rHuPH20) to facilitate systemic absorption of DARA after SC infusion into the abdominal wall. PAVO is the first study to assess the safety, pharmacokinetics, and efficacy of SC administration of DARA plus rHuPH20 (DARA-PH20) in pts with relapsed or refractory MM (RRMM). Methods : Pts had RRMM with ≥2 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD). Part 1 of the 2 part study enrolled sequential cohorts at 1200 mg and 1800 mg DARA dose levels to determine the recommended SC dose for Part 2. DARA-PH20 was administered in 4-week treatment cycles: QW for 8 weeks, Q2W for 16 weeks, and Q4W thereafter. DARA-PH20 was infused in 1200 mg doses in 60 mL over 20 min or 1800 mg in 90 mL over 30 min, via a syringe pump at rotating sites on the abdomen. Pre- and/or post-infusion medications included paracetamol, diphenhydramine, montelukast, and methylprednisolone. In part 2, pts will be randomized 1:1 to receive the recommended phase 2 dose (RP2D) of SC DARA-PH20 or IV DARA (16 mg/kg). The RP2D of DARA-PH20 will be selected based on a cumulative review of the pharmacokinetic and safety data obtained from part 1 and should achieve a maximum serum Ctrough during weekly dosing that is similar to or higher than that observed for the approved 16 mg/kg IV dose. Primary endpoints were Ctrough of DARA up to Cycle 3 Day 1 and safety. Secondary endpoints included overall response rate (ORR). Results : To date, 41 pts were treated in part 1 with SC DARA-PH20 at the 1200 mg (n=8) and 1800 mg (n=33) dose levels. Infusion related reactions (IRRs) were reported in 9/41 pts (22%) and were mostly grade 1/2 in severity including chills, fever, rigors, vomiting, itching, edema of the tongue, non-cardiac chest pain and wheezing. One pt developed grade 3 dyspnea and 1 pt required hospitalization due to fever and chills (both grade 2) after the first infusion. All IRRs developed during or within 6 hours of the first SC infusion and were controlled with antihistamine, corticosteroid, antiemetic, or bronchodilator treatment. No IRRs were reported with subsequent infusions. Overall, the adverse event profile of DARA-PH20 was consistent with that of IV DARA. Grade 3 or higher drug-related adverse events were reported in 5/41 (12%) pts including fatigue (2 pts), influenza, hypertension, dyspnea, and tumor lysis syndrome. SC administration of DARA-PH20 was well tolerated at the abdominal wall injection site with 3/41 (7%) pts reporting grade 1 erythema, induration, or burning sensation. Analysis showed a higher max Ctrough in the 1800 mg cohort in comparison to the max Ctrough achieved following IV DARA (16 mg/kg). In the 1200 mg cohort of 8 pts (median of 5 lines of prior therapy [range 2-10]; prior ASCT, 63%; PI refractory only, 0%; IMiD refractory only, 13%; double refractory to PI and IMiD, 63%) a 25% ORR was observed including 2 partial responses (PR). Median time to response was 14 (range 8-20) weeks. Among 17 response evaluable pts in the 1800 mg cohort with cycle 3 day 1 assessments (median of 4 prior lines of therapy [range 2-7]; prior ASCT, 76%; PI refractory only, 6%; IMiD refractory only, 12%; double refractory to PI and IMiD, 65%) a 41% ORR was observed consisting of 3 very good partial responses and 4 PRs. Median time to response was 4 (range 4-8) weeks. Conclusions : SC DARA-PH20 was well tolerated and achieved serum trough concentrations similar to or greater than IV DARA with a lower rate of IRRs compared to IV DARA over a significantly shorter infusion time. Preliminary data suggest that in this pt population SC DARA-PH20 may enable similar response rates to IV DARA monotherapy. The 1800 mg dose level of DARA-PH20 was selected as the RP2D for part 2 of the study. These early data support further study of SC DARA in clinical trials. Additional data on pts from part 1 will be presented at the meeting. Disclosures Usmani: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding; Britsol-Myers Squibb: Consultancy, Research Funding; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Array: Research Funding; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau. Mateos:Janssen, Celgene, Amgen, Takeda, BMS: Honoraria. Lokhorst:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Research Funding. Chari:Pharmacyclics: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Array Biopharma: Consultancy, Research Funding. Kaufman:Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy. Moreau:Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau. Oriol:Janssen: Honoraria, Other: Expert board committee; Amgen: Honoraria, Other: Expert board committee. Plesner:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hellemans:Janssen: Employment, Equity Ownership. Masterson:Janssen: Employment. Clemens:Janssen: Employment. Ahmadi:Janssen: Employment. Liu:Merck: Equity Ownership; Janssen: Employment; J&J: Equity Ownership. San-Miguel:Amgen: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.
Article
Background Rituximab (MabThera®; Rituxan®) is the standard treatment for indolent non-Hodgkin's lymphoma (iNHL). Results from the phase 3 SABRINA study (NCT01200758) showed that a fixed-dose subcutaneous (SC) formulation of rituximab shortened administration time without compromising efficacy or safety compared with intravenous (IV) infusion of rituximab. A switch to the SC formulation is expected to offer healthcare professionals (HCP) time and cost savings. Aims This study aims to quantify resource utilization in terms of active HCP time (ie, time actively dedicated to a patient) and chair time related to rituximab SC vs rituximab IV in the treatment of patients with iNHL and to estimate potential time and cost savings for the conversion from IV to SC (per administration session and for the first year of treatment). Methods This is a multinational, multicenter, prospective, observational time and motion study. Data for rituximab SC injections were collected alongside the MABCUTE (MO25455; NCT01461928) trial, while data for rituximab IV infusions were collected in a real-world setting in the same data collection period and in 23 centers in Italy (IT), Russia (RU), Slovenia (SL), United Kingdom (UK), Spain (SP), France (FR), Austria (AU), and Brazil (BR). Following interviews with a nurse and pharmacy member in each center, generic case report forms for IV, SC, and drug preparation area (including pharmacy) processes were tailored to reflect local site practices. Trained observers recorded both the time that HCPs were actively completing prespecified tasks (using a stopwatch), and patient chair time (based on length of time between patients entering and exiting chairs). This is a descriptive study with convenience-based sample sizes. A random effects regression model was run for each task (pooled sample by country) to generate task mean and 95% confidence interval (CI) using appropriate distributions. IV vs SC process time per patient was calculated as the sum of the mean task times. Results The difference in mean active HCP time saved by switching from rituximab IV to rituximab SC ranged from 6.8 min in AU to 38.4 min in the UK (Table 1). The proportionate reduction in mean HCP time ranged from 27% in SP to 57% in RU. The mean time saved (% reduction) in the treatment room ranged from 0.3 min (2%) in SP to 25.4 min (63%) in the UK. Over the course of the first-year of treatment (6 induction and 3 maintenance sessions), the estimated reduction in total HCP time associated with the switch ranged from 0.9 hr in AU to 5.1 hr in the UK. The differences in mean chair time saved with SC over IV administration ranged from 126.1 min in SL (64%) to 280.1 min (86%) in IT. Simulating these findings for a hypothetical center treating 50 patients for 9 sessions annually indicated that the amount of chair time freed would range from 105.1 (SL) to 233.4 (IT) 8-hour days. Staff opportunity cost estimates will be presented at the conference. Conclusions The current analysis indicates that a switch from rituximab IV to rituximab SC leads to a substantial reduction in administration chair time and in active HCP time. These time savings could allow more time to be used for other patient care activities, increasing the number of patients who could be treated and thus increasing the overall efficiency of treatment centers. Disclosures De Cock: F. Hoffman-La Roche Ltd: Consultancy, Research Funding. Kritikou:F. Hoffmann-La Roche Ltd: Consultancy, Research Funding. Tao:F. Hoffmann-La Roche Ltd: Consultancy, Research Funding. Wiesner:Genentech: Employment. Off Label Use: Rituximab, administered as an IV infusion, is approved for use in a number of hematologic indications. The data presented here assess a subcutaneous approach to rituximab administration in patients with indolent Non-Hodgkin’s Lymphoma.
Article
The neonatal Fc receptor (FcRn) has been demonstrated to contribute to a high bioavailability of monoclonal antibodies (mAbs). In this study, we explored the cellular sites of FcRn-mediated protection after subcutaneous (SC) and intravenous (IV) administration. SC absorption and IV disposition kinetics of a mAb were studied in hFcRn transgenic (Tg) bone marrow chimeric mice in which hFcRn was restricted to radioresistant cells or hematopoietic cells. SC bioavailabilities close to 90% were observed in hFcRn Tg mice and chimeric mice with hFcRn expression in hematopoietic cells, whereas SC bioavailabilities were markedly lower when FcRn was missing in hematopoietic cells. Our study demonstrates: 1) FcRn in radiosensitive hematopoietic cells is required for high SC bioavailability, indicating first-pass catabolism after SC administration by hematopoietic cells; 2) FcRn-mediated transcytosis or recycling by radioresistent cells is not required for high SC bioavailability; and 3) after IV administration hematopoietic and radioresistent cells contribute about equally to clearance of the mAb. A pharmacokinetic model was devised to describe a mixed elimination via radioresistent and hematopoietic cells from vascular and extravascular compartments, respectively. Overall, the study indicates a relevant role of hematopoietic cells for first-pass clearance of mAbs after SC administration and confirms their role in the overall clearance of mAbs.
Article
Objective: The subcutaneous (SC) formulation of trastuzumab represents an alternative to the intravenous (IV) infusion in the treatment of patients with HER2-positive metastatic and early breast cancer. We compared the two formulations in terms of time and cost differential. Study desing: We conducted a time, motion and cost assessment study in a lean operating day care oncology unit to determine and compare the time and costs of trastuzumab SC versus IV administration in patients with HER2-positive breast cancer. Outcomes were the mean costs and the mean dedicated time of the health care professional (HCP) and patient chair time. Direct observation methodology was applied to collect data and statistical analysis was performed. Results: The total preparation and administration time for trastuzumab IV was 4.07 times longer than the total time required for the trastuzumab SC administration. The total patient time spent in the day care oncology unit (in minutes) was 71% shorter with using SC administration. IV administration costs € 50.4 ($54,89) more in HCP time and consumable supplies and €162.53 ($177.00) of drug wastage. SC administration was associated with a total time saving of 53.7min for the HCPs and 122.5min for the patients. The administration of trastuzumab SC was translated in a cost saving of €212.93 ($231.73) per patient episode compared to trastuzumab IV, which could lead to a total potential saving of €3,832.74 ($4,171.06) over a full course of treatment (18 cycles) CONCLUSION: SC administration of trastuzumab was associated with a substantial reduction in active HCP time, patient chair time, unit time, and overall cost. These time and cost could be used to increase capacity within existing resources in a lean operating day dare oncology unit.
Article
Checkpoint receptor blockers, known to act by blocking the pathways that inhibit immune cell activation and stimulate immune responses against tumor cells, have been immensely successful in the treatment of cancer. Among several checkpoint receptors of immune cells, cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), T-cell immunoglobulin and ITIM domain (TIGIT), T-cell immunoglobulin-3 (TIM-3) and lymphocyte activation gene 3 (LAG-3) are the most commonly targeted checkpoints for cancer immunotherapy. Six drugs including one CTLA-4 blocker (ipilimumab), two PD-1 blockers (nivolumab and pembrolizumab), and three PD-L1 blockers (atezolizumab, avelumab and durvalumab) are approved for the treatment of different types of cancers including both solid tumors such as melanoma, lung cancer, head and neck cancer, bladder cancer and Merkel cell cancer as well as hematological tumors such as classic Hogdkins lymphoma. The main problem with checkpoint blockers is that only a fraction of patients respond to the therapy. Insufficient immune activation is considered as one of the main reason for low response rates and combination of checkpoint blockers has been proposed to increase the response rates. The combination of checkpoint blockers was successful in melanoma but had significant adverse events. A combination that is selected based on the mechanistic differences between checkpoints and the differences in expression of checkpoints and their ligands in the tumor microenvironment (TME) could have a synergistic effect in a given cancer subtype and also have a manageable safety profile. This review aims to help in design of optimal checkpoint blocker combinations by discussing the mechanistic details and outlining the subtle differences between major checkpoints targeted for cancer immunotherapy.
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Introduction: Multiple sclerosis (MS) is a chronic immune-mediated inflammatory disorder of the brain and spinal cord characterized by inflammation, demyelination, and axonal degeneration. Area covered: Even though the pharmacological armamentarium for MS treatment is considerably improved in the last 20 years, safety data especially for the second-line and innovative treatments are lacking. In order to analyze the safety profile of drugs used for the treatment of MS, a literature review of pre-marketing, post-marketing studies and case reports was performed. Expert opinion: Nowadays, the numerous drugs approved in the last years for the treatment of MS allow a better control of the disease and a better patient compliance. The main advantages of the new disease-modifying agents for MS (DMTs), in fact, derive from the new oral administration and the prolonged half-life with consequent improvement in compliance compared to first-line therapy which required subcutaneous administrations. However, DMTs can cause serious, sometimes life-threatening or fatal, drug adverse reactions. Due to the lack of safety data and given the recent marketing approval of the last DMTS for MS, observational studies and post-marketing surveillance activities will be necessary in order to improve the knowledge about the safety profile of these drugs and the improvement of their use in clinical practice.
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