Introduction
Biopharmaceuticals, such as monoclonal antibodies (mAbs), are used in
the treatment of a large number of chronic and life-threatening diseases
(1). Degradation and ineffective absorption of mAbs in the
gastrointestinal tract, due to molecular size and conditions such as low
pH and digestive enzymes, necessitates their parenteral administration.
However, in clinical practice, treatments administered using s.c.
injection of mAbs have been perceived as unpleasant and painful,
especially during long term use in both adults and children (2). Thus,
s.c. administration may jeopardize treatment adherence and a less
invasive and less painful method to administer mAbs is warranted.
Intradermal administration of biopharmaceuticals through hollow
microneedles is advocated as substitute for s.c. injection, due to less
pain associated with injection of drugs using microneedles (3), and i.d.
administered biopharmaceuticals may show more favourable
pharmacokinetics as compared to s.c. administration (4–7). Multiple
types of microneedles exist, such as hollow and solid microneedles, and
microneedles have different properties in comparison with conventional
needles. For instance, the injection of pharmaceutical compounds using
hollow microneedles is more superficial, i.e., into the skin (i.d.)
rather than beneath the skin (s.c.). Additionally, the diameter of
hollow microneedles is smaller than that of conventional hypodermic
needles for s.c. injection. An unbiased and systematic approach is
warranted to acquire reliable data on pain perception and patient
preferences, as these are subjective concepts (8). Therefore, it is
relevant to compare pain, acceptability and local tolerability, as well
as pharmacokinetics (PK) and pharmacodynamics (PD) between mAbs
administered i.d. using a hollow microneedle with S.C. injection using a
conventional hypodermic needle. Moreover, when using a new drug-device
combination, chemistry, manufacturing and control (CMC) aspects need
consideration.
The commercially available microneedles used in the clinical trial
reported in this paper have been used in various clinical studies (9).
Each device consists of three hollow microneedles with a length of 600
µm; this device is hereafter referred to as hollow microneedle. Although
microneedle vaccine administration has been widely investigated, there
are no systematic reports on mAb administration using microneedles in
humans. We choose adalimumab (Humira®, AbbVie) as model mAb as it is
widely used for a variety of auto-immune/auto-inflammatory diseases
including juvenile idiopathic arthritis. Adalimumab acts by binding to
the pro-inflammatory cytokine TNFα, hereby preventing its interaction
with the TNFα receptor (10).
To evaluate feasibility of i.d. adalimumab administration using hollow
microneedles, we performed a double-blind, double-dummy, randomized
controlled clinical trial in healthy adults, comparing a single i.d.
dose of adalimumab using a hollow microneedle with a single s.c. dose
using a conventional needle. Our primary aim was to systematically
investigate pain, acceptability, and local tolerability after i.d.
adalimumab administration and to compare this with S.C. administration.
Our secondary aim was to evaluate safety, PK, PD, and immunogenicity of
i.d. adalimumab administration and to compare this with s.c.
administration. Moreover, we explored the usability of optical coherence
tomography (OCT), clinical photography, thermal imaging, and laser
speckle contrast imaging (LSCI) in the evaluation of i.d. injections.
Lastly, prior to the clinical trial we performed an elaborate in
vitro protein analysis to confirm that examine whether ejection of
adalimumab through a hollow microneedle bore increases particle
formation or protein aggregation compared to ejection through a
conventional needle. One could envision that during ejection of a
protein out of a narrow microneedle, the structure of the protein might
be affected. Factors contributing to the immunogenicity of mAbs include
protein structure and physical degradation, such as aggregation (11).
The formation of anti-adalimumab antibodies may result in reduced
treatment efficacy due to increased drug clearance (CL) (12,13).
Altogether, in this paper we provide a systematic and comprehensive
approach to answer the question whether hollow microneedles can be used
safely and effectively to administer a model mAb.