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.