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Favourable pharmacokinetics of intradermal adalimumab over subcutaneous administration: results of a randomized controlled trial
  • +19
  • Justin Jacobse,
  • Wouter ten Voorde,
  • Anushka Tandon,
  • Stefan Romeijn,
  • Hendrika Grievink,
  • Koen van der Maaden,
  • Michiel van Esdonk,
  • Dirk Jan Moes,
  • Floris Loeff,
  • Karien Bloem,
  • Annick de Vries,
  • Theo Rispens,
  • Gertjan Wolbink,
  • Marieke de Kam,
  • Dimitrios Ziagkos,
  • Matthijs Moerland,
  • Wim Jiskoot,
  • Joke Bouwstra,
  • Jacobus Burggraaf,
  • Robert Rissmann,
  • Lenneke Schrier,
  • Rebecca Ten Cate
Justin Jacobse
Centre for Human Drug Research
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Wouter ten Voorde
Centre for Human Drug Research
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Anushka Tandon
Centre for Human Drug Research
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Stefan Romeijn
Leiden Academic Centre for Drug Research
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Hendrika Grievink
Centre for Human Drug Research
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Koen van der Maaden
Leiden Academic Centre for Drug Research
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Michiel van Esdonk
Leiden University
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Dirk Jan Moes
Leiden University Medical Center
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Floris Loeff
Sanquin Diagnostic Services
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Karien Bloem
Sanquin Diagnostic Services
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Annick de Vries
Sanquin Diagnostic Services
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Theo Rispens
Sanquin Diagnostic Services
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Gertjan Wolbink
Sanquin Diagnostic Services
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Marieke de Kam
Centre for Human Drug Research
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Dimitrios Ziagkos
Centre for Human Drug Research
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Matthijs Moerland
Centre for Human Drug Research
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Wim Jiskoot
Leiden Academic Centre for Drug Research
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Joke Bouwstra
Leiden Academic Centre for Drug Research
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Jacobus Burggraaf
Centre for Human Drug Research
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Robert Rissmann
Centre for Human Drug Research
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Lenneke Schrier
Leiden University Medical Center Willem Alexander Childrens Hospital
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Rebecca Ten Cate
Leiden University Medical Center Willem Alexander Childrens Hospital
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Abstract

Aim To evaluate feasibility of intradermal (i.d.) adalimumab administration using hollow microneedles, and to compare a single i.d. dose of adalimumab using a hollow microneedle with a single subcutaneous (s.c.) dose using a conventional needle. Methods In this single-centre double-blind, placebo-controlled, double-dummy clinical trial in 24 healthy adults we compared 40 mg adalimumab (0.4 mL) administered i.d. using a hollow microneedle with a s.c. dose using a conventional needle. Primary parameters were pain, acceptability, and local tolerability; secondary parameters safety, pharmacokinetics and immunogenicity. We explored usability of optical coherence tomography (OCT), clinical photography, thermal imaging, and laser speckle contrast imaging (LSCI) to evaluate skin reaction after i.d. injections. In vitro protein analysis was performed to assess compatibility of adalimumab with the hollow microneedle device. Results While feasible and safe, injection pain of i.d. adalimumab was higher compared to s.c. adalimumab (35.4 vs. 7.9 on a 101-point VAS scale). Initial absorption rate and bioavailability were higher after i.d. adalimumab (Tmax=95h(47-120); F=129%(6.46%)) compared to s.c. adalimumab (Tmax=120h(96-221)). In 50% and 83% of the subjects anti-adalimumab antibodies were detected after i.d. and s.c. adalimumab, respectively. We observed statistically significantly more erythema and skin perfusion after i.d. adalimumab, compared to s.c. adalimumab and placebo injections (p<0.0001). Cytokine secretion after whole blood LPS challenge was comparable between administration routes. Conclusion Intradermal of adalimumab using hollowing microneedles was perceived as more painful, and less accepted than s.c. administration, however, yields a higher bioavailability with similar safety and pharmacodynamic effects.

Peer review status:ACCEPTED

24 Sep 2020Submitted to British Journal of Clinical Pharmacology
25 Sep 2020Submission Checks Completed
25 Sep 2020Assigned to Editor
13 Oct 2020Reviewer(s) Assigned
16 Nov 2020Review(s) Completed, Editorial Evaluation Pending
30 Nov 2020Editorial Decision: Revise Major
09 Dec 20201st Revision Received
10 Dec 2020Submission Checks Completed
10 Dec 2020Assigned to Editor
10 Dec 2020Review(s) Completed, Editorial Evaluation Pending
27 Dec 2020Editorial Decision: Accept