Repeated intradermal lipopolysaccharide challenge responses in healthy volunteers: Implications for clinical...

Intradermal application of lipopolysaccharide (LPS), a Toll-like receptor 4 agonist, induces a local inflammatory response and is used as a human challenge model to evaluate the pharmacodynamics of investigational medicinal products. While currently applied in a single, parallel-group setting, alternative within-subject designs involving repeated LPS challenges at different skin sites and spaced across multiple timepoints would enable within-subject comparisons, potentially reducing inter-individual variability in pharmacodynamic assessments. We aimed to determine whether intradermal LPS challenges at different sites on the back, with 14-day intervals, would be an optimal design for clinical pharmacology studies.

Eight healthy volunteers received seven 5-ng intradermal LPS injections: six on the back on Days 1, 15 and 29 (two per day) and one on the volar forearm on Day 1. Local inflammation was assessed via non-invasive imaging (skin perfusion and erythema) and suction blister fluid (cytokines and leukocytes) at 10- and 24 h post-injection. Systemic responses were evaluated through blood cytokine and leukocyte levels.

Repeated intradermal LPS challenges were well tolerated. Skin perfusion, erythema and local cytokine and chemokine levels were similar across challenges. However, on subsequent challenge days there were shifts in vascular responses and counts of classical monocyte, and other leukocytes in blister fluid were reduced at 10 h on Day 15 compared to Day 1.

The results indicate that following Day 1 intradermal LPS challenges, a subtle immune adaptation may occur, potentially limiting the model's reliability for cellular endpoint-focused within-subject pharmacological investigations.