Pharmacological Challenge Models in Clinical Drug Developmental Programs

Early phase clinical research for drug development requires the investigation of safety, tolerability and efficacy of novel compounds. The latter is hampered by the absence of the disorder in healthy volunteers, which is why challenge models are often applied in order to demonstrate ‘proof of pharmacology.’ These challenge models can often be translatable from animal work and can inform the drug developer which dose, dosing regimen or application frequency should be selected prior to phase II studies in the target population. Furthermore, these challenge models represent well-controlled settings to perform activity screening of the compound. The following skin challenge models will be reviewed in this chapter: inflammation induced by Toll-like receptor agonists such as imiquimod, KLH challenge, UV-B irradiation and histamine

Oral prednisolone suppresses skin inflammation in a healthy volunteer imiquimod challenge model

Imiquimod (IMQ) is a topical agent that induces local inflammation via the Toll-like receptor 7 pathway. Recently, an IMQ-driven skin inflammation model was developed in healthy volunteers for proof-of-pharmacology trials. The aim of this study was to profile the cellular, biochemical, and clinical effects of the marketed anti-inflammatory compound prednisolone in an IMQ model. This randomized, double-blind, placebo-controlled study was conducted in 24 healthy volunteers. Oral prednisolone (0.25 mg/kg/dose) or placebo (1:1) was administered twice daily for 6 consecutive days. Two days after treatment initiation with prednisolone or placebo, 5 mg imiquimod (IMQ) once daily for two following days was applied under occlusion on the tape-stripped skin of the back for 48 h in healthy volunteers. Non-invasive (imaging and biophysical) and invasive (skin punch biopsies and blister induction) assessments were performed, as well as IMQ ex vivo stimulation of whole blood. Prednisolone reduced blood perfusion and skin erythema following 48 h of IMQ application (95% CI [−26.4%, −4.3%], p = 0.0111 and 95% CI [−7.96, −2.13], p = 0.0016). Oral prednisolone suppressed the IMQ-elevated total cell count (95% CI [−79.7%, −16.3%], p = 0.0165), NK and dendritic cells (95% CI [−68.7%, −5.2%], p = 0.0333, 95% CI [−76.9%, −13.9%], p = 0.0184), and classical monocytes (95% CI [−76.7%, −26.6%], p = 0.0043) in blister fluid. Notably, TNF, IL-6, IL-8, and Mx-A responses in blister exudate were also reduced by prednisolone compared to placebo. Oral prednisolone suppresses IMQ-induced skin inflammation, which underlines the value of this cutaneous challenge model in clinical pharmacology studies of novel anti-inflammatory compounds. In these studies, prednisolone can be used as a benchmark.</p

Omiganan Enhances Imiquimod-Induced Inflammatory Responses in Skin of Healthy Volunteers

Omiganan (OMN; a synthetic cationic peptide) and imiquimod (IMQ; a TLR7 agonist) have synergistic effects on interferon responses in vitro. The objective of this study was to translate this to a human model for proof-of-concept, and to explore the potential of OMN add-on treatment for viral skin diseases. Sixteen healthy volunteers received topical IMQ, OMN, or a combination of both for up to 4 days on tape-stripped skin. Skin inflammation was quantified by laser speckle contrast imaging and 2D photography, and molecular and cellular responses were analyzed in biopsies. IMQ treatment induced an inflammatory response of the skin. Co-treatment with OMN enhanced this inflammatory response to IMQ, with increases in perfusion (+17.1%; 95% confidence interval (CI) 5.6%–30%; P < 0.01) and erythema (+1.5; 95% CI 0.25%–2.83; P = 0.02). Interferon regulatory factor-driven and NFκB-driven responses following TLR7 stimulation were enhanced by OMN (increases in IL-6, IL-10, MXA, and IFNɣ), and more immune cell infiltration was observed (in particular CD4+, CD8+, and CD14+ cells). These findings are in line with the earlier mechanistic in vitro data, and support evaluation of imiquimod/OMN combination therapy in human papillomavirus-induced skin diseases

Oral prednisolone suppresses skin inflammation in a healthy volunteer imiquimod challenge model

Imiquimod (IMQ) is a topical agent that induces local inflammation via the Toll-like receptor 7 pathway. Recently, an IMQ-driven skin inflammation model was developed in healthy volunteers for proof-of-pharmacology trials. The aim of this study was to profile the cellular, biochemical, and clinical effects of the marketed anti-inflammatory compound prednisolone in an IMQ model. This randomized, double-blind, placebo-controlled study was conducted in 24 healthy volunteers. Oral prednisolone (0.25 mg/kg/dose) or placebo (1:1) was administered twice daily for 6 consecutive days. Two days after treatment initiation with prednisolone or placebo, 5 mg imiquimod (IMQ) once daily for two following days was applied under occlusion on the tape-stripped skin of the back for 48 h in healthy volunteers. Non-invasive (imaging and biophysical) and invasive (skin punch biopsies and blister induction) assessments were performed, as well as IMQ ex vivo stimulation of whole blood. Prednisolone reduced blood perfusion and skin erythema following 48 h of IMQ application (95% CI [−26.4%, −4.3%], p = 0.0111 and 95% CI [−7.96, −2.13], p = 0.0016). Oral prednisolone suppressed the IMQ-elevated total cell count (95% CI [−79.7%, −16.3%], p = 0.0165), NK and dendritic cells (95% CI [−68.7%, −5.2%], p = 0.0333, 95% CI [−76.9%, −13.9%], p = 0.0184), and classical monocytes (95% CI [−76.7%, −26.6%], p = 0.0043) in blister fluid. Notably, TNF, IL-6, IL-8, and Mx-A responses in blister exudate were also reduced by prednisolone compared to placebo. Oral prednisolone suppresses IMQ-induced skin inflammation, which underlines the value of this cutaneous challenge model in clinical pharmacology studies of novel anti-inflammatory compounds. In these studies, prednisolone can be used as a benchmark

Presentation_1_Oral prednisolone suppresses skin inflammation in a healthy volunteer imiquimod challenge model.pptx

Imiquimod (IMQ) is a topical agent that induces local inflammation via the Toll-like receptor 7 pathway. Recently, an IMQ-driven skin inflammation model was developed in healthy volunteers for proof-of-pharmacology trials. The aim of this study was to profile the cellular, biochemical, and clinical effects of the marketed anti-inflammatory compound prednisolone in an IMQ model. This randomized, double-blind, placebo-controlled study was conducted in 24 healthy volunteers. Oral prednisolone (0.25 mg/kg/dose) or placebo (1:1) was administered twice daily for 6 consecutive days. Two days after treatment initiation with prednisolone or placebo, 5 mg imiquimod (IMQ) once daily for two following days was applied under occlusion on the tape-stripped skin of the back for 48 h in healthy volunteers. Non-invasive (imaging and biophysical) and invasive (skin punch biopsies and blister induction) assessments were performed, as well as IMQ ex vivo stimulation of whole blood. Prednisolone reduced blood perfusion and skin erythema following 48 h of IMQ application (95% CI [−26.4%, −4.3%], p = 0.0111 and 95% CI [−7.96, −2.13], p = 0.0016). Oral prednisolone suppressed the IMQ-elevated total cell count (95% CI [−79.7%, −16.3%], p = 0.0165), NK and dendritic cells (95% CI [−68.7%, −5.2%], p = 0.0333, 95% CI [−76.9%, −13.9%], p = 0.0184), and classical monocytes (95% CI [−76.7%, −26.6%], p = 0.0043) in blister fluid. Notably, TNF, IL-6, IL-8, and Mx-A responses in blister exudate were also reduced by prednisolone compared to placebo. Oral prednisolone suppresses IMQ-induced skin inflammation, which underlines the value of this cutaneous challenge model in clinical pharmacology studies of novel anti-inflammatory compounds. In these studies, prednisolone can be used as a benchmark.</p