Pharmacological Challenge Models in Clinical Drug Developmental Programs

Abstract

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 wellcontrolled 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.

Blueprint for mechanistic, data‐rich early phase clinical pharmacology studies in dermatology

“…Such studies include in vivo or ex vivo immune challenges targeting innate immunity pathways, e.g., lipopolysaccharide for Toll‐like receptor (TLR)‐4 and imiquimod for TLR‐7 stimulation, or adaptive pathways, e.g., the neoantigen keyhole limpet hemocyanin driving an antigen‐specific T‐cell and B‐cell response 15,16 . Other valuable models include histamine or capsaicin challenges via skin prick, as model for pruritus as was reviewed by Assil et al 17 Combining a dose‐ranging trial with a proof‐of‐pharmacology trial at the earliest clinical stage (i.e., in healthy volunteers) results in proving the pharmacological action and supports rational dose selection for a subsequent “proof‐of‐concept” trial in a relevant patient population. Of note, for topical drugs, the healthy volunteer part can often be minimized or omitted, and the assessments can be performed directly in the relevant patient population.…”

Intradermal substance P as a challenge agent in healthy individuals

“…SP is upstream in the inflammatory response signaling cascade and may be a useful challenge agent for the investigation of locally acting mediators in some settings 3,13 . Challenge models mimic pharmacologically induced conditions, providing a valuable tool to assess an inflammatory response in healthy human volunteers and analyze the potential efficacy of drugs in development before going to patient populations 5,14–16 . Increasing doses of SP via intradermal injection are associated with an increased wheal and flare response, 9–11 as well as intradermal release of several inflammatory mediators, such as histamine and tryptase.…”

“… 3 , 13 Challenge models mimic pharmacologically induced conditions, providing a valuable tool to assess an inflammatory response in healthy human volunteers and analyze the potential efficacy of drugs in development before going to patient populations. 5 , 14 , 15 , 16 Increasing doses of SP via intradermal injection are associated with an increased wheal and flare response, 9 , 10 , 11 as well as intradermal release of several inflammatory mediators, such as histamine and tryptase. Histamine can be used as an active control versus SP, as histamine is an agent known to produce wheal and flare responses.…”