Early-Stage Derisking of a Topical JAK Inhibitor Candidate in Healthy Human Skin Explants: Dermal Stability and Pharmacokinetics

PURPOSE: Topical JAK inhibitors (JAKi) offer promising treatment for inflammatory skin disorders while minimizing systemic side effects. Understanding their pharmacokinetic and pharmacodynamic properties in skin is essential for their development. This pharmacokinetic study evaluated dermal penetration, metabolism, and stability of a novel, topical JAKi candidate and its inactive metabolite using dermal open flow microperfusion (dOFM) as a translational technology bridging ex vivo to in vivo findings. PATIENTS AND METHODS: Skin penetration of parent compound (JAKi-o) was investigated ex vivo in human skin explants from three donors by dOFM sampling. Different test formulations (0.75%, 1.5%) and different dosing were compared with approved ruxolitinib 1.5% cream as reference. Stability and metabolic conversion into the inactive metabolite (JAKi-mb) were tested in extracted interstitial fluid and ex vivo after intradermal dOFM application. RESULTS: Topical JAKi-o formulations (0.75%; 1.5%) produced dermal concentrations below the quantification limit (5 nM) at all timepoints. Reference ruxolitinib showed continuous concentration increases, reaching levels 63 times higher than the maximum JAKi-o concentrations. Pharmacokinetic profiles were consistent between explants and occlusion did not significantly affect dermal concentrations. Metabolic conversion in pure ISF was minimal, with only 14.4% of JAKi-o metabolized to JAKi-mb after 120 minutes. Intradermal application via dOFM confirmed intradermal metabolism, with a ratio of 1.6 (JAKi-o to JAKi-mb) during intradermal JAKi-o application which reversed to a ratio of 0.8 (JAKi-o to JAKi-mb) when only residual JAKi-o from the dermal tissue was available for metabolism. CONCLUSION: dOFM effectively detected dermal penetration and metabolism of small molecules in human skin ex-vivo, enabling prediction of human metabolization behaviour. This time-saving preclinical method supports early-phase drug development by determining whether compounds achieve sufficient skin concentrations without systemic availability, allowing early candidate selection and reducing development risks for topical therapies targeting epidermis and dermis.