Skin and Plasma Pharmacokinetics of Povorcitinib After Oral Administration in Healthy Participants: An Open-Label, Multiple-Dose Phase 1 Study

This open-label phase 1 study characterized the concentrations and pharmacokinetic (PK) profile of povorcitinib, an oral, JAK1-selective inhibitor, in skin tissue and plasma of 18 healthy adults receiving 75 mg once daily (Days 1–10). Plasma PK parameters were estimated from individual concentration-time profiles; skin PK parameters from pooled mean concentration-time data. 216 serial plasma (through 168 hours postdose on Day 10) and 72 skin biopsy samples (collected Days 10–17 and predose Day 10) were analyzed. Mean povorcitinib concentrations in skin and plasma from Day 10 onward were generally comparable, peaking 2 hours postdose in plasma and 6 hours in skin (first biopsy time point), with monoexponential decline. Skin and plasma PK exposure parameters were similar; skin-to-plasma ratios ranged 0.841–0.949 for C max, C min , and AUC 0-24 . Povorcitinib was well tolerated; although transient, asymptomatic platelet decreases, which resolved without sequelae, occurred in 55.6% of participants. In conclusion, povorcitinib exhibited substantial skin distribution following oral administration. Observed skin and plasma povorcitinib levels were sufficient to maintain JAK1 inhibition for 48 hours postdose and were consistent with a low likelihood of clinically meaningful off-target JAK2 inhibition, supporting the potential of povorcitinib for treating inflammatory disorders involving skin and other tissues. Clinical Trial Registration : ClinicalTrials.gov NCT06505265.