LAUSR

AIMS First, utilize population pharmacokinetic analyses to characterize upadacitinib pharmacokinetics in adolescent and adult participants with atopic dermatitis (AD) and identify patient covariates that may impact upadacitinib pharmacokinetics. Second, evaluate the exposure-response relationship for upadacitinib with efficacy and safety endpoints and characterize the effect of age and concomitant use of topical corticosteroids (TCS) on the exposure-response relationship and dose selection for patients with AD. METHODS A two-compartment model with combined first- and zero-order absorption adequately characterized the upadacitinib concentration-time profiles in 911 healthy volunteer, adolescent and adult participants with AD who received upadacitinib 15mg or 30mg orally once daily (QD) as monotherapy or in combination with TCS for 16 weeks. Logistic regression models were developed to characterize the exposure-efficacy and safety relationship and simulations were performed based on final exposure-response models to predict efficacy responses in participants with AD who received placebo or upadacitinib as monotherapy or in combination with TCS. RESULTS Upadacitinib exposures were comparable between adolescents and adults. Mild or moderate renal impairment was predicted to increase upadacitinib area under the plasma concentration-time curve from time zero to 24 hours after dosing (AUC24 ) approximately 12% and 25%, respectively, compared to participants with normal renal function. Female participants were predicted to have 20% higher AUC24 compared to male participants. Participants with AD were predicted to have 18% higher AUC24 compared to healthy participants. Simulated clinical efficacy responses show added clinical efficacy benefit for all endpoints evaluated (8-14%) with upadacitinib 30mg once-daily regimen compared to 15mg once-daily in both age groups. In participants receiving upadacitinib in combination with TCS, significant exposure-dependent increases in upadacitinib efficacy endpoints were observed. No significant effects of age or weight were identified in any of the exposure-response models. CONCLUSION The results of these analyses support the dose justification for upadacitinib in adult and adolescent patients with moderate-to-severe AD.