Population pharmacokinetic and exposure‐response modelling to inform upadacitinib dose selection in adolescent and adult patients with atopic dermatitis

Aims First, population pharmacokinetic analyses were used to characterize upadacitinib pharmacokinetics in adolescent and adult participants with atopic dermatitis (AD) and to identify patient covariates that may impact upadacitinib pharmacokinetics. Second, the exposure‐response relationship for upadacitinib with efficacy and safety endpoints, and the effect of age and concomitant use of topical corticosteroids (TCS) on the exposure‐response relationship and dose selection for patients with AD were evaluated. 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 15 or 30 mg 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 relationships, 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 the upadacitinib area under the plasma concentration‐time curve from time zero to 24 h after dosing (AUC 24 ) approximately 12% and 25%, respectively, compared to participants with normal renal function. Female participants were predicted to have 20% higher AUC 24 compared to male participants. Participants with AD were predicted to have 18% higher AUC 24 compared to healthy participants. Simulated clinical efficacy responses showed added clinical efficacy benefit for all endpoints evaluated (8‐14%) with the upadacitinib 30 mg once‐daily regimen compared to 15 mg 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.