Exposure‐Response Analyses for Upadacitinib Efficacy in Subjects With Atopic Dermatitis—Analyses of Phase 2b Study to Support Selection of Phase 3 Doses

Mohamed, Mohamed‐Eslam F.; Gopalakrishnan, Sathej; Teixeira, Henrique D.; Othman, Ahmed A.

doi:10.1002/jcph.1782

Cited by 8 publications

(8 citation statements)

References 31 publications

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“…In subjects with dermatological inflammatory disease such as AD, 30 mg QD is predicted to achieve 20% greater efficacy across different endpoints compared to 15 mg QD. 26 Lastly, in patients with inflammatory bowel disease doses exceeding 30 mg QD of upadacitinib are expected to provide incremental efficacy benefit during the induction period compared to 30 mg QD or lower doses. 25 The population pharmacokinetic and exposure-response analyses reported in the current work were conducted using data from two global phase 3 studies in patients with active PsA, 10,11 were the first to characterize the pharmacokinetics of upadacitinib and the relationships between the plasma exposures of upadacitinib and its efficacy/ safety in patients with moderate to severe PsA.…”

Section: Introductionmentioning

confidence: 99%

“… 18 , 19 , 20 , 21 , 22 , 23 , 24 Upadacitinib pharmacokinetics were similar across different patient populations, such as RA, ulcerative colitis (UC), Crohn’s disease (CD), and atopic dermatitis (AD). 1 , 25 , 26 , 27 Upadacitinib exposures associated with optimal clinical benefit differed from indication to indication due to the individual pathophysiological nature of each condition. In patients with RA, optimal benefit‐risk exposures were achieved by the 15 mg once daily (q.d.)…”

Section: Introductionmentioning

confidence: 99%

“…In subjects with dermatological inflammatory disease, such as AD, 30 mg q.d. is predicted to achieve 20% greater efficacy across different endpoints compared to 15 mg q.d.. 26 Last, in patients with inflammatory bowel disease, doses exceeding 30 mg q.d. of upadacitinib are expected to provide incremental efficacy benefit during the induction period compared to 30 mg q.d.…”

Section: Introductionmentioning

confidence: 99%

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Upadacitinib pharmacokinetics and exposure‐response analyses of efficacy and safety in psoriatic arthritis patients – Analyses of phase III clinical trials

Muensterman

Engelhardt

Gopalakrishnan

et al. 2021

Clinical Translational Sci

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Upadacitinib is an oral Janus kinase inhibitor approved for the treatment of rheumatoid arthritis (RA) and recently approved by the European Medicines Agency for the treatment of psoriatic arthritis (PsA). The efficacy and safety profile of upadacitinib in PsA have been established in the SELECT-PsA program in two global phase 3 studies which evaluated upadacitinib 15 and 30mg QD. The analyses described here characterized upadacitinib pharmacokinetics and exposure-response relationships for efficacy and safety endpoints using data from the SELECT-PsA studies. Upadacitinib pharmacokinetics in PsA patients were characterized through a Bayesian population analysis approach and were comparable to pharmacokinetics in RA patients. Exposure-response relationships for key efficacy and safety endpoints were characterized using data from 1,916 PsA patients. The percentage of patients achieving efficacy endpoints at Week 12 (ACR50 and ACR70), 16 and 24 (sIGA0/1) increased with increasing upadacitinib average plasma concentration over a dosing interval, while no clear exposure-response trend was observed for ACR20 at Week 12 or ACR20/50/70 at Week 24 within the range of plasma exposures evaluated in the phase 3 PsA studies. No clear trends for exposure-response relationships were identified for experiencing pneumonia, herpes zoster infection, hemoglobin <8g/dL, lymphopenia (Grade≥3), or neutropenia (Grade≥3) after 24 weeks of treatment. Shallow relationships with plasma exposures were observed for serious infections and hemoglobin decrease >2g/dL from baseline at Week 24. Based on exposure-response analyses, the upadacitinib 15mg QD regimen is predicted to achieve robust efficacy in PsA patients and to be associated with limited incidences of reductions in hemoglobin or occurrence of serious infections.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Upadacitinib pharmacokinetics and exposure‐response analyses of efficacy and safety in psoriatic arthritis patients – Analyses of phase III clinical trials

Muensterman

Engelhardt

Gopalakrishnan

et al. 2021

Clinical Translational Sci

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“…[17][18][19][20][21][22][23][24] In a previous phase 2b dose-ranging study (NCT02925117), which evaluated 7.5-, 15-and 30-mg doses of the extended-release formulation of upadacitinib or placebo given once daily (QD) in participants with moderate to severe AD, upadacitinib demonstrated favourable efficacy after 16 weeks of treatment. 25 This phase 2b study was the basis for granting breakthrough therapy designation by the Food and Drug Administration (FDA) to upadacitinib development in AD. Based on exposure-response analyses of the phase 2b AD study, 25 exposures associated with upadacitinib 15 and 30 mg QD using the extended-release tablet formulation were predicted to maximize efficacy in the treatment of participants with moderate to severe AD, and these doses were assessed further as upadacitinib monotherapy or in combination with topical corticosteroids (TCS) in multiple phase 3 studies in adolescents and adults with AD.…”

Section: Introductionmentioning

confidence: 99%

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

Ismail

Doelger

Eckert

et al. 2023

Brit J Clinical Pharma

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AimsFirst, 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.MethodsA 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.ResultsUpadacitinib 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 (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 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.ConclusionThe results of these analyses support the dose justification for upadacitinib in adult and adolescent patients with moderate to severe AD.

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“…Population pharmacokinetics and exposure-response analyses have been conducted for upadacitinib for several indications, such as RA [ 9 , 10 ], CD [ 11 ], PsA [ 12 ], and AD [ 13 ], which have informed optimal dosing for clinical benefit specific to each disease. The population pharmacokinetics and exposure-response analyses in this work characterized upadacitinib pharmacokinetics in patients with moderately to severely active UC across Phase 2b and 3 trials and evaluated the relationships between upadacitinib plasma exposures and key efficacy and safety endpoints using data from these trials during induction and maintenance treatment.…”

Section: Introductionmentioning

confidence: 99%

Upadacitinib Population Pharmacokinetics and Exposure-Response Relationships in Ulcerative Colitis Patients

et al. 2022

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Background and Objective Upadacitinib, an oral selective and reversible Janus kinase (JAK) inhibitor, showed favorable efficacy and safety in patients with moderate-to-severe ulcerative colitis (UC). The objective was to characterize upadacitinib pharmacokinetics in UC patients across Phase 2b and 3 trials and evaluate the relationships between upadacitinib plasma exposures and key efficacy or safety endpoints. Methods Population pharmacokinetics and exposure-response analyses were performed to characterize upadacitinib pharmacokinetics in UC patients and evaluate the relationships between plasma exposures and key efficacy or safety endpoints at the end of 8-week induction and 52-week maintenance periods. Data from 1234 UC patients from Phase 2 and 3 induction trials and 449 UC patients from a Phase 3 maintenance trial were used for these analyses. Additionally, data from patients with rheumatoid arthritis, atopic dermatitis, Crohn's disease, and healthy volunteers were used in the pharmacokinetics analysis. Quartile plots and logistic regression models were used to evaluate the exposure-response relationships across upadacitinib doses of 7.5-45 mg once daily (QD) for induction and 15-30 mg QD for maintenance. Results Upadacitinib plasma exposures were dose-proportional in UC patients across the evaluated dose range. Upadacitinib pharmacokinetics in UC were consistent between the induction and maintenance periods, and with other patient populations. Upadacitinib plasma exposures associated with the 45 mg QD induction dose maximized efficacy for Week 8 clinical and endoscopic endpoints. Plasma exposures associated with upadacitinib 30 mg maintenance dose provided additional incremental benefit compared to 15 mg QD for Week 52 key clinical and endoscopic endpoints. No trends were observed in the evaluated safety events with increasing plasma exposures at the end of induction or maintenance periods. Conclusion These analyses supported selection of upadacitinib UC induction and maintenance doses. Trial Registration Data from studies NCT02819635 and NCT03653026 were included in these analyses.

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Exposure‐Response Analyses for Upadacitinib Efficacy in Subjects With Atopic Dermatitis—Analyses of Phase 2b Study to Support Selection of Phase 3 Doses

Cited by 8 publications

References 31 publications

Upadacitinib pharmacokinetics and exposure‐response analyses of efficacy and safety in psoriatic arthritis patients – Analyses of phase III clinical trials

Upadacitinib pharmacokinetics and exposure‐response analyses of efficacy and safety in psoriatic arthritis patients – Analyses of phase III clinical trials

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

Upadacitinib Population Pharmacokinetics and Exposure-Response Relationships in Ulcerative Colitis Patients

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