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Exposure-Response Analyses of Upadacitinib Efficacy in Phase 2 Trials in Rheumatoid Arthritis and Basis for Phase 3 Dose Selection

Author

Mohamed MF1, Klünder B2, Camp HS3, Othman AA1. Clin Pharmacol Ther. 2019 Jun 13. doi: 10.1002/cpt.1543. [Epub ahead of print]

Author Information

1 Clinical Pharmacology and Pharmacometrics, AbbVie, North Chicago, United States.

2 Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen am Rhein, Germany.

3 Immunology Clinical Development, AbbVie, North Chicago, United States.

Abstract

The relationships between upadacitinib, an oral selective Janus Kinase 1 inhibitor, plasma exposures and its efficacy (assessed by ACR20/50/70 responses over time) in moderate-to severe active rheumatoid arthritis (RA) were characterized using data from 574 patients, on background methotrexate and inadequate response to methotrexate or anti-TNF therapy, from two Phase 2 trials conducted with twice-daily dosing of an immediate-release formulation. The developed time-continuous Markov models were used to simulate efficacy of QD regimens of upadacitinib extended-release incorporating sources of uncertainty. Upadacitinib plasma concentrations associated with 15 and 30 mg extended-release QD doses were predicted to achieve that plateau of response across RA subpopulations. Results from these analyses provided the rationale that supported selection, and de-risked evaluation, of upadacitinib extended-release doses for the first time in more than 4000 patients in five large Phase 3 trials.