Model-Informed Paradigm in Drug Development-An End-To-End Case Study From Upadacitinib Development

Abstract

Model-informed drug development (MIDD) entails applying quantitative approaches to assist with decision-making during drug development and has been used for dose optimization, to inform clinical trial design, and to support clinical trial waivers. With increasing cost and competitiveness in drug development, the use of tools that improve efficiency, like MIDD, is increasingly crucial. A unique case for the successful application of MIDD approaches from early Phase 1 through postapproval for the upadacitinib development program is described herein. Upadacitinib is an orally administered selective Janus kinase inhibitor, which is approved for rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, axial spondylarthritis, nonradiographic axial spondyloarthritis, ulcerative colitis, and Crohn's disease for adults, in addition to recent approvals for polyarticular juvenile idiopathic arthritis and pediatric patients with psoriatic arthritis. Applications and impact of modeling and simulation approaches for informing key development decisions are presented to highlight the success of using MIDD for the clinical development of upadacitinib. The lessons learned can provide a framework for the clinical development of other drugs.

FIGURE 1

Timeline of modeling activities. DDI, drug–drug interaction; ER, extended release; IR, immediate release; PBPK, physiologically based pharmacokinetic; TQT, thorough QT clinical study.

FIGURE 2

Planning for modeling and simulation across the phases of upadacitinib development. BA, bioavailability; BE, bioequivalence; BID, twice daily; DDI, drug–drug interaction; ECG, electrocardiogram; HV, healthy volunteer; IVIVC, in vitro–in vivo correlation; JAK, Janus kinase; MAD, multiple ascending dose; PBPK, physiologically based pharmacokinetic; PD, pharmacodynamic; PK, pharmacokinetic; QD, once daily; SAD, single ascending dose; UPA, upadacitinib.