Preferential Inhibition of JAK1 Relative to JAK3 by Upadacitinib: Exposure‐Response Analyses of Ex Vivo Data From 2 Phase 1 Clinical Trials and Comparison to Tofacitinib

• Published in: Journal of clinical pharmacology Vol. 60; no. 2; pp. 188 - 197
• Main Authors: Mohamed, Mohamed‐Eslam F., Beck, Denise, Camp, Heidi S., Othman, Ahmed A.
• Format: Journal Article
• Language: English
• Published: England 01.02.2020
• Subjects: Adolescent; Adult; Arthritis, Rheumatoid - drug therapy; Clinical Trials, Phase I as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Healthy Volunteers; Heterocyclic Compounds, 3-Ring - administration & dosage; Heterocyclic Compounds, 3-Ring - pharmacokinetics; Heterocyclic Compounds, 3-Ring - pharmacology; Heterocyclic Compounds, 3-Ring - therapeutic use; Humans; IL‐6; IL‐7; JAK1; JAK3; Janus kinase; Janus Kinase 1 - antagonists & inhibitors; Janus Kinase 3 - antagonists & inhibitors; Male; Middle Aged; Models, Biological; Phosphorylation - drug effects; Piperidines - administration & dosage; Piperidines - pharmacokinetics; Piperidines - pharmacology; Piperidines - therapeutic use; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Pyrimidines - administration & dosage; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; rheumatoid arthritis; STAT3; STAT3 Transcription Factor - drug effects; STAT3 Transcription Factor - metabolism; STAT5; STAT5 Transcription Factor - drug effects; STAT5 Transcription Factor - metabolism; target engagement; tofacitinib; upadacitinib; Young Adult; upadacitinib; STAT3; Janus kinase; STAT5; target engagement; JAK3; rheumatoid arthritis; IL-6; IL-7; JAK1; tofacitinib
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1002/jcph.1513

Upadacitinib is a selective Janus kinase (JAK) 1 inhibitor being developed for treatment of rheumatoid arthritis. This study characterizes the relationships between upadacitinib exposure and interleukin (IL)‐6–induced signal transducer and activator of transcription proteins 3 (STAT3) phosphorylation (pSTAT3) and IL‐7–induced STAT5 phosphorylation (pSTAT5) in the ex vivo setting as measures for JAK1 and JAK1/JAK3 inhibition, respectively, with comparison to tofacitinib. Drug plasma concentrations and ex vivo IL‐6–induced pSTAT3 and IL‐7–induced pSTAT5 in blood from subjects evaluated in 2 phase 1 studies who received immediate‐release 1 mg to 48 mg upadacitinib, 5 mg twice daily (BID) tofacitinib, or placebo were determined. Exposure‐response models were developed, and the effects of different upadacitinib doses on ex vivo biomarker responses were simulated and compared to tofacitinib. Upadacitinib (and tofacitinib) reversibly inhibited IL‐6–induced pSTAT3 and IL‐7–induced pSTAT5 in a concentration‐dependent manner. Model‐estimated values of 50% of the maximum effect were 60.7 nM for upadacitinib and 119 nM for tofacitinib for IL‐6–induced pSTAT3 inhibition, and 125 nM for upadacitinib and 79.1 nM for tofacitinib for IL‐7–induced pSTAT5 inhibition. Tofacitinib 5 mg BID is estimated to have a similar magnitude of effect on IL‐6–induced pSTAT3 to ∼3 mg BID of upadacitinib (immediate‐release formulation), whereas a 4‐fold higher dose of upadacitinib (∼12 mg BID), is estimated to show a similar magnitude of inhibition on IL‐7–induced pSTAT5 as tofacitinb 5 mg BID. This study confirms that in humans, upadacitinib has greater selectivity for JAK1 vs JAK3 relative to the rheumatoid arthritis approved dose of tofacitinib, and results from these analyses informed the selection of upadacitinib IR doses evaluated in phase 2.