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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

Mohamed MF, Beck D, Camp HS, Othman AA. - Pharmacodynamics. 2020

Ex vivo pharmacodynamic assay results demonstrated a greater selectivity of UPA on JAK1 versus JAK3 compared to TOF.

This analysis conducted ex vivo stimulation of STAT3 phosphorylation by IL-6 as a measure of JAK1 activity and STAT5 phosphorylation by IL-7 as a measure of JAK1/JAK3 activity. Change in pSTAT3 and pSTAT5 were calculated at 1, 6 and 12 hours following drug administration using samples collected from healthy subjects and subjects with RA, from 2 phase 1 studies. Exposure-response models were built using pharmacokinetic parameters to simulate effects of UPA 1 - 48 mg (immediate-release), TOF 5 mg or PBO on IL6-induced pSTAT3 and IL7-induced pSTAT5.

UPA demonstrated reversible and concentration-dependent inhibition of pSTAT3 and pSTAT5 in both healthy subjects and subjects with RA. Agreeing with in vitro results, the ex vivo pharmacodynamic assay showed a greater selectivity of UPA on JAK1 versus JAK3 compared to TOF. UPA 3 mg BID is estimated to have a similar magnitude of effect on pSTAT3 to TOF 5 mg BID, whereas a 4-fold higher dose of UPA 12 mg BID is estimated to show a similar magnitude of inhibition on pSTAT5 as TOF 5 mg BID. This also suggested that UPA doses >12 mg BID begin to lose JAK1 selectivity. The analyses were limited by the small number of subjects with RA included in the analyses.

Keywords: JAK, Upadacitinib, Preclinical, MOA

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Upload date: February 2020

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