Publications

Different JAKinibs modulated distinct cytokine pathways to varying degrees, and no agent potently or continuously inhibited an individual cytokine signalling pathway throughout the dosing interval. This study aimed to compare the in vitro cellular pharmacology of BARI, TOF and UPA across relevant leukocyte subpopulations, coupled with their in vivo PK, to determine their effects on distinct cytokine pathways. Peripheral blood mononuclear cells from healthy donors were incubated with different JAKinibs. Levels of phosphorylated signal transducer and activator of transcription were measured following cytokine stimulation, and IC50 values were calculated in phenotypically gated leukocyte subpopulations. The most potent inhibitors of JAK1/3 dependent cytokines (IL-2, 4, 15 and 21) were UPA and TOF, whereas BARI was the least potent. UPA also proved the most potent inhibitor of IL-3 and GM-CSF (JAK2/2), followed by BARI and TOF. However, TOF was the most potent inhibitor of G-CSF (JAK2/TYK2), followed by UPA and BARI. All JAKinibs tested inhibited JAK1/2, JAK1/TYK2, JAK2/2, and JAK2/TYK2 dependent cytokines, but mostly to significantly differing degrees. Different JAKinibs demonstrated different in vitro and in vivo pharmacologic and PK profiles, suggesting that they may work via modulating differing cytokine pathways to varying degrees. No JAKinibs studied completely or continuously inhibited an individual cytokine signalling pathway over the dosing interval. These observations may have implications for the efficacy and safety profiles observed with different JAKinibs across different disease states. These findings may inform JAKinib development tailored to capitalize on the most clinically beneficial pharmacological features that will emerge as several agents are established in clinical practice.