Dosing Time-Dependent Anti-arthritic Effects of Peficitinib in Collagen-Induced Arthritis Rats

We previously reported that stronger therapeutic effects were observed in rheumatoid arthritis (RA) patients and RA model animals when the dosing times of methotrexate (MTX) and tacrolimus were selected according to the circadian rhythms of the inflammatory response and cytokine levels. Peficitinib is a Janus kinase inhibitor that is used to treat RA in the same manner as MTX and tacrolimus. The present study investigated whether the dosing time-dependent therapeutic effects of peficitinib were detectable in collagen-induced arthritis rats. Peficitinib was given perorally once a day at 5:00 or 17:00 for 4 weeks on the day after the first immunization, and dose-dependent inhibitory effects on the progression of arthritis were observed. Anti-arthritic effects were significantly stronger in the 5:00-treated group than in the 17:00-treated group. Arthritis scores were markedly lower in the 5:00-treated group than in the control and 17:00-treated groups when the agent was administered after the onset of arthritis. To estimate pharmacokinetics, the blood concentrations of peficitinib were measured. Plasma levels were higher in the 5:00-treated group than in the 17:00-treated group, and the area under the curve_0→12h was 1.24-fold higher in the 5:00-treated group. These results suggest that improvements in the therapeutic index of RA therapy are achievable by administering peficitinib at a time of day when the inflammatory reaction begins to activate, cytokine levels start to increase, and blood concentrations become higher.