Application of Physiologically-Based Pharmacokinetic Modeling for the Prediction of Tofacitinib Exposure in Japanese.

Tofacitinib (3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3 -oxopropanenitrile) is an oral Janus kinase inhibitor that is approved in countries including Japan and the United States for the treatment of rheumatoid arthritis, and is being developed across the globe for the treatment of inflammatory diseases. In the present study, a physiologically-based pharmacokinetic model was applied to compare the pharmacokinetics of tofacitinib in Japanese and Caucasians to assess the potential impact of ethnicity on the dosing regimen in the two populations. Simulated plasma concentration profiles and pharmacokinetic parameters, i.e. maximum concentration and area under plasma concentration-time curve, in Japanese and Caucasian populations after single or multiple doses of 1 to 30 mg tofacitinib were in agreement with clinically observed data. The similarity in simulated exposure between Japanese and Caucasian populations supports the currently approved dosing regimen in Japan and the United States, where there is no recommendation for dose adjustment according to race. Simulated results for single (1 to 100 mg) or multiple doses (5 mg twice daily) of tofacitinib in extensive and poor metabolizers of CYP2C19, an enzyme which has been shown to contribute in part to tofacitinib elimination and is known to exhibit higher frequency in Japanese compared to Caucasians, were also in support of no recommendation for dose adjustment in CYP2C19 poor metabolizers. This study demonstrated a successful application of physiologically-based pharmacokinetic modeling in evaluating ethnic sensitivity in pharmacokinetics at early stages of development, presenting its potential value as an efficient and scientific method for optimal dose setting in the Japanese population.