Evaluation of the potential drug interactions mediated through P-gp, OCT2, and MATE1/2K with filgotinib in healthy subjects

Filgotinib, a preferential Janus Kinase-1 inhibitor, is approved in Europe and Japan for treatment of rheumatoid arthritis and is being developed for treatment of other chronic inflammatory diseases. Three drug-drug interactions studies were conducted in healthy subjects to evaluate the effect of P-glycoprotein (P-gp) modulation (study 1: P-gp inhibition by itraconazole and study 2: P-gp induction by rifampin) on filgotinib pharmacokinetics and the potential of filgotinib to impact exposure of metformin, an organic cation transporter (OCT) 2 and multidrug and toxin extrusion (MATE) 1/2K substrate (study 3). Co-administration of filgotinib with itraconazole increased filgotinib exposure (maximum concentration [C_max ] by 64% and area under the curve to infinity [AUC_inf ] by 45%) but had no effect on the exposure of GS-829845, filgotinib's primary metabolite. Rifampin moderately reduced exposures of filgotinib and GS-829845 (C_max by 26% and AUC_inf by 27% for filgotinib; C_max by 19% and AUC_inf by 38% for GS-829845). The data confirmed that filgotinib is a P-gp substrate. However, the magnitude of change in filgotinib/GS-829845 exposure by P-gp modulators is not deemed to be clinically relevant based on filgotinib exposure-response analyses in subjects with rheumatoid arthritis. Filgotinib did not alter metformin exposures, indicating that filgotinib and GS-829845 do not inhibit OCT2 and MATE1/2K at the clinical doses. Filgotinib was generally well-tolerated when administered alone or with the co-administered drugs in the studies. Results from these studies were the basis to enable the use of P-gp modulators and substrates of OCT2, MATE1, and MATE2K with filgotinib without the need for dose modifications in the current approved rheumatoid arthritis population.