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

Abstract

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; 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). Coadministration of filgotinib with itraconazole increased filgotinib exposure (C max by 64% and 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 24% for filgotinib; C max by 19% and AUC inf by 38% for GS-829845). The data confirmed filgotinib to be a P-gp substrate. However, the magnitude of change in filgotinib/GS-829845 exposure by P-gp modulators was not deemed clinically relevant based on filgotinib exposureresponse analyses in subjects with rheumatoid arthritis. Filgotinib did not alter metformin exposures, indicating 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 coadministered 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 modification in the current approved rheumatoid arthritis population.

Filgotinib: A Clinical Pharmacology Review

“…3 a, b). Itraconazole increased the combined AUC eff of filgotinib and its primary metabolite by 21%, so no dose adjustment of filgotinib was deemed necessary [ 31 ]. The effect of the P-gp inducer rifampin (600 mg QD) on the pharmacokinetics of filgotinib (200 mg single dose) in healthy subjects was also evaluated.…”

“…With coadministration, filgotinib AUC ∞ and C max were reduced by 27% and 26%, respectively, and the primary metabolite AUC ∞ and C max were reduced by 38% and 19%, respectively (Fig. 3 a, b) [ 31 ]. The combined AUC eff was reduced by 33%.…”

“…Metformin percentage GLSM ratios and associated 90% CIs for AUC ∞ and C max were not altered by coadministration of filgotinib (Fig. 4 ), meaning that filgotinib dose adjustment with concomitant use of metformin and other OCT2 and MATE transporter substrates was deemed unnecessary [ 31 ].…”

“…Filgotinib pharmacokinetics appear to be similar between healthy subjects and patients with RA [ 10 , 13 ] or UC [ 17 ], and intrinsic factors such as age, mild renal impairment, and mild-to-moderate hepatic impairment have either no or minimal impact on the pharmacokinetics of filgotinib and its primary metabolite [ 23 , 26 , 29 ]. Filgotinib has a low drug–drug interaction potential, without clinically significant interactions with commonly administered comedications, including methotrexate; oral contraceptives and other CYP3A4 substrates; statins; and acid-reducing agents, such as proton pump inhibitors and histamine antagonists [ 21 , 24 , 31 , 32 , 35 ]. No dose adjustment is required when filgotinib is coadministered with other drugs [ 10 , 24 ].…”

“…No dose adjustment is required when filgotinib is coadministered with other drugs [ 10 , 24 ]. Both filgotinib and its primary metabolite are substrates of P-gp; however, coadministration with P-gp inhibitors or inducers does not affect filgotinib pharmacokinetics sufficiently to warrant dose adjustment [ 31 ]. Neither filgotinib nor its primary metabolite have shown an effect on QTcF interval [ 20 ].…”