OBJECTIVE: The selective Janus kinase 1 inhibitor filgotinib (GLPG0634), which 
is currently in clinical development for the treatment of rheumatoid arthritis 
(RA) and Crohn's disease, demonstrated encouraging safety and efficacy profiles 
in RA patients after 4 weeks of daily dosing. As RA patients might be treated 
with multiple medications simultaneously, possible drug-drug interactions of 
filgotinib with cytochrome P450 enzymes and with key drug transporters were 
evaluated in vitro and in clinical studies.
METHODS: The enzymes involved in filgotinib's metabolism and the potential 
interactions of the parent and its active major metabolite with 
drug-metabolizing enzymes and drug transporters, were identified using 
recombinant enzymes, human microsomes, and cell systems. Furthermore, 
filgotinib's interaction potential with CYP3A4 was examined in an open-label 
study in healthy volunteers, which evaluated the impact of filgotinib 
co-administration on the CYP3A4-sensitive substrate midazolam. The potential 
interaction with the common RA drug methotrexate was investigated in a clinical 
study in RA patients.
RESULTS: In vitro, filgotinib and its active metabolite at clinically relevant 
concentrations did not interact with cytochrome P450 enzymes and uridine 
5'-diphospho-glucuronosyltransferases, and did not inhibit key drug 
transporters. In the clinic, a lack of relevant pharmacokinetic drug 
interactions by filgotinib and its active metabolite with substrates of CYP3A4, 
as well as with organic anion transporters involved in methotrexate elimination 
were found.
CONCLUSION: the collective in vivo and in vitro data on drug-metabolizing 
enzymes and on key drug transporters, support co-administration of filgotinib 
with commonly used RA drugs to patients without the need for dose adjustments.