Florence Namour*, Julie Desrivot, Annegret Van der Aa, Pille Harrison, Chantal Tasset and Gerben van`t Klooster Pages 38 - 48 ( 11 )
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.
Carboxylesterases, CYP450, drug-drug interaction, drug transporters, filgotinib, selective JAK1.
Galapagos SASU, 102 avenue Gaston Roussel, 93230 Romainville, Galapagos SASU, 102 avenue Gaston Roussel, 93230 Romainville, Galapagos NV, Generaal de Wittelaan L11 A3, 2800 Mechelen, Galapagos NV, Generaal de Wittelaan L11 A3, 2800 Mechelen, Galapagos NV, Generaal de Wittelaan L11 A3, 2800 Mechelen, Galapagos NV, Generaal de Wittelaan L11 A3, 2800 Mechelen