title: Clinical Confirmation that the Selective JAK1 Inhibitor Filgotinib (GLPG0634) has a Low Liability for Drug-drug Interactions.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Galapagos SASU, 102 avenue Gaston Roussel, 93230 Romainville, France. florence.namour@glpg.com.
authors.forename: Florence
authors.initials: F
authors.lastname: Namour
authors.forename: Julie
authors.initials: J
authors.lastname: Desrivot
authors.forename: Annegret
authors.initials: A
authors.lastname: Van der Aa
authors.forename: Pille
authors.initials: P
authors.lastname: Harrison
authors.forename: Chantal
authors.initials: C
authors.lastname: Tasset
authors.forename: Gerben
authors.initials: G
authors.lastname: van't Klooster
mesh_terms: D000328:Adult; D000818:Animals; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001711:Biotransformation; D016466:CHO Cells; D003412:Cricetulus; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008727:Methotrexate / Q000008:administration & dosage; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008874:Midazolam / Q000378:metabolism; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011994:Recombinant Proteins / Q000378:metabolism; D018570:Risk Assessment; D013379:Substrate Specificity; D014162:Transfection; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D018501:Antirheumatic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; C584571:GLPG0634; D026901:Membrane Transport Proteins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011994:Recombinant Proteins; D014230:Triazoles; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D014453:Glucuronosyltransferase; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D008874:Midazolam; D008727:Methotrexate