Clinical Confirmation that the Selective JAK1 Inhibitor Filgotinib (GLPG0634) has a Low Liability for Drug-drug Interactions

• Published in: Drug metabolism letters Vol. 10; no. 1; p. 38
• Main Authors: Namour, Florence, Desrivot, Julie, Van der Aa, Annegret, Harrison, Pille, Tasset, Chantal, van't Klooster, Gerben
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 2016
• Subjects: Adult; Animals; Antirheumatic Agents - administration & dosage; Antirheumatic Agents - adverse effects; Antirheumatic Agents - pharmacokinetics; Biotransformation; CHO Cells; Cricetulus; Cytochrome P-450 CYP3A - metabolism; Cytochrome P-450 Enzyme Inhibitors - pharmacology; Drug Interactions; Glucuronosyltransferase - metabolism; Humans; Janus Kinase 1 - antagonists & inhibitors; Janus Kinase 1 - metabolism; Male; Membrane Transport Proteins - drug effects; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Methotrexate - administration & dosage; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Midazolam - metabolism; Middle Aged; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Pyridines - administration & dosage; Pyridines - adverse effects; Pyridines - pharmacokinetics; Recombinant Proteins - metabolism; Risk Assessment; Substrate Specificity; Transfection; Triazoles - administration & dosage; Triazoles - adverse effects; Triazoles - pharmacokinetics
• ISSN: 1874-0758

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. 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. 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. 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.