David Ternant1,2,3,4, Marc Pfister5, Olivier Le Tilly6,7, Denis Mulleman8,9, Laurence Picon10, Stéphanie Willot11, Christophe Passot12, Theodora Bejan-Angoulvant6,7, Thierry Lecomte8,10, Gilles Paintaud6,7, Gilbert Koch5. 1. Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland. david.ternant@univ-tours.fr. 2. EA 4245 'Transplantation, Immunology, Inflammation', Université de Tours, Tours, France. david.ternant@univ-tours.fr. 3. Department of Clinical Pharmacology, CHRU de Tours, Tours, France. david.ternant@univ-tours.fr. 4. Laboratoire de Pharmacologie-Toxicologie, CHU de Tours, 2 boulevard Tonnellé, 37044, Tours Cedex, France. david.ternant@univ-tours.fr. 5. Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland. 6. EA 4245 'Transplantation, Immunology, Inflammation', Université de Tours, Tours, France. 7. Department of Clinical Pharmacology, CHRU de Tours, Tours, France. 8. EA 7501 'Groupe Innovation et Ciblage Cellulaire', Université de Tours, Tours, France. 9. Department of Rheumatology, CHRU de Tours, Tours, France. 10. Department of Gastroenterology, CHRU de Tours, Tours, France. 11. Department of Paediatrics, CHRU de Tours, Tours, France. 12. Département de Biopathologie, Institut de Cancérologie de l'Ouest, Angers, France.
Abstract
BACKGROUND AND OBJECTIVE: Infliximab, an anti-tumour necrosis factor (TNF)-α monoclonal antibody, has been approved in chronic inflammatory disease, including rheumatoid arthritis, Crohn's disease and ankylosing spondylitis. This study aimed to investigate and characterise target-mediated drug disposition of infliximab and antigen mass turnover during infliximab treatment. METHODS: In this retrospective cohort of 186 patients treated with infliximab for rheumatoid arthritis, Crohn's disease or ankylosing spondylitis, trough infliximab concentrations were determined from samples collected between weeks 0 and 22 after treatment initiation. Target-mediated pharmacokinetics of infliximab was described using target-mediated drug disposition modelling. Target-mediated elimination parameters were determined for rheumatoid arthritis and Crohn's disease, assuming ankylosing spondylitis with no target-mediated elimination. RESULTS: The quasi-equilibrium approximation of a target-mediated drug disposition model allowed a satisfactory description of infliximab concentration-time data. Estimated baseline TNF-α amounts were similar in Crohn's disease and rheumatoid arthritis (R0 = 0.39 vs 0.46 nM, respectively), but infliximab-TNF complex elimination was slower in Crohn's disease than in rheumatoid arthritis (kint = 0.024 vs 0.061 day-1, respectively). Terminal elimination half-lives were 13.5, 21.5 and 16.5 days for rheumatoid arthritis, Crohn's disease and ankylosing spondylitis, respectively. Estimated amounts of free target were close to baseline values before the next infusion suggesting that TNF-α inhibition may not be sustained over the entire dose interval. CONCLUSIONS: The present study is the first to quantify the influence of target antigen dynamics on infliximab pharmacokinetics. Target-mediated elimination of infliximab may be complex, involving a multi-scale turnover of TNF-α, especially in patients with Crohn's disease. Additional clinical studies are warranted to further evaluate and fine-tune dosing approaches to ensure sustained TNF-α inhibition.
BACKGROUND AND OBJECTIVE: Infliximab, an anti-tumour necrosis factor (TNF)-α monoclonal antibody, has been approved in chronic inflammatory disease, including rheumatoid arthritis, Crohn's disease and ankylosing spondylitis. This study aimed to investigate and characterise target-mediated drug disposition of infliximab and antigen mass turnover during infliximab treatment. METHODS: In this retrospective cohort of 186 patients treated with infliximab for rheumatoid arthritis, Crohn's disease or ankylosing spondylitis, trough infliximab concentrations were determined from samples collected between weeks 0 and 22 after treatment initiation. Target-mediated pharmacokinetics of infliximab was described using target-mediated drug disposition modelling. Target-mediated elimination parameters were determined for rheumatoid arthritis and Crohn's disease, assuming ankylosing spondylitis with no target-mediated elimination. RESULTS: The quasi-equilibrium approximation of a target-mediated drug disposition model allowed a satisfactory description of infliximab concentration-time data. Estimated baseline TNF-α amounts were similar in Crohn's disease and rheumatoid arthritis (R0 = 0.39 vs 0.46 nM, respectively), but infliximab-TNF complex elimination was slower in Crohn's disease than in rheumatoid arthritis (kint = 0.024 vs 0.061 day-1, respectively). Terminal elimination half-lives were 13.5, 21.5 and 16.5 days for rheumatoid arthritis, Crohn's disease and ankylosing spondylitis, respectively. Estimated amounts of free target were close to baseline values before the next infusion suggesting that TNF-α inhibition may not be sustained over the entire dose interval. CONCLUSIONS: The present study is the first to quantify the influence of target antigen dynamics on infliximab pharmacokinetics. Target-mediated elimination of infliximab may be complex, involving a multi-scale turnover of TNF-α, especially in patients with Crohn's disease. Additional clinical studies are warranted to further evaluate and fine-tune dosing approaches to ensure sustained TNF-α inhibition.