Erwin Dreesen1, Filip Baert2, David Laharie3, Peter Bossuyt4, Yoram Bouhnik5, Anthony Buisson6, Guy Lambrecht7, Edouard Louis8, Bas Oldenburg9, Benjamin Pariente10, Marieke Pierik11, C Janneke van der Woude12, Geert D'Haens13, Séverine Vermeire14, Ann Gils15. 1. Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, University of Leuven, Leuven, Belgium. Electronic address: erwin.dreesen@kuleuven.be. 2. Department of Gastroenterology, AZ Delta, Roeselare, Belgium. 3. Service d'Hépato-gastroentérologie et Oncologie Digestive, Hôpital Haut-Lévêque, Bordeaux, France. 4. Inflammatory Bowel Disease Clinic, Imelda General Hospital, Bonheiden, Belgium. 5. Department of Gastroenterology, Beaujon Hospital, APHP, Paris Diderot University, Clichy, France. 6. Department of Gastroenterology, Estaing University Hospital, Clermont-Ferrand, France. 7. Department of Gastroenterology, AZ Damiaan, Oostende, Belgium. 8. Department of Gastroenterology, Liège University Hospital CHU Liège, Belgium. 9. Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands. 10. Department of Gastroenterology, Huriez Hospital, Lille 2 University, Lille, France. 11. Department of Gastroenterology and Hepatology, University Medical Centre, Maastricht, The Netherlands. 12. Department of Gastroenterology and Hepatology, Erasmus Medical Centre, Rotterdam, The Netherlands. 13. Department of Gastroenterology, Academic Medical Centre, Amsterdam, The Netherlands. 14. Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium. 15. Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, University of Leuven, Leuven, Belgium.
Abstract
BACKGROUND & AIMS: In the TAILORIX trial, no benefit could be shown by infliximab dose escalation based on pharmacokinetic (infliximab serum concentrations) and pharmacodynamic (biomarkers and symptoms) monitoring compared with dose escalation based on symptoms alone in patients with Crohn's disease (CD). We investigated whether integration of pharmacokinetic and pharmacodynamic monitoring can be used to evaluate responses to infliximab induction and maintenance therapy, based on findings from endoscopy. METHODS: We performed a post hoc analysis of patients with CD included in a trial to test the effects of infliximab dose escalation, based on biomarkers and serum concentrations of infliximab, on symptoms (the Study Investigating Tailored Treatment With Infliximab for Active Crohn's Disease trial; n = 122). We analyzed data from this study to determine whether concentrations of biomarkers and serum concentrations of infliximab were associated with endoscopic outcomes (n = 116). The primary end points were endoscopic response (CD endoscopic index of severity decrease ≥50% from baseline), endoscopic remission (CD endoscopic index of severity, <3), and absence of ulcers at weeks 12 and 54 of infliximab treatment. RESULTS: Infliximab trough concentrations greater than 23.1 mg/L at week 2 and greater than 10.0 mg/L at week 6 were associated with endoscopic remission at week 12 (positive predictive values, 72% and 76%; negative predictive values, 65% and 59%, respectively). During maintenance therapy, we found evidence for an exposure-response relationship only after dose escalation; trough concentrations greater than 10.6 mg/L were associated with the absence of ulcers at week 54 (positive predictive value, 49%; negative predictive value, 92%). Low fecal concentrations of calprotectin during therapy were associated with endoscopic response and remission (P < .05). Dose escalations increased trough concentrations of infliximab; persistent increase in fecal concentration of calprotectin, despite dose escalation, was associated with a lack of endoscopic response and remission. A significantly higher proportion of patients with antibodies to infliximab, identified by a drug-tolerant assay, dropped out of the study compared with patients without antibodies (P < .0001). CONCLUSIONS: In a post hoc analysis of data from a trial to test the effects of infliximab dose escalation on symptoms, we found that during maintenance therapy, the combination of fecal concentration of calprotectin and trough concentration of infliximab can guide dose adjustment and increase the chances for endoscopic response and remission. ClinicalTrialsRegister.eu EudraCT no: 2011-003038-14.
BACKGROUND & AIMS: In the TAILORIX trial, no benefit could be shown by infliximab dose escalation based on pharmacokinetic (infliximab serum concentrations) and pharmacodynamic (biomarkers and symptoms) monitoring compared with dose escalation based on symptoms alone in patients with Crohn's disease (CD). We investigated whether integration of pharmacokinetic and pharmacodynamic monitoring can be used to evaluate responses to infliximab induction and maintenance therapy, based on findings from endoscopy. METHODS: We performed a post hoc analysis of patients with CD included in a trial to test the effects of infliximab dose escalation, based on biomarkers and serum concentrations of infliximab, on symptoms (the Study Investigating Tailored Treatment With Infliximab for Active Crohn's Disease trial; n = 122). We analyzed data from this study to determine whether concentrations of biomarkers and serum concentrations of infliximab were associated with endoscopic outcomes (n = 116). The primary end points were endoscopic response (CD endoscopic index of severity decrease ≥50% from baseline), endoscopic remission (CD endoscopic index of severity, <3), and absence of ulcers at weeks 12 and 54 of infliximab treatment. RESULTS: Infliximab trough concentrations greater than 23.1 mg/L at week 2 and greater than 10.0 mg/L at week 6 were associated with endoscopic remission at week 12 (positive predictive values, 72% and 76%; negative predictive values, 65% and 59%, respectively). During maintenance therapy, we found evidence for an exposure-response relationship only after dose escalation; trough concentrations greater than 10.6 mg/L were associated with the absence of ulcers at week 54 (positive predictive value, 49%; negative predictive value, 92%). Low fecal concentrations of calprotectin during therapy were associated with endoscopic response and remission (P < .05). Dose escalations increased trough concentrations of infliximab; persistent increase in fecal concentration of calprotectin, despite dose escalation, was associated with a lack of endoscopic response and remission. A significantly higher proportion of patients with antibodies to infliximab, identified by a drug-tolerant assay, dropped out of the study compared with patients without antibodies (P < .0001). CONCLUSIONS: In a post hoc analysis of data from a trial to test the effects of infliximab dose escalation on symptoms, we found that during maintenance therapy, the combination of fecal concentration of calprotectin and trough concentration of infliximab can guide dose adjustment and increase the chances for endoscopic response and remission. ClinicalTrialsRegister.eu EudraCT no: 2011-003038-14.
Authors: Konstantinos Papamichael; Niels Vande Casteele; Jenny Jeyarajah; Vipul Jairath; Mark T Osterman; Adam S Cheifetz Journal: Am J Gastroenterol Date: 2021-05-01 Impact factor: 12.045
Authors: Ruben J Colman; Yi-Ting Tsai; Kimberly Jackson; Brendan M Boyle; Joshua D Noe; Jeffrey S Hyams; Geert R A M D'Haens; Johan van Limbergen; Michael J Rosen; Lee A Denson; Phillip Minar Journal: Inflamm Bowel Dis Date: 2021-06-15 Impact factor: 7.290