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OP25 Targeting endoscopic outcomes through combined pharmacokinetic and pharmacodynamic monitoring of infliximab therapy in patients with Crohn’s disease

E. Dreesen*1, F. Baert2, D. Laharie3, P. Bossuyt4, Y. Bouhnik5, A. Buisson6, G. Lambrecht7, E. Louis8, B. Oldenburg9, B. Pariente10, M. Pierik11, C. J. van der Woude12, G. D’Haens13, S. Vermeire14,15, A. Gils1

1University of Leuven, Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium, 2AZ Delta, Department of Gastroenterology, Roeselare, Belgium, 3Hôpital Haut-Lévêque, Service d’Hépato-gastroentérologie et Oncologie Digestive, Bordeaux, France, 4Imelda General Hospital, IBD Clinic, Bonheiden, Belgium, 5Beaujon Hospital, APHP, Paris Diderot University, Department of Gastroenterology, Clichy, France, 6Estaing University Hospital, Department of Gastroenterology, Clermont-Ferrand, France, 7AZ Damiaan, Department of Gastroenterology, Oostende, Belgium, 8Liège University Hospital, Department of Gastroenterology, Liège, Belgium, 9University Medical Centre, Department of Gastroenterology and Hepatology, Utrecht, The Netherlands, 10Huriez Hospital, Lille 2 University, Department of Gastroenterology and Hepatology, Lille, France, 11University Medical Centre, Department of Gastroenterology and Hepatology, Maastricht, The Netherlands, 12Erasmus Medical Centre, Department of Gastroenterology and Hepatology, Rotterdam, The Netherlands, 13Academic Medical Centre, Department of Gastroenterology, Amsterdam, The Netherlands, 14University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium, 15University of Leuven, Department of Chronic Diseases, Metabolism and Ageing, Leuven, Belgium

Background

In TAILORIX, infliximab (IFX) trough concentrations (TC) >23.1 mg/l at Week 2 and >10.0 mg/l at Week 6 predicted endoscopic remission (Crohn’s disease (CD) endoscopic index of severity <3) at Week 12.1 During maintenance therapy, no exposure–response relation was observed, but faecal calprotectin (FC) was lower in patients achieving the endoscopic outcomes compared with patients who did not.1

Methods

A two-compartment population PK (popPK) model was developed based on data from 1329 samples from 116 patients in TAILORIX (NONMEM 7.4).2

Results

In line with the previously observed higher IFX TC,1 also the estimated IFX clearance (CL) during induction therapy was lower in patients achieving endoscopic remission at Week 12 (−0.067 ± 0.020 l/day, p = 0.001), but this was not observed during maintenance therapy (P > 0.05). During maintenance therapy, an exposure–response relationship was observed only after dose escalation, with a TC >10.8 mg/l after dose escalation predicting the absence of ulcers at Week 54 (Figure 1A). However, this exposure–response relation only appeared after three infusions at the elevated dose (Figure 1B). Furthermore, in patients with elevated FC (>250 mg/kg), a significant drop was observed right upon dose escalation, resulting in FC concentrations that were lower in patients without ulcers compared with patients with ulcers (p = 0.033) (Figure 1C). Antibodies to IFX (ATI), measured using a drug-tolerant assay, increased IFX CL with ~48%, resulting in a reduction of the terminal half-life from 9.4 to 6.4 days (Table 1). Even when dose escalations masked the detection of ATI, the popPK model still estimated an effect of ATI on IFX CL. In addition, IFX exposure reduced when albumin was lower and FC and fat-free mass were higher.

Conclusion

We recommend proactive and reactive monitoring of FC during IFX maintenance therapy, but when FC does not normalise upon dose escalation, the IFX TC provides information on the mechanism of failure and can thus guide clinical decision-making (Figure 2). Future prospective trials are needed to evaluate this proposed TDM algorithm.

Abstract OP025

(A) Density plot and ROC curve and (B) boxplots representing the relation between IFX TC after dose escalation and the absence/presence of ulcers at Week 54. (C) The difference in FC upon dose escalation (T1) between patients with/without ulcers at Week 54.

ParameterEstimate% relative standard errorInterindividual variability (%)Interoccasion variability (%)Bootstrap estimateBootstrap 95% confidence intervalBootstrap deviation (%)
Clearance (CL), l/day0.2793.827.712.00.278[0.257 to 0.300]−0.36
Antibodies to infliximab on CL0.47518.30.477[0.297 to 0.648]+0.42
Albumin on CL−0.76630.9−0.798[−1.323 to −0.439]−4.18
Faecal calprotectin on CL0.055424.40.0553[0.0280 to 0.0813]−0.18
Fat-free mass on CL0.39130.20.396[0.138 to 0.615]+1.28
Volume of distribution in the central compartment (Vc), l3.797.018.23.76[3.26 to 4.18]−0.79
Volume of distribution in the peripheral compartment (Vp), l1.145.71.14[1.06 to 1.21]0.00
Intercompartmental clearance (Q), l/day0.1567.90.157[0.143 to 0.169]+0.64

Parameter estimates from the final population pharmacokinetic model for infliximab (extract).

Abstract OP025

Algorithm implementing proactive PD monitoring (left) and a tiered approach for reactive PD and PK monitoring (right) during infliximab maintenance therapy.

References

1. Dreesen E, D’Haens G, Baert F, et al. DOP047 infliximab exposure predicts superior endoscopic outcomes in patients with active Crohn’s disease: pharmacokinetic–pharmacodynamic analysis of TAILORIX, ECCO, 2018. https://www.ecco-ibd.eu/publications/congress-abstract-s/abstracts-2018/item/dop047-infliximab-exposure-predicts-superior-endoscopic-outcomes-in-patients-with-active-crohn-x2019-s-disease-pharmacokinetic-x2013-pharmacodynamic-analysis-of-tailorix.html

2. D’Haens G, Vermeire S, Lambrecht G, et al. Increasing infliximab dose based on symptoms, biomarkers, and serum drug concentrations does not increase clinical, endoscopic, and corticosteroid-free remission in patients with active luminal Crohn’s disease. Gastroenterology 2018;154:1343–1351.e1.