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DOP047 Infliximab exposure predicts superior endoscopic outcomes in patients with active Crohn’s disease: pharmacokinetic–pharmacodynamic analysis of TAILORIX

E. Dreesen1*, G. D'Haens2, F. Baert3, B. Pariente4, Y. Bouhnik5, J. vander Woude6, J. Moreau7, D. Laharie8, S. Vermeire9,10, A. Gils1

1KU Leuven, Departement of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium, 2Academic Medical Centre, Amsterdam, The Netherlands, 3AZ Delta, Roeselare, Belgium, 4Hospital Claude Huriez, Lille, France, 5Hospital Beaujon, Clichy, France, 6Erasmus MC, Rotterdam, The Netherlands, 7CHU, Toulouse, Belgium, 8Hospital Haut-Lévêque, Bordeaux, France, 9University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium, 10KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Leuven, Belgium

Background

In the TAILORIX study, “proactive” dose escalation based on infliximab (IFX) serum concentrations (TDM groups) had no added value to “reactive” dose escalation based on symptoms (TDM groups and control group).1 In patients randomised to TDM groups, reactive dose escalation was only allowed in the presence of elevated serum CRP (>5 mg/l) and/or faecal calprotectin (FC, >250 μg/g). We explored the value of pharmacokinetic (PK) and pharmacodynamic (PD) monitoring of IFX therapy in patients with Crohn’s disease (CD) in TAILORIX.

Methods

We studied associations between PK markers (IFX concentrations), PD markers (CD activity index or CDAI, CRP and FC) and the endoscopic remission (CD endoscopic index of severity, CDEIS <3), using prospectively collected data from 122 patients with CD in TAILORIX.

Results

During induction therapy, IFX trough concentrations (TC) were significantly higher in patients achieving endoscopic remission by w12 compared with patients who did not (Table 1). An IFX TC ≥23.1 μg/ml at w2 and ≥10.0 μg/ml at w6 predicted endoscopic remission by w12 (p = 0.002 and p = 0.013) (Figure 1). Also, FC ≤250 μg/g at w2 and w6 was associated with 69% and 68% endoscopic remission by w12, while only 44% and 26% of the patients with FC >250 μg/g demonstrated endoscopic remission by w12 (p = 0.021 and p = 0.0002). During maintenance therapy, FC was significantly lower in patients achieving endoscopic remission by w54 (p < 0.0001). Using classification tree analysis, endoscopic remission at w12 and w54 was found to be best predicted by FC. Overall, the strongest PK-PD correlation was found between IFX concentrations and FC at the same time point. IFX concentrations were significantly higher when FC was ≤250 μg/g (p < 0.0001). Out of 43 dose escalation opportunities based on CDAI in the TDM groups, 23 (53%) were avoided per protocol as biomarkers were not elevated. This additional biomarker criterion did not apply to the control group, where normal CRP and/or FC was observed in nine out of 15 (60%) of the CDAI based dose escalation events.

Table 1. Summary statistics of PK and PD markers during IFX induction therapy for patients with CD achieving endoscopic remission by week 12 or not. Differences were evaluated using the Mann–Whitney U test.

Endoscopic remission at week 12 (n = 52)No endoscopic remission at week 12 (n = 54)P valueWeek 2: IFX26.5 [23.8–34.9] μg/ml22.5 [17.8–27.9] μg/ml0.002Week 2: CDAI159 [109–215]194 [145–241]0.056Week 2: FC218 [100–716] μg/g768 [171–1729] μg/g0.001Week 2: CRP2 [1–6] mg/l3 [2–6] mg/l0.079Week 6: IFX19.4 [14.8–26.3] μg/ml15.6 [8.5–21.3] μg/ml0.013Week 6: CDAI122 [72–198]138 [73–186]0.455Week 6: FC116 [100–289] μg/g447 [194–934] μg/g<0.0001Week 6: CRP1 [1–4] mg/l3 [1–7] mg/l0.123

Figure 1. Flow-diagram of study inclusion.

Figure 1. Receiver operating characteristic (ROC) curves of infliximab trough concentrations at (A) week 2 and (B) week 6 as a predictor of endoscopic remission at week 12. se: sensitivity; sp: specificity; AUROC: area under the ROC curve.

Conclusion

In TAILORIX, a clear exposure-response relation was observed during IFX induction therapy. The additional value of IFX concentration-based dose escalation during maintenance therapy might be blurred due to CDAI based dose escalations that increased the background IFX exposure and response.

Reference

1.D'Haens G, Vermeire S, Lambrecht G, et al. 692 Drug-level based dosing versus symptom-based dose adaptation in patients with Crohn's disease: a prospective, randomised multicenter study (TAILORIX). Gastroenterology, 2016:S143, http://www.gastrojournal.org/article/S0016-5085(16)30583-2/abstract.