In the multicentre, randomised, controlled TAILORIX trial, it was not possible to show a benefit of infliximab dose escalation based on a combination of pharmacokinetic monitoring (i.e. serum concentrations of infliximab) and pharmacodynamic monitoring (i.e. symptoms and biomarker) as compared to dose escalation based on symptoms alone . However, infliximab dose escalations only commenced after the induction regimen. In the current post hoc pharmacokinetic–pharmacodynamic analysis of TAILORIX, we examined the roles of pharmacokinetic and pharmacodynamic monitoring during infliximab induction and maintenance therapy for targeting endoscopic outcomes .
Serum concentrations of infliximab at trough >23.1 mg/l at week 2 and >10.0 mg/l at week 6 predicted endoscopic remission (i.e. Crohn’s Disease Endoscopic Index of Severity <3) at week 12. During maintenance therapy, an exposure–response relationship was observed only after dose escalation, with a serum concentration of infliximab at trough >10.8 mg/l predicting absence of ulceration at week 54. However, this exposure–response relationship was only observed after three infusions at the elevated dose. Therefore, we conclude that infliximab trough concentrations early upon dose escalation are not informative in predicting endoscopic outcomes. In addition, we conclude that higher infliximab trough concentrations may need to be targeted for achievement of endoscopic outcomes as compared to clinical outcomes . As a consequence, the infliximab trough concentration target of 3.0 mg/l used in TAILORIX was too low to achieve the primary endpoint, which included absence of ulceration.
In addition, we validated the use of the faecal concentration of calprotectin as a reliable biomarker predicting endoscopic improvement . Already from week 2 onwards, faecal concentrations of calprotectin were predictive of endoscopic healing and this association persisted throughout the infliximab treatment. In patients with elevated calprotectin concentrations (>250 mg/kg) just before dose escalation, a significant drop was observed immediately upon dose escalation, resulting in significantly lower calprotectin concentrations in patients who achieved absence of ulceration as compared with patients who did not achieve absence of ulceration (p=0.033).
Based on these findings, we conclude that there is a role for monitoring of serum concentrations of infliximab at week 2 and week 6 during induction therapy. During maintenance therapy, we recommend dose escalation based on faecal concentrations of calprotectin. Normalisation of the calprotectin concentration upon dose escalation predicts absence of ulceration. When the calprotectin concentration does not normalise, the serum concentration of infliximab at trough may provide information on the mechanism of failure (pharmacokinetic versus pharmacodynamic failure). Therefore, we recommend a tiered approach for monitoring of faecal concentrations of calprotectin (pharmacodynamic monitoring) and serum concentrations of infliximab at trough (pharmacokinetic monitoring) during maintenance therapy. Nevertheless, future prospective trials are needed to evaluate this proposed therapeutic drug monitoring approach.
Erwin Dreesen at ECCO'19 © ECCO