P501 Relationship between measures of infliximab exposure and clinical outcome of infliximab intensification at therapeutic failure in Crohn's disease
C. Steenholdt*1, H. Edlund2, 3, M.A. Ainsworth1, J. Brynskov1, O.Ø. Thomsen1, W. Huisinga4, C. Kloft2
1Herlev Hospital, Dept of Gastroenterology, Herlev, Denmark, 2Freie Universitaet Berlin, Dept. of Clinical Pharmacy and Biochemistry, Berlin, Germany, 3Freie Universitaet Berlin, Graduate Research Training Program PharMetrX, Berlin, Germany, 4Universitaet Potsdam, Institute of Mathematics, Potsdam, Germany
It is recommended to intensify the infliximab (IFX) regimen in case of flare of Crohn's disease during ongoing IFX maintenance therapy, as it is assumed that drug exposure often is insufficient in this situation. The relationship between drug exposure and clinical outcome has thus far primarily been assessed using the serum IFX concentration obtained immediately prior to the next IFX administration (Ctrough). This study explored if alternative pharmacokinetic (PK) measures provide additional information and more accurately link IFX exposure with clinical outcomes.
Post-hoc analysis of randomized controlled trial which included 69 Crohn's disease patients with symptomatic IFX treatment failure (CDAI ≥220 or ≥1 draining perianal fistula).(1) Patients who had received an intensified IFX regimen with infusions every 4-6 weeks throughout the 20-week study period were included in the present study (n=30). Clinical outcome assessed by CDAI was evaluated at all study visits (weeks 0, 4, 8, 12, and 20). Individual PK parameters were estimated using a predefined population PK model (2) combined with each patient's IFX dosing regimen and Ctrough determined by radioimmunoassay at time of manifestation of IFX treatment failure.(1) Based on these parameters, complete concentration-time profiles were simulated. NCT00851565.
In this cohort, no overall association was observed between different PK measures of IFX exposure and clinical outcomes. Assessed models comprised: (a) IFX concentration at time of CDAI evaluation, area under the drug concentration-time curve (AUC) of the 1-3 preceding dosing intervals, and cumulated AUC (cAUC) during IFX intensification linked to CDAI; (b) cAUC between CDAI measurements linked to change in CDAI; (c) cAUC during IFX intensification linked to CDAI change from baseline; (d) AUC of prior IFX maintenance therapy linked to baseline CDAI. However, when patients were stratified according to clinical response type (i.e. response vs. response followed by relapse vs. no response), notable trends in most models indicated that increased IFX exposure associates with lowered disease activity in the subgroup of patients with clinical response.
Clinical outcome of applying an intensified IFX regimen at therapeutic failure only relates to increased IFX exposure in a subgroup of patients. This observation supports that pharmacodynamic mechanisms, with a shift to a non-TNF driven disease phenotype, often play a role in IFX treatment failure. Introduction of biologic drugs with different therapeutic targets may prove a favorable alternative to switching between TNF-inhibitors in selected subgroups.
(1) Steenholdt et al. Gut (2014)
(2) Fasanmade et al. Clin Ther (2011)