Mo1847 - Reactive Dose Escalation of Infliximab in Patients with Crohn's Disease in Tailorix Leads to Improved Outcomes

Background: Papamichael et al. reported short-term mucosal healing (STMH, Mayo endoscopic subscore #1) in 53% of patients with ulcerative colitis (UC) after infliximab (IFX) induction therapy and demonstrated a correlation between IFX trough concentrations (TC) and STMH. 1Aims: To explore opportunities for IFX treatment optimization during induction therapy to avoid primary non-response related to insufficient IFX exposure.Methods: A population pharmacokinetic (popPK) and pharmacodynamic (popPD) model was developed (sequential approach) to describe correlations between IFX exposure (area under the curve, AUC) and the post-induction Mayo endoscopic subscore, using retrospectively collected data from 204 patients with UC during IFX induction therapy. 1 All calculations were done with NONMEM 7.3.The model was recoded in SIMULO to perform simulations.Results: IFX exposure was best described by a 1-compartment popPK model (typical clearance 0.365 L/day & typical volume of distribution 8.1 L).The popPD model was a logistic regression model that described the relation between IFX dose, exposure and the probability of attaining STMH based on ordered transitions (pretreatment versus post-induction) between Mayo endoscopic subscore states 3, 2 and #1.In the best model, cumulative AUC (cAUC) from the first dose up to time of endoscopy was identified as the dominant predictor of STMH (Figure 1).This model predicted a 75% STMH rate when the cAUC w0fi w12 is 4380 µg*day/ mL.Simulations were performed with five different dosing regimens (200 patients each) and rates of STMH and drug expenditure were calculated and compared ( Table 1).Simulation of regimen A confirmed the STMH rate observed in our study population (55%) where most patients indeed received 3x 5 mg/kg, lending credibility to the model.The therapeutic drug monitoring (TDM) based dosing regimens D and E started from a 10 mg/kg dose at w0 for all patients, followed by a dose optimization at w2 and w6 based on an IFX TC