Treatment Targets Should Influence Choice of Infliximab Dose Intensification Strategy in Inflammatory Bowel Disease: A Pharmacokinetic Simulation Study

Abstract

Background The optimal infliximab dose intensification strategy to address loss of response associated with subtherapeutic infliximab trough levels remains uncertain, as does whether post-intensification trough and treatment targets should influence this decision. Objectives This pharmacokinetic simulation study aimed to identify infliximab dose intensification strategies capable of achieving post-intensification infliximab trough thresholds associated with clinical and objective treatment targets in Crohn’s disease and ulcerative colitis. Methods A validated pharmacokinetic infliximab model, applied to 200 simulated patients, identified those with subtherapeutic (< 3.00 mg/L) trough levels after 30 weeks of standard (5 mg/kg 8-weekly) dosing, and subsequently applied 10 dose intensification strategies over a further 32 weeks. The proportion of simulations achieving 32-week post-intensification infliximab trough levels associated with endoscopic remission (ulcerative colitis > 7.50 mg/L, Crohn’s disease > 9.70 mg/L) was the primary outcome, with perianal fistula healing (Crohn’s disease > 10.10 mg/L) and clinical improvement (ulcerative colitis > 3.70 mg/L, Crohn’s disease > 7.00mg/L) evaluated as secondary outcomes. All outcomes were stratified by intensity of dose intensification, with standard (≤ 10 mg/kg 8-weekly or 5 mg/kg 4-weekly; n = 5) and intensive (> 10 mg/kg 8-weekly or 5 mg/kg 4-weekly; n = 5) dosing strategies defined, respectively. Results The median pre-intensification infliximab trough level was 0.91 mg/L (interquartile range 1.37). Intensive dosing strategies were more likely to achieve infliximab trough concentrations associated with endoscopic remission (ulcerative colitis 36.48% vs. 10.80%, Crohn’s disease 25.98 vs. 4.68%), perianal fistula healing (24.52% vs. 4.36%) and clinical improvement (ulcerative colitis 61.90% vs. 34.86%, Crohn’s disease 40.32 vs. 12.08%) than standard intensification strategies (all p < 0.01). When controlling for cumulative (mg/kg) infliximab dose over 32 weeks, strategies that concurrently dose increased and interval shortened achieved the highest infliximab trough levels (all p < 0.01). Conclusion This simulation-based analysis highlights the potential of using post-intensification infliximab trough thresholds associated with aspirational treatment targets in Crohn’s disease and ulcerative colitis to guide choice of infliximab dose intensification strategy. Intensive dose intensification strategies, particularly those that concurrently dose increase and interval shorten, appear to achieve higher infliximab levels than standard dose intensification strategies. This may be particularly important in the pursuit of stringent endpoints, such as endoscopic remission and fistula healing, which have been consistently associated with hi...