Abstract
Background: Substantial interindividual variability in infliximab pharmacokinetics and pharmacodynamics (PKPD) complicates dose optimization in patients with inflammatory bowel disease (IBD). Infliximab concentration-guided dosing (CGD) mostly relies on the Therapeutic Window Approach (TWA). Although this approach is widely used in clinical practice, its implications in the setting of substantial variability remain insufficiently characterized. Methods: Model-based simulations evaluated the probability of target (non)-attainment across standard and intensified dosing strategies for intravenous and subcutaneous infliximab. Target attainment was predefined using a therapeutic window (3–7 mg/L) for intravenous infliximab and a threshold (≥12 mg/L) for subcutaneous infliximab. Results: Across dosing strategies, substantial exposure variability resulted in a proportion of patients remaining below the predefined targets. For intravenous infliximab, interval shortening achieved a greater probability of target attainment than dose escalation alone; for example, among patients receiving 5 mg/kg, 50.5% achieved concentrations ≥3 mg/L with Q6W versus 24.5% with Q8W. For subcutaneous infliximab, simulated 180 and 240 mg doses increased the probability of target attainment (≥12 mg/L) versus the approved 120 mg dose, in higher body weight cohorts (72.0% and 86.5%, respectively, vs. 35.5%), potentially highlighting limitations of the current “one-size-fits-all” dosing paradigm. Conclusions: In the presence of substantial infliximab PKPD variability and IBD dynamics, the predefined therapeutic window and fixed threshold may not adequately account for individual variability, potentially contributing to clinical discordance between drug exposure, predefined target attainment, and clinical outcomes. These considerations support evaluating the Target Concentration Approach (TCA) in clinical trials and routine IBD management, given its potential to dynamically adapt dosing to achieve patient-specific target concentration.