Zvonimir Petric 1
1 Department of Pharmacological Sciences, Research Institute for Medicines, Faculty of Pharmacy, University of Lisbon (Lisbon, Portugal)
Introduction: Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the digestive tract. Infliximab, a monoclonal antibody administered intravenously or subcutaneously, is a key treatment for IBD, with pharmacokinetics (PK) and pharmacodynamics (PD) shaped by inflammatory burden as well as immunological and patient-specific factors. A subcutaneous infliximab formulation was recently introduced to the EU market at a flat-fixed dose of 120 mg, approved exclusively for adult patients as a switching option following intravenous induction. Treatment failure with infliximab in IBD is frequently attributed to underexposure, while substantial and often unpredictable PKPD variability complicates clinical decision-making [1]. Therefore, concentration-guided dosing (CGD) aims to optimize infliximab use via the therapeutic window approach (TWA) [2], which assumes that trough concentrations within a (pre)defined “range” are associated with therapeutic success. For subcutaneous infliximab, the TWA is based on a trough cutoff concentration of 12 mg/L.
Objective: Using modeling and simulation approaches within a population (pop) PK framework, this study illustrates the probability of target (un)attainment under the TWA and its implications for personalized dosing decisions for subcutaneous infliximab in virtual adult cohorts with moderate to severe IBD.
Methods: PK profiles for virtual patient cohorts were generated by imputing fixed and random effects from published popPK model [3]. Each simulated scenario included 100 patients across 10 trial replicates, with the probability of target (un)attainment summarized by the median value. Pharmacometric analyses were performed using Monolix Suite – popPK models were developed using Monolix, while subsequent simulations were conducted in Simulx (version 2024 R1).
Results: For the subcutaneous 120 mg fixed dose, virtual cohorts averaged around 70 kg typical individual had a 36% probability of troughs below 12 mg/L, while those averaged around 120 kg typical individual had a 64.5% probability. These findings reflect a clinically plausible pattern; however, applying a single cutoff value uniformly across diverse patients may not reflect appropriate clinical reasoning. Because of substantial infliximab PKPD variability in IBD, a flat-fixed 120 mg dose is unlikely to be appropriate for all patient subgroups. In a hypothetical scenario, increasing the subcutaneous regimen to 240 mg every 2 weeks yielded the greatest probability of target attainment in heavier virtual patients (median 86.5%, > 12 mg/L), suggesting that higher (or more frequent) dosing may be required to overcome underexposure in this subgroup. These results argue against one-size-fits-all dosing paradigm and highlight the need for further clinical evaluation.
Conclusion: Given the substantial PKPD variability of infliximab in IBD, effective personalized dosing decisions require moving beyond arbitrarily (pre)defined therapeutic window, as relying solely on fixed trough concentration “range”, i.e., therapeutic window, reflects poor clinical pharmacology. Likewise, the one-size-fits-all paradigm is inadequate in the context of IBD and the inherent PKPD variability of infliximab. Thus, patient-centered clinical reasoning must remain the primary anchor guiding personalized dosing decisions.
References:
1. Petric Z., et al. Infliximab in Inflammatory Bowel Disease: Leveraging Physiologically Based Pharmacokinetic Modeling in the Clinical Context. Biomedicines, 2024.
2. Holford N. & Petric Z., The Rational Basis for Personalized Treatment using Concentration-Guided Dosing. Ther Drug Monit, 2025.
3. Hanzel, J., et al., Population pharmacokinetics of subcutaneous infliximab CT-P13 in Crohn’s disease and ulcerative colitis. Aliment Pharmacol Ther, 2021.
Reference: PAGE 34 (2026) Abstr 11941 [www.page-meeting.org/?abstract=11941]
Poster: Drug/Disease Modelling - Other Topics