Zvonimir Petric, Paulo Paixao, Joao Goncalves
1Department of Pharmacological Sciences - Faculty of Pharmacy, Lisbon, 2Biopharmaceutical and Molecular Biotechnology Unit - Faculty of Pharmacy, Lisbon
Introduction: Inflammatory bowel disease (IBD) comprises two distinct yet closely related disorders: Crohn’s disease and ulcerative colitis. Infliximab, a monoclonal antibody (MAb), is a key treatment for IBD. Its pharmacokinetics and therapeutic effects are influenced by factors such as time-varying inflammatory burden, immunological characteristics, and patient-specific attributes. Neglecting to address an inadequate treatment response may lead to therapeutic failure, which is in general linked to underexposure [1]. Recently, a subcutaneous formulation of infliximab was 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 [2]. Objectives: Using a physiologically based pharmacokinetic (PBPK) modeling framework, this study aimed to evaluate whether a one-size-fits-all approach to dosing is pharmacologically optimal for all adults with IBD (e.g., adult weighing 70 kg vs. 120 kg). Additionally, it explored the potential for extending approval of the 120 mg subcutaneous flat-fixed dose of infliximab to other patient groups, such as pediatric patients with IBD. Methods: The PBPK modeling exercise was performed using the PK-Sim® platform (version 11.2, Open Systems Pharmacology Suite, Bayer Technology Services, Leverkusen, Germany). This platform provides a model specifically tailored to describe the pharmacokinetics of protein drugs and large molecules, such as MAbs, and is developed as an extension of a standard model for small molecules. The baseline PBPK model of infliximab was initially constructed to represent a virtual human corresponding to the average (i.e., mean) pharmacokinetic and biometric profile of the population in a real-world trial, specifically healthy adults receiving intravenous infliximab (5 mg/kg) [2]. Additionally, virtual patients with moderate to severe IBD were assigned a specific endosomal clearance rate of 1.6 per minute. This rate was used as a proxy to capture the various immune-mediated and non-immune-mediated clearance pathways that influence infliximab disposition and, ultimately, its effectiveness [1, 2]. Since PK-Sim® does not include a subcutaneous administration module, the fat compartment was designated as the target organ for subcutaneous delivery of infliximab, with plasma serving as the target compartment. A first-order input, based on published literature data [3], was assumed to model the absorption. To reflect the true concentration of infliximab in the biophase, the subcutaneous dose was modified accounting for bioavailability (F). Results: PBPK simulations suggest that patients exceeding the typical trial weight (e.g., 120 kg) may require higher subcutaneous infliximab doses (e.g., 240 mg) to avoid underexposure. While the 120 mg dose is currently approved for adults, older pediatric patients (e.g., 14 years old, 60 kg) exhibit similar drug exposure to adults receiving this dose. Conclusion: The approved 120 mg fixed subcutaneous dose of infliximab for adult IBD treatment may be inadequate for heavier patients, underscoring the limitations of a one-size-fits-all dosing approach. However, this dose appears appropriate for older and heavier pediatric patients. These findings support expanding subcutaneous infliximab approval for pediatric IBD treatment. The PBPK framework can serve as a valuable tool in clinical pharmacology for advancing insights into IBD treatment optimization.
[1] Petric Z, Gonçalves J, Paixão P. Under the Umbrella of Clinical Pharmacology: Inflammatory Bowel Disease, Infliximab and Adalimumab, and a Bridge to an Era of Biosimilars. Pharmaceutics. 2022 Aug 24;14(9):1766. doi: 10.3390/pharmaceutics14091766. [2] Petric Z, Gonçalves J, Paixão P. Infliximab in Inflammatory Bowel Disease: Leveraging Physiologically Based Pharmacokinetic Modeling in the Clinical Context. Biomedicines. 2024 Sep 1;12(9):1974. doi: 10.3390/biomedicines12091974. [3] Hanzel, J.; Bukkems, L.H.; Gecse, K.B.; D’Haens, G.R.; Mathôt, R.A.A. Population pharmacokinetics of subcutaneous infliximab CT-P13 in Crohn’s disease and ulcerative colitis. Aliment. Pharmacol. Ther. 2021, 54, 1309–1319.
Reference: PAGE 33 (2025) Abstr 11626 [www.page-meeting.org/?abstract=11626]
Poster: Drug/Disease Modelling - Absorption & PBPK