Ana Homšek1, Srdan Markovic2, Petar Svorcan2, Marija Jovanovic1, Katarina Vucicevic1
1Faculty of Pharmacy – University of Belgrade, Department of Pharmacokinetics and Clinical Pharmacy, 2University Hospital Medical Center
Introduction: Acute severe ulcerative colitis (ASUC) is diagnosed in about 25% of patients suffering from ulcerative colitis (UC) when they experience more than six bloody stools per day and have either high heart rate or fever or haemoglobin under 105 g/L or erythrocyte sedimentation rate over 30 mm/h [1, 2]. Since the introduction of anti-TNFa drugs in the management of inflammatory bowel diseases, only infliximab (IFX) has proven to be effective as rescue therapy in ASUC, and is, therefore, the antibody of choice for these patients [1]. However, due to frequent relapses there is a need for more guidance when it comes to dosing IFX in ASUC. Objectives: The aim of this research was to generate a pharmacokinetic (PK) model obtained from data of ASUC patients. Estimated PK parameters were compared with those available from other PK models of IFX on patients with any type of UC. Methods: Based on clinical evaluation and diagnosis of clinicians of the Department of gastroenterology and hepatology, patients with ASUC were selected and data was collected retrospectively from the medical charts. Random samples were obtained during treatment, but blood was drawn always right before the administration of the next dose (trough concentration) and IFX concentrations were measured at the hospital from October 2015 until December 2024. Each patient received the calculated fixed dose based on their body weight (300-700 mg) via two-hour infusion after appropriate premedication. The drug was administered according to the standard (week 0, 2 and 6) and accelerated induction (every or every other week) protocols, followed by maintenance therapy (every 4, 6 or 8 weeks). PK parameters were obtained by applying a population modelling approach using NONMEM 7.5 software (ICON Development Solutions Inc., Dublin, Ireland) [3]. Using stepwise covariate model analysis, four covariates were tested – two categorical (disease remission status and induction/maintenance phase) and two continuous (haemoglobin and platelet level). After analysis, data were processed using appropriate packages from the R program. Results: A total of 46 patients were included in the research (male 63%, age at diagnosis 39.5 (19-67) years, baseline weight 75.5 (47-110) kg). Concentrations over the upper limit of quantification were excluded from the analysis due to the small number in overall dataset (4.1%), and concentrations below the lower limit of quantification were accounted for using the M3 method [4]. Final dataset contained 210 trough concentrations. Out of the 210 visits, patients achieved or maintained clinical remission status in 156 (74.28%) time points. In the literature, for UC patients, both one- and two-compartment models can be found [5-7], therefore each was applied on our dataset. Models were evaluated by comparing the objective function values (OFV) as well as goodness-of-fit diagnostic plots and visual predictive check plots. A two-compartment model using the ADVAN3 TRANS3 subroutine with first order elimination and a proportional error model best described the data. Clinical remission was included as a covariate (?OFV = -15.25) in the final model. The estimated values of parameters (with relative standard error) were: •Clearance = 0.329 L/day (6.1 %) •Steady-state volume of distribution = 6.83 L (0.04 %) •Intercompartmental clearance = 0.148 L/day (the value was fixed) •Central volume of distribution= 1.02 L (the value was fixed) •CL-Relapse = 0.245 (3.6%) •Inter-individual variability on clearance = 0.0651 (12.3 %) •Inter-individual variability on steady-state volume of distribution = 0.2 (0.03 %) •Proportional error = 0.501 (0.01%) Compared to data available in the literature, the obtained value of IFX clearance in our patient population was slightly lower when the patients were in remission (mean CL = 0.336 L/day). However, if the patient is not clinically stable, there is an increase in clearance (mean CL = 0.446 L/day). Conclusion: These results suggest that patients with ASUC have higher IFX clearance during disease relapse. Each patient would benefit from calculating an individual dose to maintain the steady state concentrations.
[1] Nakase H. (2023). Acute Severe Ulcerative Colitis: Optimal Strategies for Drug Therapy. Gut and liver, 17(1), 49–57. https://doi.org/10.5009/gnl220017. [2] Honap, S., Jairath, V., Sands, B. E., Dulai, P. S., Danese, S., & Peyrin-Biroulet, L. (2024). Acute severe ulcerative colitis trials: the past, the present and the future. Gut, 73(10), 1763–1773. https://doi.org/10.1136/gutjnl-2024-332489 [3] Owen J.S., Fiedler-Kelly J. Introduction to population pharmacokinetic/pharmacodynamic analysis with nonlinear mixed effects models. John Wiley & Sons; 2014. [4] Beal S. L. (2001). Ways to fit a PK model with some data below the quantification limit. Journal of pharmacokinetics and pharmacodynamics, 28(5), 481–504. https://doi.org/10.1023/a:1012299115260 [5] Brandse, J. F., Mathôt, R. A., van der Kleij, D., Rispens, T., Ashruf, Y., Jansen, J. M., Rietdijk, S., Löwenberg, M., Ponsioen, C. Y., Singh, S., van den Brink, G. R., & D’Haens, G. R. (2016). Pharmacokinetic Features and Presence of Antidrug Antibodies Associate With Response to Infliximab Induction Therapy in Patients With Moderate to Severe Ulcerative Colitis. Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association, 14(2), 251–8.e82. https://doi.org/10.1016/j.cgh.2015.10.029 [6] Fasanmade, A. A., Adedokun, O. J., Ford, J., Hernandez, D., Johanns, J., Hu, C., Davis, H. M., & Zhou, H. (2009). Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis. European journal of clinical pharmacology, 65(12), 1211–1228. https://doi.org/10.1007/s00228-009-0718-4 [7] Dreesen, E., Faelens, R., Van Assche, G., Ferrante, M., Vermeire, S., Gils, A., & Bouillon, T. (2019). Optimising infliximab induction dosing for patients with ulcerative colitis. British journal of clinical pharmacology, 85(4), 782–795. https://doi.org/10.1111/bcp.13859
Reference: PAGE 33 (2025) Abstr 11472 [www.page-meeting.org/?abstract=11472]
Poster: Drug/Disease Modelling - Other Topics