Ana Homšek (1), Srđan Marković (2,3), Petar Svorcan (2,3), Đorđe Kralj (2), Olga Odanović (2), Tamara Knežević Ivanovski (2), Marija Jovanović (1), Katarina Vučićević (1)
(1) Faculty of Pharmacy – University of Belgrade, Department of Pharmacokinetics and Clinical Pharmacy, Belgrade, Republic of Serbia, (2) University Hospital Medical Center
Introduction: The development of fistulas in patients with Crohn’s disease is a recognised complication of this chronic disorder, posing challenges for both patients and gastroenterologists. While infliximab (IFX), an anti-tumour necrosis factor alpha antibody, has demonstrated efficacy in treating this form of the disease [1], numerous challenges persist in ensuring optimal patient care and achieving disease remission.
Objectives: To better inform treatment approaches for patients with fistulizing Crohn’s disease, an evaluation of existing IFX population pharmacokinetic models was conducted. The aim was to assess their predictive capabilities within this population, evaluate the alignment of population pharmacokinetic model parameters with the individual therapeutic drug monitoring data, and determine their suitability for everyday clinical practice.
Methods: After conducting an extensive literature search of the PubMed database, a total of nineteen IFX population pharmacokinetic models were selected. Subsequently, based on considerations of model structure, included covariates, and patient characteristics, nine models were selected for evaluation, and appropriate codes were prepared for analysis [2-10]. We utilized NONMEM 7.5 (ICON Development Solutions Inc.) software to obtain individual predicted concentrations (IPRED) and normalised prediction distribution error (NPDE). To assess and compare models’ performances, we employed both prediction-based and simulation-based methods. Prediction-based method included the calculation of mean prediction error (MPE) and relative mean prediction error (rMPE) to evaluate model accuracy, and root mean squared error (RMSE) and relative root mean squared error (rRMSE) to assess precision. Simulation-based method included visual predictive checks (VPC) and NPDE plots. The obtained data was processed using appropriate packages in R software.
Results: A total of 154 concentrations from 41 patients with fistulizing Crohn’s disease treated at the Clinical Hospital Center “Zvezdara” were included in the dataset for evaluation. Based on the calculated MPEs, three models [3, 6, 9] exhibited confidence intervals that included zero, and were therefore selected as the more accurate ones. Additionally, rMPEs of Ternant (0.09%) [3] and Matsuoka (-0,20%) [10] models were notably low. Also, the most precise models according to rRMSE were the same ones (0.61% and 9.4% respectively) [3, 10]. Regression analysis revealed that the Ternant model [3] exhibited the strongest correlation between measured concentrations and IPRED (R2=0.9999). Therefore, according to the prediction-based analysis, the Ternant model [3] was identified as the most accurate and precise. However, upon reviewing VPCs, three different models [4, 5, 10] outperformed others. Notably, the NPDE plots highlighted the superiority of the Xu model [4] according to simulation-based methods.
Conclusion: Although some models performed better predictions than others, none of them met all criteria assessed in this evaluation. The inconclusive nature of the results suggests that none of the models fully suited our patient population. Considering that this specific patient population has not been included during the development of any tested models, there is a clear need to develop a new model that accounts for fistulizing Crohn’s disease characteristics. Doing so would improve predictions of IFX trough concentrations for this disease form and, therefore, facilitate a more individualised approach to treatment.
Acknowledgement: This research was supported by the Science Fund of the Republic of Serbia, grant no. 6777, project: Improving Clinical Outcomes with Precision Dosing in Patients with Inflammatory Bowel Disease Through Investigating Variability of Monoclonal Antibodies Based on Population Pharmacokinetic-Pharmacodynamic Modeling – optYmAb.
References:
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Reference: PAGE 32 (2024) Abstr 11171 [www.page-meeting.org/?abstract=11171]
Poster: Methodology - Model Evaluation