The influence of subclinical active inflammation on IFX pharmacokinetic modeling and disease progression assessment: findings from a prospective real-world study in inflammatory bowel disease patients

Fernando Magro; Samuel Fernandes; Marta Patita; Bruno Arroja; Paula Lago; Isadora Rosa; Helena Tavares de Sousa; Paula Ministro; Irina Mocanu; Ana Vieira; Joana Castela; Joana Moleiro; Joana Roseira; Eugénia Cancela; Paula Sousa; Francisco Portela; Luís Correia; Paula Moreira; Sandra Dias; Joana Afonso; Silvio Danese; Laurent Peyrin-Biroulet; Katarina M Vucicevic; Mafalda Santiago

doi:10.1093/ecco-jcc/jjae014

The influence of subclinical active inflammation on IFX pharmacokinetic modeling and disease progression assessment: findings from a prospective real-world study in inflammatory bowel disease patients

J Crohns Colitis. 2024 Jan 19:jjae014. doi: 10.1093/ecco-jcc/jjae014. Online ahead of print.

Authors

Fernando Magro^{1

2

3

4

5}, Samuel Fernandes^{6

7}, Marta Patita⁸, Bruno Arroja⁹, Paula Lago^{5

10}, Isadora Rosa¹¹, Helena Tavares de Sousa^{12

13}, Paula Ministro^{5

14}, Irina Mocanu⁸, Ana Vieira⁸, Joana Castela¹¹, Joana Moleiro¹¹, Joana Roseira^{12

13}, Eugénia Cancela¹⁴, Paula Sousa¹⁴, Francisco Portela^{5

15}, Luís Correia^{5

6}, Paula Moreira⁴, Sandra Dias⁵, Joana Afonso⁵, Silvio Danese^{16

17}, Laurent Peyrin-Biroulet¹⁸, Katarina M Vucicevic¹⁹, Mafalda Santiago⁵

Affiliations

¹ Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal.
² Department of Gastroenterology, São João Hospital University Centre, Porto, Portugal.
³ Centre for Health Technology and Services Research, Health Research Network (CINTESIS@RISE), Faculty of Medicine of the University of Porto, Portugal.
⁴ Unidade de Farmacologia Clínica, São João Hospital University Centre, Porto, Portugal.
⁵ Portuguese Group of Studies in Inflammatory Bowel Disease (Grupo de Estudos da Doença Inflamatória Intestinal - GEDII), Porto, Portugal.
⁶ Department of Gastroenterology, Northern Lisbon University Hospital Centre, Lisbon, Portugal.
⁷ Clinica Universitária de Gastrenterologia da Universidade de Medicina de Lisboa, Lisbon, Portugal.
⁸ Department of Gastroenterology, Garcia da Orta Hospital, Almada, Portugal.
⁹ Department of Gastroenterology, Braga Hospital, Braga, Portugal.
¹⁰ Department of Gastroenterology, Porto Hospital University Centre, Porto, Portugal.
¹¹ Department of Gastroenterology, IPOLFG, EPE, Lisbon, Portugal.
¹² Department of Gastroenterology, Algarve Hospital University Centre - Portimão Unit, Portimão, Portugal.
¹³ ABC - Algarve Biomedical Center, University of Algarve, Faro, Portugal.
¹⁴ Department of Gastroenterology, Viseu-Tondela Hospital Centre, Viseu, Portugal.
¹⁵ Department of Gastroenterology, Coimbra Hospital University Centre, Coimbra, Portugal.
¹⁶ Department of Biomedical Sciences, Humanitas University, Milan, Italy.
¹⁷ IBD Center, Humanitas Research Hospital, IRCCS, Milan, Italy.
¹⁸ Department of Gastroenterology and Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, Nancy, France.
¹⁹ Department of Pharmacokinetics and Clinical Pharmacy, University of Belgrade, Serbia.

PMID: 38243908
DOI: 10.1093/ecco-jcc/jjae014

Abstract

Background and aims: Effective management of inflammatory bowel disease (IBD) relies on a comprehensive understanding of infliximab (IFX) pharmacokinetics (PK). This study's primary goal was to develop a robust PK model, identifying key covariates influencing IFX clearance (CL), while concurrently evaluating the risk of disease progression during the maintenance phase of IBD treatment.

Methods: The multicenter, prospective, real-world DIRECT study was conducted in several care centers, which included 369 IBD patients in the maintenance phase of IFX therapy. A two-compartment population PK model was used to determine IFX CL and covariates. Logistic and Cox regressions were applied to elucidate the associations between disease progression and covariates embedded in the PK model.

Results: The PK model included the contributions of weight, albumin, antidrug antibody (ADA), and fecal calprotectin (FC). On average, higher ADA, FC concentration and weight, and lower albumin concentration resulted in higher IFX CL. In the multivariate regression analyses, FC levels influenced the odds of disease progression in all its different definitions, when adjusted for several confounding factors. Additionally, alongside FC, both IFX and CL demonstrated a significant impact on the temporal aspect of disease progression.

Conclusion: In this 2-year real-world study, readily available clinical covariates, notably FC, significantly impacted IFX availability in IBD patients. We demonstrated that subclinical active inflammation, as mirrored by FC or CRP, substantially influenced IFX clearance. Importantly, FC emerged as a pivotal determinant, not only of IFX pharmacokinetics but also of disease progression. These findings underscore the need to integrate FC into forthcoming IFX pharmacokinetic models, amplifying its clinical significance.

Keywords: inflammatory bowel disease; infliximab; pharmacokinetic model.