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Review
. 2022 Sep 30;14(10):2095.
doi: 10.3390/pharmaceutics14102095.

Ulcerative Colitis and Acute Severe Ulcerative Colitis Patients Are Overlooked in Infliximab Population Pharmacokinetic Models: Results from a Comprehensive Review

Alix Démaris  1   2 , Ella S K Widigson  1   2 , Johan F K F Ilvemark  3 , Casper Steenholdt  3 , Jakob B Seidelin  3 , Wilhelm Huisinga  4 , Robin Michelet  1 , Linda B S Aulin  1 , Charlotte Kloft  1
Affiliations
Review

Ulcerative Colitis and Acute Severe Ulcerative Colitis Patients Are Overlooked in Infliximab Population Pharmacokinetic Models: Results from a Comprehensive Review

Alix Démaris et al. Pharmaceutics. .

Abstract

Ulcerative colitis (UC) is part of the inflammatory bowels diseases, and moderate to severe UC patients can be treated with anti-tumour necrosis α monoclonal antibodies, including infliximab (IFX). Even though treatment of UC patients by IFX has been in place for over a decade, many gaps in modelling of IFX PK in this population remain. This is even more true for acute severe UC (ASUC) patients for which early prediction of IFX pharmacokinetic (PK) could highly improve treatment outcome. Thus, this review aims to compile and analyse published population PK models of IFX in UC and ASUC patients, and to assess the current knowledge on disease activity impact on IFX PK. For this, a semi-systematic literature search was conducted, from which 26 publications including a population PK model analysis of UC patients receiving IFX therapy were selected. Amongst those, only four developed a model specifically for UC patients, and only three populations included severe UC patients. Investigations of disease activity impact on PK were reported in only 4 of the 14 models selected. In addition, the lack of reported model codes and assessment of predictive performance make the use of published models in a clinical setting challenging. Thus, more comprehensive investigation of PK in UC and ASUC is needed as well as more adequate reports on developed models and their evaluation in order to apply them in a clinical setting.

Keywords: acute severe ulcerative colitis; disease activity; inflammatory bowel disease; infliximab; pharmacokinetic; pharmacometrics; ulcerative colitis.

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Conflict of interest statement

C.K. and W.H. report grants from an industry consortium (AbbVie Deutschland GmbH & Co. KG, AstraZeneca, Boehringer Ingelheim Pharma GmbH & Co. KG, Grünenthal GmbH, F. Hoffmann-La Roche Ltd., Merck KGaA and SANOFI) for the PharMetrX PhD program. C.K. reports grants for the Innovative Medicines Initiative-Joint Undertaking (“DDMoRe”), Diurnal Ltd., the Federal Ministry of Education and Research within the Joint Programming Initiative on Antimicrobial Resistance Initiative (JPIAMR) and from the European Commission within in the Horizon 2020 framework programme (“FAIR”), all outside the submitted work. All other authors declared no competing interests for this work.

Figures

Figure 1
Figure 1
Selection process of records reporting on population pharmacokinetic models for infliximab in ulcerative colitis patients. The flowchart was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [35].
Figure 2
Figure 2
Impact of identified covariates in the 14 models on infliximab PK parameters. As one- or two-compartment PK models were developed, the second compartment and the associated mass transfer process are displayed with dashed lines. Abbreviations: ADA: Anti-drug antibodies; CD: Crohn’s disease; CL: Clearance; CRP: C-reactive protein; HBI: Harvey–Bradshow index; Q: Intercompartmental clearance; RA: Rheumatoid arthritis; TNF: Tumour necrosis factor; UC: Ulcerative colitis; V1: Volume of distribution of the central compartment; V2: Volume of distribution of the peripheral compartment.
Figure 3
Figure 3
Scheme of the 26 selected articles linked to one or several of the identified original models. Arrows link the selected articles to the original model used in their study. Konecki (2021) [60] and Schräpel (2021) [61], in blue, are displayed in a different colour, as their studies consisted in evaluated published models, thus including several original models in their publication. Fasamnade (2009) [49], in red, Fasanmade (2011) [64], in orange, and Xu (2012) [65] in yellow are displayed in different colours, as their original models were extensively re-used in studies from the selected articles.
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