Introduction

Tioguanine is metabolised by less enzymatic steps compared to azathioprine and mercaptopurine, without generating 6-methylmercaptopurine ribonucleotides. However, thiopurine S-methyl transferase (TPMT) plays a role in early toxicity in all thiopurines. We aimed to describe the hazards and opportunities of tioguanine use in inflammatory bowel disease (IBD) patients with aberrant TPMT metabolism and propose preventative measures to safely prescribe tioguanine in these patients.

Aims & Methods

In this retrospective cohort study, all determined TPMT genotypes (2016 – 2021) were evaluated for aberrant metabolism (i.e. intermediate and poor TPMT metabolisers). Subsequently, all IBD patients on tioguanine with aberrant TPMT genotypes were evaluated for tioguanine dosages, adverse drug events, lab abnormalities, treatment duration and effectiveness.

Results

TPMT genotypes were determined in 485 patients of whom 50 (10.3%) and 4 patients (0.8%) were intermediate and poor metabolisers, respectively. Of these patients, 12 intermediate and 4 poor TPMT metabolisers had been prescribed tioguanine in varying doses. In one poor TPMT metaboliser, tioguanine 10 mg/day induced delayed pancytopenia. In general, reduced tioguanine dosages of 5 mg/day for intermediate TPMT metabolisers, and 10 mg two-weekly for poor TPMT metabolisers, resulted in a safe, long-term treatment strategy.

Conclusion

Diminished or absent TPMT enzyme activity was related with a pharmacokinetic shift of tioguanine metabolism which is associated with relatively late occurring myelotoxicity in patients on standard tioguanine dose. However, in strongly reduced dose regimens with strict therapeutic drug and safety monitoring, tioguanine treatment remained a safe and effective option in IBD patients with dysfunctional TPMT.

Disclosure

The authors disclose no conflicts of interest with respect to this manuscript.
DD, LD, BB, RC, AN and DW have nothing to declare, AvB has served as speaker, adviser and/or principal investigator for AbbVie, Arandal, Arena, Celgene, Ferring, Galapagos, Janssen, Pfizer, Roche, TEVA, and received research grants from TEVA, Eurostars funding, ZonMW, and Pfizer.

Introduction

Thioguanine (TG) has recently been rediscovered as an immunosuppressive agent in the treatment of inflammatory bowel disease (IBD). This prodrug is directly converted into its active metabolites, 6-thioguanine nucleotides (6-TGNs), targeting the inhibition of RAC1 GTPase in inflammatory conditions, disrupting key cellular signaling pathways necessary for T-cell activation and survival, thereby contributing to its immunosuppressive action. In IBD, TG is used fixed dose and may benefit from model-informed precision dosing (MIPD) to optimize treatment efficacy and minimize toxicity. However, a population pharmacokinetic (PopPK) model to do so is lacking.

Aims & Methods

The aim was to develop a PopPK model for TG in IBD patients, enhancing the understanding of TG's pharmacokinetics and supporting the implementation of model-informed precision dosing (MIPD). We employed a dataset comprising 131 6-TGN trough concentrations from 28 IBD patients treated with TG. The data were analyzed using nonlinear mixed-effects modeling (NONMEM) to estimate pharmacokinetic parameters and explore the influence of covariates such as weight and 5-ASA use on drug disposition. Model fit-for-purpose was evaluated through computation of the model’s forecasting performance.

Results

The developed PopPK model was a one-compartment model with first-order absorption. A one-compartment TG model was stable, and able to estimate PK parameters with good precision (RSE 11-15%) with weight and 5-ASA use significantly affected TG clearance. Forecasting performance was also adequate with an rRMSE of 24.1% and practically no systematic bias (MPE 0.2%).

Conclusion

This study presents the first PopPK model of thioguanine for IBD, offering a novel tool for MIPD in clinical settings. Future studies should explore additional covariates such as TPMT genotype and drug interactions to further refine dosing recommendations for diverse patient populations.

Disclosure

AB has received funding from HLW Pharma BV, NdB has served as a speaker for AbbVie and MSD and has served as a consultant and/or principal investigator for TEVA Pharma BV and Takeda. He has received a research grant (unrestricted) from Dr. Falk, TEVA PharmaBV, Dutch Digestive Foundation (MLDS) and Takeda. LD has served as a speaker for AbbVie, Celltrion, Janssen-Cilag and Takeda and has developed continuing education materials for Ferring, All outside the submitted work. RJK is a an employee and stockholder of InsightRX.

Introduction

Patients (pts) with inflammatory bowel disease (IBD) have a significantly higher risk of venous thromboembolic events (VTEs) compared to the general population [1]. Thromboprophylaxis (TP) is recommended for patients with IBD during all-cause hospitalization [2]. Evidence supporting this practice in the clinical context of IBD is scarce. This retrospective, real-world, single-center study aims to evaluate the effectiveness and safety of TP in preventing VTEs in a large cohort of hospitalized patients with IBD. The secondary endpoint of the study was to measure adherence to the TP prescription.

Aims & Methods

Disease-related real-world data were retrospectively collected from the Hospital Information System using automated data extraction strategies and through the implementation of a patient-centred data repository (the IBD Data Mart) [3]. The study population was identified from the medical records of patients who met the following inclusion criteria during 2020-2023: hospitalized adult patients (aged ≥18 years) diagnosed with Crohn's disease (CD) (ICD9-CM diagnosis codes 555) or ulcerative colitis (UC) (ICD9-CM diagnosis codes 556). Variables of interest, including demographics, comorbidities, surgery procedures, and treatment information, were collected using data extraction strategies. Specific ETL (Extract, Transform, Load) procedures were implemented to automatically retrieve data from heterogeneous data sources: data were acquired from a structured data source or extracted using clinically-validated text mining techniques from an unstructured data source. We assessed the use of anticoagulant treatments in this setting and during hospitalization. The TP included one of the following therapeutic protocols: low-molecular-weight heparin (LMWH) at a variable dose of 4000 to 8000 IU once daily, fondaparinux 2.5-3.5 mg/day, or calciparin at a dosage of up to 5000 IU twice daily. Patients were divided into two groups: patients with or without TP. Incidence of VTEs was assessed, also based on IBD type and hospitalization.

Results

Of the 1359 identified pts (42% with UC), 724 (53.3%) were treated with anticoagulant therapy during hospitalization. 79 pts (5.8%) presented a VTE. 259 pts were already in treatment with anticoagulant or antiplatelet therapy before hospitalization. 472 pts started anticoagulant treatment during hospitalization (472/1101, 42.9%). Among them, 431 (91.3%) began TP immediately after hospitalization, and 34 (7.2%) were excluded from the analysis because they were treated with a therapeutic dose of anticoagulant immediately after hospitalization, meaning they already had a VTE. Therefore, 1067 patients were evaluated for the efficacy of TP in preventing VTEs during hospitalization. Our results showed that TP is almost significantly effective in reducing VTE episodes (p=0.053). Regarding safety, we did not observe significant differences in the need for blood transfusions between patients treated or not treated with TP (p=0.37). Furthermore, TP interruption was rare, as only 28 patients (6.5%) discontinued treatment.

Conclusion

TP is effective in a real-world cohort of hospitalized patients with IBD in reducing VTEs. It is also a safe procedure as it does not increase the risk of severe bleeding requiring blood transfusions, and treatment discontinuation is an infrequent event. However, the rate of TP in our cohort is still suboptimal, and strategies to significantly implement this practice are recommended to reduce the occurrence of VTEs further.

References

[1] Papa A, et al. Prevention and treatment of venous thromboembolism in patients with IBD: a trail still climbing. Inflamm Bowel Dis. 2015 May;21(5):1204-13.
[2] Olivera PA et al. International consensus on preventing venous and arterial thrombotic events in patients with inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2021 Dec;18(12):857-873.
[3] Damiani A, et al. Building an artificial intelligence laboratory based on real-world data: the experience of Gemelli generator. Front Comput Sci. 2021;3.

Introduction

Immunomodulators and biologicals play an essential role in current IBD management, but are associated with increased risk of infections. In light of the growing number of treatment options, the benefit-risk balance of drugs is becoming increasingly important in clinical decision making. Post-marketing surveillance studies are pivotal to assess infection risk, yet mainly focus on severe infections. As a result, data on mild and moderate infections are scarce. However, mild and moderate infections take longer to clear in immunosuppressed patients, have been reported to be the most burdensome adverse drug reaction according to patients, and can negatively influence drug adherence.

Aims & Methods

Aim: To assess the incidence of all infections and identify risk factors for the development of infections in IBD patients.
Methods: We previously developed and validated a Patient-Reported Infections Questionnaire (PRIQ), with excellent diagnostic accuracy, covering 15 infection categories with a 3-month recall period. [1] The current prospective, multicentre, observational cohort study was performed between Jun, 1 2020 and Jul, 1 2021, enrolling consecutive IBD patients and using the PRIQ which was implemented in myIBDcoach, an established telemedicine platform. Infection severity was defined as mild (self-limiting or topical treatment), moderate (oral antibiotics, antivirals or antifungals) or severe (hospitalization or IV treatment). Incidence rates (IR) were calculated for all infections, stratified for severity and subtype. Multivariable logistic regression, adjusting for relevant confounders, was performed to identify risk factors for infections.

Results

In total, 629 IBD patients (n=346 CD, n=283 UC, 58.3% female, mean age at cohort entry 48.3 years [SD 14.8], mean disease duration 12.4 years [SD 10.8]) were included which completed 2391 PRIQs during 572 person-years (PY) of follow-up. This resulted in 990 reported infections, corresponding to IRs of 17.3, 11.8, 5.1, and 0.4 per 10PY for all, mild, moderate, and severe infections, respectively. Upper respiratory tract (IR 26.9/100PY) and urinary tract infections (IR 14.8/100PY) were the most commonly reported mild and moderate infections types, respectively (Table 1). Compared to patients without treatment, patients on immunosuppressive treatment more frequently experienced infections of any severity (mild vs. no treatment: IR ratio (IRR) 1.57 [95%CI 1.21-2.06] p<0.001, moderate vs. no treatment: IRR 1.42 [95%CI 1.20-1.69] p<0.001). On multivariable logistic regression, female sex (mild adjusted odds ratio [aOR] 1.96 [95%CI 1.38-2.79]; moderate aOR 1.71 [95%CI 1.15-2.54]), smoking status (mild aOR 1.66 [95%CI 1.15-2.41]; moderate aOR 1.86 [95%CI 1.05-3.28]), higher BMI (moderate aOR 1.05 [95%CI 1.02-2.00]), and more comorbidities (mild aOR 2.41 [95%CI 1.46-3.98]; moderate aOR 1.82 [95%CI 1.07-3.11]) were all significantly associated with the development of mild and moderate infections.

Conclusion

​In this real-world prospective study, immune suppressive therapy was associated with mild and moderate infections of any kind in IBD patients. These infections particularly occur in females, smokers, patients with higher BMI and more comorbidities. This information should be considered in personalised treatment selection.

References

[1] Rezazadeh Ardabili A, van Esser D, Wintjens D, et al. Development and validation of a remote monitoring tool for assessment of mild, moderate, and severe infections in Inflammatory Bowel Disease [published online ahead of print, 2023 Feb 16]. J Crohns Colitis. 2023;jjad023. doi:10.1093/ecco-jcc/jjad023

Disclosure

M.P. reports grants and non-financial support from Falk Pharma, grants from European commission, grants from ZonMw (Dutch national research fund), grants and non-financial support from Takeda, grants and non-financial support from Johnson and Johnson, grants and non-financial support from Abbvie, non-financial support from Ferring, non-financial support from Immunodiagnostics, non-financial support from MSD, all outside the submitted work. D.J. reports grants from Top Knowledge Institute (Well on Wheat), grants from Horizon 2020 DISCOvERIE, grants from NWO-CCC Partnership program (Carbokinetics), all outside the submitted work. Z.M. reports grants form MLDS, Niels Stensen Fellowship and Galapagos. A.v.B. has served as speaker, adviser and/or principal investigator for AbbVie, Arandal, Arena, Celgene, Ferring, Galapagos, Janssen, MSD, Pfizer, Roche, Takeda, TEVA, and received research grants from Pfizer, TEVA, Eurostars funding, ZonMw, all outside the submitted work.
The other authors have nothing to disclose relevant to this publication.