This study evaluated the effectiveness of NUDT15 codon 139 genotyping in optimizing thiopurine treatment for inflammatory bowel disease (IBD) in Japan, using real-world data, and aimed to establish genotype-based treatment strategies.
A retrospective analysis of 4628 IBD patients who underwent NUDT15 codon 139 genotyping was conducted. This study assessed the purpose of the genotyping test and subsequent prescriptions following the obtained results. Outcomes were compared between the Genotyping group (thiopurine with genotyping test) and Non-genotyping group (thiopurine without genotyping test). Risk factors for adverse events (AEs) were analyzed by genotype and prior genotyping status.
Genotyping test for medical purposes showed no significant difference in thiopurine induction rates between Arg/Arg and Arg/Cys genotypes, but nine Arg/Cys patients opted out of thiopurine treatment. In the Genotyping group, Arg/Arg patients received higher initial doses than the Non-genotyping group, while Arg/Cys patients received lower ones (median 25 mg/day). Fewer AEs occurred in the Genotyping group because of their lower incidence in Arg/Cys cases. Starting with < 25 mg/day of AZA reduced AEs in Arg/Cys patients, while Arg/Arg patients had better retention rates when maintaining ≥ 75 mg AZA. Nausea and liver injury correlated with thiopurine formulation but not dosage. pH-dependent mesalamine reduced leukopenia risk in mesalamine users.
NUDT15 codon 139 genotyping effectively reduces thiopurine-induced AEs and improves treatment retention rates in IBD patients after genotype-based dose adjustments. This study provides data-driven treatment strategies based on genotype and identifies risk factors for specific AEs, contributing to a refined thiopurine treatment approach.

BACKGROUND: Risk factors for developing pancreatitis due to thiopurines in patients with inflammatory bowel disease (IBD) are not clearly identified. Our aim was to evaluate the predictive pharmacogenetic risk of pancreatitis in IBD patients treated with thiopurines.
METHODS: We conducted an observational pharmacogenetic study of acute pancreatitis events in a cohort study of IBD patients treated with thiopurines from the prospectively maintained ENEIDA registry biobank of GETECCU. Samples were obtained and the CASR, CEL, CFTR, CDLN2, CTRC, SPINK1, CPA1, and PRSS1 genes, selected based on their known association with pancreatitis, were fully sequenced.
RESULTS: Ninety-five cases and 105 controls were enrolled; a total of 57% were women. Median age at pancreatitis diagnosis was 39 years. We identified 81 benign variants (50 in cases and 67 in controls) and a total of 35 distinct rare pathogenic and unknown significance variants (10 in CEL, 21 in CFTR, 1 in CDLN2, and 3 in CPA1). None of the cases or controls carried pancreatitis-predisposing variants within the CASR, CPA1, PRSS1, and SPINK1 genes, nor a pathogenic CFTR mutation. Four different variants of unknown significance were detected in the CDLN and CPA1 genes; one of them was in the CDLN gene in a single patient with pancreatitis and 3 in the CPA1 gene in 5 controls. After the analysis of the variants detected, no significant differences were observed between cases and controls.
CONCLUSIONS: In patients with IBD, genes known to cause pancreatitis seem not to be involved in thiopurine-related pancreatitis onset.

UNASSIGNED: Thiopurines are commonly used to treat inflammatory bowel disease but withdrawal due to side effects are common. Thioguanine has been suggested to be better tolerated than conventional thiopurines.
UNASSIGNED: We studied drug-survival of low dose of thioguanine in real-life clinical practice in comparison to conventional thiopurines.
UNASSIGNED: Retrospective observational study.
UNASSIGNED: All patients born 1956 and later, and who at least once started thiopurine treatment between 2006 and 2022 were included. A medical chart review was performed that noted drug-survival for every thiopurine treatment attempt. The Mantel-Cox rank test was used to test differences in drug-survival for different thiopurines. Blood chemistry analysis and faecal calprotectin levels were registered for the first 5 years of treatment.
UNASSIGNED: In the study population, there was 379 initiated thiopurine treatments (210 for Crohn\'s disease and 169 for ulcerative colitis) in 307 patients with inflammatory bowel disease (IBD). Low-dose thioguanine (median dose 11 mg; 25-75th percentile 7-19 mg) had been initiated in 31 patients. Overall, when including all thiopurine attempts, thioguanine had the longest drug-survival [Mantel-Cox rank test: thioguanine versus azathioprine p = 0.014; thioguanine versus 6-mercaptopurine (6-MP) p < 0.001]. For second-line thiopurine treatment thioguanine had longer drug-survival than 6-MP (Mantel-Cox rank test: p = 0.006). At 60 months, 86% of the patients who started low-dose thioguanine were still on treatment compared to 42% of the patients who started 6-MP (p = 0.022). The median 6-thioguanine nucleotide levels in patients treated with thioguanine was 364 pmol/8 × 108. Patients on thioguanine treatment showed significantly lower values of median mean corpuscular volume at follow-up than patients treated with azathioprine and 6-MP. Patients treated with 6-MP showed significantly lower levels of FC in the third year of treatment compared to patient treated with azathioprine (59 versus 109 µg/g; p = 0.023), but there was no significant difference in FC levels for thioguanine compared to azathioprine (50 versus 109 µg/g; p = 0.33).
UNASSIGNED: Treatment with a low dose of thioguanine is well-tolerated in patients with IBD and had a significantly higher drug-survival than conventional thiopurines.
Low-dose of the immunomodulator drug thioguanine are well tolerated by patients with inflammatory bowel disease Thiopurines are commonly used to treat inflammatory bowel disease but it is common that patients end treatment due to side-effects. The thiopurine thioguanine has been suggested to be better tolerated than other thiopurines. We aimed to study if a low-dose of thioguanine had been tolerated better and used longer than other thiopurines in patients with inflammatory bowel disease at our clinic. In the study population there was 379 initiated thiopurine treatments in 307 patients with inflammatory bowel disease. Among those patients a low-dose thioguanine had been initiated in 31 patients. Overall, when including all thiopurine attempts, thioguanine had longest drug-survival of all thiopurines. For second line thiopurine treatment thioguanine had longer drug-survival than the thiopurine 6-mercaptopurine that are usually used as second line thiopurine treatment. At 60 months, 86% of the patients who started low dose thioguanine was still on treatment compared to 42% of the patients who started 6-mercaptopurine.There was a similar response on inflammatory markers the first five years from starting treatment with thioguanines compared to conventional used thiopurines. We conclude that treatment with a low-dose of thioguanine is well tolerated in patients with inflammatory bowel disease and have a significantly higher drug survival than conventional thiopurines.

BACKGROUND: 6-Mercaptopurine (6MP) is the mainstay chemotherapy for acute lymphoblastic leukemia (ALL) and is conventionally available as 50 mg tablets. A new 6MP powder for oral suspension (PFOS 10 mg/mL) was developed recently by IDRS Labs, India, intended for pediatric use. A comparative pharmacokinetics of PFOS with T. mercaptopurine was conducted to determine the dose equivalence.
METHODS: An open-label, randomized, two-treatment, two-period, two-sequence, single oral dose, crossover, bioequivalence study was conducted on 51 healthy adult subjects. Post hoc, a population pharmacokinetic (PopPK) model was developed using the healthy volunteer data to perform simulations with various PFOS doses and select a bioequivalent dose. Further, to confirm the safety of PFOS in pediatrics, a simulation of 6MP and 6-thioguanine exposures was performed by incorporating the formulation-specific parameters derived from the healthy volunteer study into the PopPK model in childhood ALL available in literature.
RESULTS: The 6MP PFOS had 47% higher oral bioavailability compared to the reference product. Simulations using a two-compartmental PopPK model with dissolution and transit compartments showed that 40 mg of PFOS was found to be equivalent to 50 mg tablets. The simulated 6-thioguanine nucleotide concentrations in children using the dose adjusted for PFOS were between 114 and 703.6 pmol/8 × 108 RBC, which was within the range reported in pediatric ALL studies.
CONCLUSIONS: 6MP PFOS 10 mg/mL should be administered at a 20% lower dose than the tablet to achieve comparable exposure. 6MP PFOS addresses an unmet medical need for a liquid formulation of 6MP in the Indian subcontinent.

Thiopurines are established treatments for inflammatory bowel disease (IBD), yet concerns remain regarding their safety.
To evaluate the use of thiopurine-allopurinol combination therapy compared to standard thiopurine therapy in IBD.
We performed a multicentre, randomised, placebo-controlled trial to compare the efficacy and safety of thiopurine-allopurinol versus thiopurine with placebo for adults commencing a thiopurine for IBD. Patients had active disease at baseline; dosing of therapy was based on a pre-specified regimen and subsequent metabolites. The primary outcome was the proportion of patients achieving a composite of symptomatic disease activity remission (Harvey Bradshaw Index <5 for Crohn\'s disease, Simple Clinical Colitis Activity Index <4 for ulcerative colitis) and a faecal calprotectin <150 μg/g after 26 weeks of treatment.
The trial was terminated early due to slow recruitment. We randomised 102 participants (54 thiopurine-allopurinol, 48 thiopurine with placebo) with similar age (median 42 vs 48 years) and sex distribution (46% women per group). A higher proportion achieved the primary outcome in the thiopurine-allopurinol group (50% vs 35%, p = 0.14) and fewer participants stopped their allocated therapy due to adverse events (11% vs 29%, p = 0.02). Also, within the thiopurine-allopurinol group, thiopurine dose adjustments were less frequent (69% vs 92%, p = 0.03), a higher proportion achieved an early therapeutic 6-TGN level at week 6 (71% vs 53%, p = 0.19), and adverse events attributed to therapy were less frequent (15% vs 44%, p = 0.002).
Thiopurine-allopurinol therapy is safe and mitigates thiopurine adverse effects, thus enhancing tolerability without compromising efficacy (ACTRN12613001347752).

OBJECTIVE: SELECTION is the first study to assess the impact of concomitant thiopurine and other immunomodulator [IM] use on the efficacy and safety of a Janus kinase inhibitor, filgotinib, in patients with ulcerative colitis.
METHODS: Data from the phase 2b/3 SELECTION study were used for this post hoc analysis. Patients were randomised [2:2:1] to two induction studies [biologic-naive, biologic-experienced] to filgotinib 200 mg, 100 mg, or placebo. At Week 10, patients receiving filgotinib were re-randomised [2:1] to continue filgotinib or to switch to placebo until Week 58 [maintenance]. Outcomes were compared between subgroups with and without concomitant IM use.
RESULTS: At Week 10, similar proportions of patients in the +IM and -IM groups treated with filgotinib 200 mg achieved Mayo Clinic Score [MCS] response [biologic-naive: 65.8% vs 66.9%; biologic-experienced: 61.3% vs 50.5%] and clinical remission [biologic-naive: 26.0% vs 26.2%; biologic-experienced: 11.3% vs 11.5%]. At Week 58, similar proportion of patients in the +IM and -IM groups treated with filgotinib 200 mg achieved MCS response [biologic-naive: 74.2% vs 75.0%; biologic-experienced: 45.5% vs 61.4%] and clinical remission [biologic-naive: 51.6% vs 47.4%; biologic-experienced: 22.7% vs 24.3%]. The probability of protocol-specified disease worsening during the maintenance study in patients treated with filgotinib 200 mg did not differ between +IM and -IM groups [p = 0.6700]. No differences were observed in the incidences of adverse events between +IM and -IM groups in the induction/maintenance studies.
CONCLUSIONS: The efficacy and safety profiles of filgotinib treatment in SELECTION did not differ with or without concomitant IM use.
BACKGROUND: NCT02914522.

Thiopurine drugs are immunomodulatory antimetabolites relevant for pediatric patients characterized by dose-dependent adverse effects such as myelosuppression and hepatotoxicity, often related to inter-individual differences, involving the activity of important enzymes at the basis of their biotransformation, such as thiopurine S-methyltransferase (TPMT). Surface Enhanced Raman Scattering (SERS) spectroscopy is emerging as a bioanalytical tool and represents a valid alternative in terms of affordable costs, shorter analysis time and easier sample preparation in comparison to the most employed methods for pharmacokinetic analysis of drugs. The aim of this study is to investigate mercaptopurine and thioguanine pharmacokinetics by SERS in cell lysates of a B-lymphoblastoid cell line (NALM-6), that did (TPMT*1) or did not (MOCK) overexpress the wild-type form of TPMT as an in vitro cellular lymphocyte model to discriminate between cells with different levels of TPMT activity on the base of the amount of thioguanosine nucleotides (TGN) metabolites formed. SERS analysis of the cell lysates was carried out using SERS substrates constituted by Ag nanoparticles deposited on paper and parallel samples were used for quantification of thiopurine nucleotides with liquid chromatography-tandem mass spectrometry (LC-MS/MS). A direct SERS detection method has been set up that could be a tool to study thiopurine drug pharmacokinetics in in vitro cellular models to qualitatively discriminate between cells that do and do not overexpress the TPMT enzyme, as an alternative to other more laborious techniques. Results underlined decreased levels of TGN and increased levels of methylated metabolites when TPMT was overexpressed, both after mercaptopurine and thioguanine treatments. A strong positive correlation (Spearman\'s rank correlation coefficient rho = 0.96) exists between absolute quantification of TGMP (pmol/1 x 106 cells), obtained by LC-MS/MS, and SERS signal (intensity of TGN at 915 cm-1). In future studies, we aim to apply this method to investigate TPMT activity in pediatric patients\' leukocytes.

We analyzed the mercaptopurine adsorption on AlN nanostructures consisting of zero-dimensional nanoclusters, one-dimensional nanotubes, and two-dimensional nanosheets using calculations based on density functional theory (DFT). The adsorption energy, energy band gap, fluctuations in the energy band gap, charge transfers, and types of interactions that take place after mercaptopurine is adsorbed on the AlN nanostructures have all been calculated using DFT. The results show MP adsorption energies on AlN nanoparticles are -4.22, -5.95, and -8.70 eV. In this situation, MP molecules have been drawn to the surface due to the higher adsorption energies available on the AlN nanosheet (a process known as chemisorption). The Atoms in Molecules inquiry was conducted to learn more about and better comprehend the binding properties of the investigated AlN nanostructures utilizing mercaptopurine. Our findings indicate the mercaptopurine/AlN nanosheet bonding\'s electrostatic properties. Additionally, the electrical conductivity of the AlN nanostructures increases whenever mercaptopurine is adsorbed on them. This shows that the AlN nanoparticles might function as chemical sensors and offer an electrical signal in mercaptopurine. The following is the order of sensitivity: AlN nanosheet > AlN nanotube > AlN nanocluster. The outcomes indicate that the nanosheet has the most potential for mercaptopurine detection among the AlN nanostructures.Communicated by Ramaswamy H. Sarma.

OBJECTIVE: Thiopurines are an effective treatment for the maintenance of remission in inflammatory bowel disease (IBD). They can present adverse effects (AEs), with myelotoxicity being the most relevant. This study aims to determine the incidence of AEs related to the starting of thiopurines in our centre.
METHODS: Retrospective study. The AEs in patients that were started on thiopurines between January 2016 and June 2020 were registered, with a two-year follow-up. The mean and standard deviation were used to describe the quantitative variables, and percentages and confidence intervals were used for the qualitative variables. The statistical significance was set at a p-value < 0.05.
RESULTS: 98 patients were included, with 64 AEs detected in 48 patients (49%). Most of the AEs appeared in the first 6 months. The most relevant were: 21 neutropenia (21.4%), 19 hypertransaminasemia (19.4%), 13 digestive intolerances (13.2%), 6 acute pancreatitis (6.12%), 3 phototoxicity (3%), and 2 unknown origin fevers (2%). In 29 patients (29.4%) the treatment had to be suspended due to AEs. In 11 cases (11.2%), azathioprine (AZA) was switched to 6-mercaptopurine (6 MP) as 5 showed tolerance and 6 patients needed suspension due to AEs. Eight patients required hospital admission, but none of them needed intensive care unit admission. There were no fatal adverse effects.
CONCLUSIONS: Thiopurines are a safe drug with few AEs, especially after the first months of treatment. These results suggest that periodic analytic follow-up may not be necessary after the initial period of treatment.

Infertility is a frequent long-term adverse effect of cancer therapy for children. Compromised testicular functions in adolescence are frequent observations after chemotherapy and there are currently no well-established alternatives to avoid this damage. Antimetabolites such as 6-mercaptopurine (6-MP) are used to treat a variety of cancer; however, its treatment-associated adverse effects on the male reproductive functions are overlooked. Here, the molecular processes underlying 6-MP-induced male germ cell damage in juvenile Sprague-Dawley (SD) rats (3 weeks) have been investigated. Rats were administered with low (5 mg/kg), medium (10 mg/kg), and high (20 mg/kg) doses of 6-MP per orally either singly (1 week × 1 cycle) or intermittently (1 week treatment followed by 1 week remission period × 3 cycles). The toxicity was evaluated in terms of genotoxicity and testes- and sperm-related cellular and molecular parameters. Single cycle of exposure either produced mild or no toxic manifestations at the end of the 6th week. Intermittent cycles of exposure, particularly at the 10 and 20 mg/kg, decreased body and organ weights, increased micronucleated cells in the peripheral blood, induced oxidative/nitrosative stress, altered sperm chromatin quality, reduced serum testosterone and follicle stimulating hormone (FSH) levels, increased testicular structural aberrations, DNA damage, and apoptosis, and upregulated TNF-α expression and downregulated p-AMPK and β-catenin expressions. Conclusively, intermittent cycles of exposure at 10 and 20 mg/kg doses to the juvenile rats significantly induced oxidative stress, genotoxicity, and cellular and molecular perturbations in the testes and sperm of adult rats.