Exploring Associations of 6-Thioguanine Nucleotide Levels and Other Predictive Factors with Therapeutic Response to Azathioprine in Pediatric Patients with IBD Using Multilevel Analysis

Nguyen, Thi-Van-Anh; Vu, Dinh Hoa; Nguyen, Thi-Mai-Hoang; Lachaux, Alain; Boulieu, Roselyne

doi:10.1097/mib.0b013e3182a508c6

Cited by 19 publications

(16 citation statements)

References 39 publications

(53 reference statements)

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“…Some studies showed a relation between mild leucopenia (defined as WBC count ≥3.0 and <5.0 × 10 9 /L) and treatment efficacy . This increased treatment efficacy in case of leucopenia was independent from 6‐TGN levels . Therefore, if our observations are correct, a more preserved strategy in case of moderate leucopenia would not increase infection risk, prevents a patient from under‐dosing, and possibly increases treatment efficacy.…”

Section: Discussionmentioning

confidence: 97%

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Risk factors for thiopurine‐induced myelosuppression and infections in inflammatory bowel disease patients with a normal TPMT genotype

Broekman

Coenen²,

Wanten

et al. 2017

Aliment Pharmacol Ther

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SummaryBackgroundLeucopenia is a common side effect in patients treated with thiopurines. Variants in the thiopurine S‐methyltransferase (TPMT) gene are the best‐known risk factor, but only explain up to 25% of leucopenia cases.AimTo identify the clinical risk factors for thiopurine‐induced leucopenia in patients without a common TPMT variant, and explore if these patients are at increased risk for infections.MethodsPost hoc analysis of the Thiopurine response Optimisation by Pharmacogenetic testing in Inflammatory bowel disease Clinics (TOPIC) trial. For this analysis, patients without a variant in TPMT (*2, *3A or*3C) were included. Uni‐ and multivariate Cox‐proportional hazard models were used to identify risk factors for leucopenia and infections. Leucopenia was defined as a white blood cell (WBC) count <3.0 × 109/L and infections were classified according to the Common Terminology Criteria for Adverse Events.ResultsSixty hundred and ninety‐five patients (90.6%) included in the TOPIC‐trial had no variant in TPMT, of which 45 (6.5%) developed leucopenia. Median time to leucopenia was 56 (29‐112) days. Multivariate analysis showed that use of mercaptopurine compared to azathioprine was associated with leucopenia (hazard ratio [HR] 2.61 [95% CIs, 1.39‐4.88; P < .01]) and a higher baseline WBC count was protective (HR 0.80 [95% CIs, 0.71‐0.89; P < .01]). Risk factors for infections were older age (per 10 year; HR 2.07 [95% CIs, 1.18‐3.63; P = .01]) and concomitant use of biologic drugs (HR 2.15 [95% CIs, 1.14‐4.07; P = .02]).ConclusionsLow baseline WBC count and mercaptopurine, due to a relatively higher dose, were risk factors for thiopurine‐induced leucopenia in patients without a TPMT variant.

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Section: Discussionmentioning

confidence: 97%

“…The lack of association between leucopenia and infections might have great implications for clinical practice. Some studies showed a relation between mild leucopenia (defined as WBC count ≥3.0 and <5.0 × 10 9 /L) and treatment efficacy . This increased treatment efficacy in case of leucopenia was independent from 6‐TGN levels .…”

Section: Discussionmentioning

confidence: 99%

Risk factors for thiopurine‐induced myelosuppression and infections in inflammatory bowel disease patients with a normal TPMT genotype

Broekman

Coenen²,

Wanten

et al. 2017

Aliment Pharmacol Ther

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“…Although some previous studies suggested that the correlation between 6TGN serum levels and weight-based thiopurine dosing might be poor, recent data have shown good positive correlation between oral dosage of AZA and 6TGN serum levels in paediatric population 33 39–41. Therefore, adjusting AZA dosing according to 6TGN serum levels can be a useful tool leading to improved outcomes at least in cases of inefficacy or adverse events, as it has been recently shown in a retrospectively observational study focused on the clinical usefulness of thiopurine metabolites monitoring in South Australia 42.…”

Section: Monitoring Thiopurine Metabolitesmentioning

confidence: 98%

“…Even though leucopenia is a well-recognised effect of thiopurines and closely related to their therapeutic mechanism, its association with therapeutic efficacy has yet to be determined. In spite of recent research, correlation between 6TGN serum levels and lymphopenia or leucopenia still remains uncertain, although a prospective observational study has recently shown that MCV>101fL reliably excluded subtherapeutic 6TGN levels 33 41 45–47…”

Section: Monitoring Thiopurine Metabolitesmentioning

confidence: 99%

Monitoring thiopurine metabolites in inflammatory bowel disease

González-Lama

Gisbert²

2016

Frontline Gastroenterol

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Thiopurines (azathioprine and mercaptopurine) are one of the immunosuppressive mainstays for the treatment of inflammatory bowel disease. In spite of its widespread use, thiopurine metabolism is still not fully understood, and a significant proportion of patients suffer toxicity or lack of efficacy. Different enzymatic pathways with individual variations constitute a pharmacogenetic model that seems to be suitable for monitoring and therapeutic intervention. This review is focused on current concepts and recent research that may help clinicians to rationally optimise thiopurine treatment in patients with inflammatory bowel disease.

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“…A polymorphism of this enzyme can lead to inefficacy or, conversely, cellular toxicity. Patients with high TPMT activity have a metabolism that could shift to the formation of methylated derivatives with lower concentrations of 6‐TGN, where an increase in doses would be required to have an effect . Similarly, 30%‐60% of patients with intermediate activity have been shown to have cytotoxic effects with standard doses.…”

Section: Introductionmentioning

confidence: 99%

Red Blood cell IMPDH activity in adults and children with or without azathioprine: Relationship between thiopurine metabolites, ITPA and TPMT activities

Citterio-Quentin

Mahmoudi

Perret

et al. 2018

Basic Clin Pharma Tox

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Inosine monophosphate dehydrogenase (IMPDH) is considered as the limiting enzyme of thiopurine metabolism for the formation of 6-thioguanine nucleotides (6-TGN). No data are available on the influence of RBC IMPDH activity on the metabolism of thiopurine drugs in individuals with IBD. The aims of this study were as follows: (a) to carry out a phenotypic study of RBC IMPDH activity in adults and children treated or not with azathioprine (AZA) for autoimmune diseases, and (b) to investigate the relationship between the activities of IMPDH, thiopurine metabolites, inosine triphosphatase (ITPA) and thiopurine methyltransferase (TPMT). IMPDH activity was determined in 97 adults and 67 children treated or not with AZA. 6-Thioguanine nucleotides (6-TGN), 6-methylmercaptopurine nucleotide (6-MeMPN) levels, and ITPA as well as TPMT activities

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Exploring Associations of 6-Thioguanine Nucleotide Levels and Other Predictive Factors with Therapeutic Response to Azathioprine in Pediatric Patients with IBD Using Multilevel Analysis

Cited by 19 publications

References 39 publications

Risk factors for thiopurine‐induced myelosuppression and infections in inflammatory bowel disease patients with a normal TPMT genotype

Risk factors for thiopurine‐induced myelosuppression and infections in inflammatory bowel disease patients with a normal TPMT genotype

Monitoring thiopurine metabolites in inflammatory bowel disease

Red Blood cell IMPDH activity in adults and children with or without azathioprine: Relationship between thiopurine metabolites, ITPA and TPMT activities

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