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            -Methyltransferase Testing for Averting Drug Toxicity in Patients Receiving Thiopurines: a Systematic Review

Roy, L.; Zur, Richard M.; Uleryk, Elizabeth; Carew, Chris; Itô, Shinya; Ungar, Wendy J.

doi:10.2217/pgs.16.12

Cited by 16 publications

(9 citation statements)

References 74 publications

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“…There is an ongoing debate about the advantages and disadvantages of a genotyping vs phenotyping approach, which is discussed in depth in other publications. 63,72 It is important to note that blood transfusions in a 3-month time interval before TPMT phenotyping might affect the analyses and yield unreliable results. Despite observational studies reporting significantly higher risk of myelosuppression in a subset of patients treated with thiopurines, the quality of evidence supporting routine TPMT testing to guide thiopurine dosing was deemed low based on RCTs.…”

Section: Quality Of Evidencementioning

confidence: 99%

American Gastroenterological Association Institute Technical Review on the Role of Therapeutic Drug Monitoring in the Management of Inflammatory Bowel Diseases

et al. 2017

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Therapeutic drug monitoring (TDM), which involves measurement of drug or active metabolite levels and anti-drug antibodies, is a promising strategy that can be used to optimize inflammatory bowel disease therapeutics. It is based on the premise that there is a relationship between drug exposure and outcomes, and that considerable inter-individual variability exists in how patients metabolize the drug (pharmacokinetics) and the magnitude and duration of response to therapy (pharmacodynamics). Therefore, the American Gastroenterological Association has prioritized clinical guidelines on the role of TDM in the management of inflammatory bowel disease. To inform these clinical guidelines, this technical review was developed in accordance with the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework for interventional and prognostic studies, and focused on the application of TDM for biologic therapy, specifically anti-tumor necrosis factor-α agents, and for thiopurines. Focused questions address the benefits and risks of a strategy of reactive TDM (in patients with active inflammatory bowel disease) to guide treatment changes compared with empiric treatment changes, and the benefits and risks of a strategy of routine proactive TDM (during routine clinical care in patients with quiescent disease) compared with no routine TDM. Additionally, the review addresses the benefits and risks of routine measurement of thiopurine methyltransferase enzyme activity or genotype before starting thiopurine therapy compared with empiric weight-based dosing and explores the performance of different trough drug concentrations for anti-tumor necrosis factor agents and thiopurines to inform clinical decision making when applying TDM in a reactive setting. Due to a paucity of data, this review does not address the role of TDM for more recently approved biologic agents, such as vedolizumab or ustekinumab.

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Section: Quality Of Evidencementioning

confidence: 99%

American Gastroenterological Association Institute Technical Review on the Role of Therapeutic Drug Monitoring in the Management of Inflammatory Bowel Diseases

et al. 2017

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“…The calculated sensitivity to detect a homozygous or heterozygous mutation ranged from 13.4% to 100.0% and the calculated specificity ranged from 90.9% to 100.0%. 29 A previous systematic review by Donnan et al reported ranges for the sensitivity and specificity of the TPMT genotype test of 55-100% and 94-100%, respectively. The TPMT phenotype test sensitivity and specificity ranged from 92% to 100% and from 86% to 98%, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…29 Eligible studies were those that: (1) evaluated either a TPMT genotype or TPMT phenotype technology in comparison to a reference standard; (2) presented results on the sensitivity and specificity or positive/negative predictive values together with prevalence, or allowed these measures to be calculated from data in the text, in supplemental files, or from data obtained from study authors; (3) were conducted in any age group; (4) were conducted in any disease group; and (5) were published in any language, so long as translation was possible. Studies not conducted in humans, including animal, tissue and in vitro studies were excluded.…”

Section: Study Selectionmentioning

confidence: 99%

Thiopurine S-methyltransferase testing for averting drug toxicity: a meta-analysis of diagnostic test accuracy

et al. 2016

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Thiopurine S-methyltransferase (TPMT) deficiency increases the risk of serious adverse events in persons receiving thiopurines. The objective was to synthesize reported sensitivity and specificity of TPMT phenotyping and genotyping using a latent class hierarchical summary receiver operating characteristic meta-analysis. In 27 studies, pooled sensitivity and specificity of phenotyping for deficient individuals was 75.9% (95% credible interval (CrI), 58.3-87.0%) and 98.9% (96.3-100%), respectively. For genotype tests evaluating TPMT*2 and TPMT*3, sensitivity and specificity was 90.4% (79.1-99.4%) and 100.0% (99.9-100%), respectively. For individuals with deficient or intermediate activity, phenotype sensitivity and specificity was 91.3% (86.4-95.5%) and 92.6% (86.5-96.6%), respectively. For genotype tests evaluating TPMT*2 and TPMT*3, sensitivity and specificity was 88.9% (81.6-97.5%) and 99.2% (98.4-99.9%), respectively. Genotyping has higher sensitivity as long as TPMT*2 and TPMT*3 are tested. Both approaches display high specificity. Latent class meta-analysis is a useful method for synthesizing diagnostic test performance data for clinical practice guidelines.

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“…Targeted panels may also include genes in drug metabolism. Including genes such as TMPT and NUDT15 on a hematological cancer panel can provide crucial genotype information that clinicians may use to alter thiopurine dosing, reducing medication toxicity [Burnett et al, 2014;Yang et al, 2015;Roy et al, 2016].…”

Section: Detection Of Underlying Germline Variantsmentioning

confidence: 99%

The Genomic Era of Clinical Oncology: Integrated Genomic Analysis for Precision Cancer Care

Surrey

Luo²,

Chang³

et al. 2016

Cytogenet Genome Res

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Genomic alterations are important biological markers for cancer diagnosis and prognosis, disease classification, risk stratification, and treatment selection. Chromosomal microarray analysis (CMA) and next-generation sequencing (NGS) technologies are superb new tools for evaluating cancer genomes. These state-of-the-art technologies offer high-throughput, highly accurate, targeted and whole-genome evaluation of genomic alterations in tumor tissues. The application of CMA and NGS technologies in cancer research has generated a wealth of useful information about the landscape of genomic alterations in cancer and their implications in cancer care. As the knowledge base in cancer genomics and genome biology grows, the focus of research is now shifting toward the clinical applications of these technologies to improve patient care. Although not yet standard of care in cancer, there is an increasing interest among the cancer genomics communities in applying these new technologies to cancer diagnosis in the Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories. Many clinical laboratories have already started adopting these technologies for cancer genomic analysis. We anticipate that CMA and NGS will soon become the major diagnostic means for cancer genomic analysis to meet the increasing demands of precision cancer care.

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Thiopurine S -Methyltransferase Testing for Averting Drug Toxicity in Patients Receiving Thiopurines: a Systematic Review

Abstract: Clinical decision-makers require high-quality evidence of clinical validity and clinical utility of TPMT genotyping to ensure appropriate use in patients.

Cited by 16 publications

References 74 publications

American Gastroenterological Association Institute Technical Review on the Role of Therapeutic Drug Monitoring in the Management of Inflammatory Bowel Diseases

American Gastroenterological Association Institute Technical Review on the Role of Therapeutic Drug Monitoring in the Management of Inflammatory Bowel Diseases

Thiopurine S-methyltransferase testing for averting drug toxicity: a meta-analysis of diagnostic test accuracy

The Genomic Era of Clinical Oncology: Integrated Genomic Analysis for Precision Cancer Care

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