Systematic Review of Thiopurine Methyltransferase Genotype and Enzymatic Testing Strategies (original) (raw)
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Clinical Pharmacology & Therapeutics, 2019
Thiopurine methyltransferase (TPMT) activity exhibits a monogenic codominant inheritance and catabolizes thiopurines. TPMT variant alleles are associated with low enzyme activity and pronounced pharmacologic effects of thiopurines. Loss-of-function alleles in the NUDT15 gene are common in Asians and Hispanics and reduce the degradation of active thiopurine nucleotide metabolites, also predisposing to myelosuppression. We provide recommendations for adjusting starting doses of azathioprine, mercaptopurine, and thioguanine based on TPMT and NUDT15 genotypes (updates on www.cpicpgx.org). This document is an update to the Clinical Implementation Consortium (CPIC) Guidelines for Thiopurine Methyltransferase Genotype and Thiopurine guideline updated last in April 2013. The guideline text, evidence table, and recommendations have been updated to reflect new evidence. Specifically, this guideline adds a recommendation for NUDT15 genotype with minor changes to the TPMT recommendations. Although most of the dosing recommendations have been generated from clinical studies in just a few diseases, we have extrapolated recommended doses to all conditions, given the pharmacokinetic nature of the genotype/phenotype associations. CPIC guidelines are published and periodically updated on www.cpicpgx.org. Detailed guidelines for use of phenotypic tests (e.g., TPMT activity and thiopurine metabolite levels) as well as analyses of cost-effectiveness are beyond the scope of this document.
2010
Thiopurine methyltransferase (TPMT) metabolises the widely prescribed thiopurine drugs. The activity of this enzyme varies between individuals and this can influence treatment success. Rapid and accurate assays of TPMT and 6TGN, the active thiopurine metabolites, are increasingly recognised as valuable clinical tools, to guide dosing and treatment. This work examines and develops methods for determining a patient's TPMT status and measuring 6TGN levels, adapting them for analysis using whole blood rather than washed red blood cell preparations. The advantages and limitations of these new assays in practice are investigated, which clearly shows that the more rapid new methods have increased clinical significance and utility. Experimental work and research provides an increased understanding of factors influencing determination and significance of a patient's TPMT status and thiopurine metabolite levels. This includes possible misclassification of TPMT status when expressing results in relation to patient haemoglobin and a longitudinal study of TPMT activity of patients commencing thiopurine therapy which demonstrates no enzyme induction.
Evidence report/technology assessment, 2010
To examine whether pretreatment determination of thiopurine methyltransferase (TPMT) enzymatic activity (phenotyping) or TPMT genotype, to guide thiopurine therapy in chronic autoimmune disease patients, reduces treatment harms. Other objectives included assessing: preanalytic, analytic, and postanalytic requirements for TPMT testing; diagnostic accuracy of TPMT genotyping versus phenotyping; association of thiopurine toxicity with TPMT genotypic or phenotypic status; and costs of testing, care, and treating drug-associated complications. MEDLINE®, EMBASE®, and Healthstar were searched from inception to May 2010; the Cochrane Library® to October 2009; and BIOSIS®, Genetics Abstracts, and EconLit™ to May 2009, for English language records. A reviewer screened records, and a second reviewer verified exclusions and subsequent selection of relevant studies. Studies in patients with leukemia and organ transplant were excluded. Additionally, laboratories that provide TPMT analytical servi...
British Journal of Clinical Pharmacology, 1994
Thiopurine methyltransferase (TPMT) is a cytosolic enzyme involved in the catabolism of thiopurine drugs, which are used to treat cancer patients and organ transplant recipients. Because TPMT activity is polymorphic and under genetic control, large interindividual variations in the immunosuppressive activity and toxicity of these drugs may, at least in part, be inherited. 2 We have developed a specific h.p.l.c. method for measuring 6-methyl mercaptopurine formed from 6-mercaptopurine (6-MP) in red blood cell lysates during the TPMT assay procedure. In blinded assays of 55 samples from adult blood donors, the results of the h.p.l.c. method correlated with those of the radiochemical reference method (r = 0.83, P < 0.001). 3 Using this h.p.l.c. assay, we tested the effect of known inhibitors of TPMT activity (syringic acid, p-anisic acid and tropolone) in vitro and showed that they were highly inhibitory. We also found that drugs often administered concomitantly with 6-MP (prednisone, prednisolone, 6-methylprednisolone, cyclophosphamide, methotrexate, and trimethoprim-sulphamethoxazole) had little or no effect on TPMT activity in vitro. 4 In a group of 300 French individuals, TMPT activity was highly variable, ranging from 4.7 to 35.3 nmol h-1 ml-' of packed red blood cells (nmol h-1 ml-' PRBC) with a mean value of 19.3 ± 4.9. TMPT activity was not influenced by sex. 5 This sensitive and reproducible h.p.l.c. assay for TPMT activity in red blood cells may prove useful for prospective clinical studies designed to optimise dosage regimens of thiopurine drugs (detection limit for 6-methyl mercaptopurine is 5 ng ml-', intra-and inter-assay variations are 6.8 and 8.2%, respectively).
Cardiovascular & hematological agents in medicinal chemistry, 2017
Thiopurine S-methyltransferase (TPMT) enzyme metabolizes thiopurine drugs which are widely used in various disciplines as well as in leukemias. Individual enzyme activity varies depending on the genetic polymorphisms of TPMT gene located at chromosome 6. Up to 14% of population is known to have a decreased enzyme activity, and if treated with standard doses of thiopurines, these individuals are at the high risk of severe adverse drug reactions (ADR) as myelosuppression, gastrointestinal intolerance, pancreatitis and hypersensitivity. However, TPMT-deficient patients can successfully be treated with decreased thiopurine doses if enzyme status is identified by a prior testing. TPMT status identification is a pioneering experience in an application of a pharmacogenetic testing in clinical settings. 4 TPMT (*2,*3A, *3B, *3C) alleles are known to account for 80-95% of a decreased enzyme activity, and therefore, identifying the presence of these alleles supported by phenotypic measurement...
Pharmacotherapy, 2008
To determine if laboratories with disparate alanine aminotransferase (ALT) reference ranges would report different rates of elevation greater than the upper limit of reference range (ULRR) and thus have the potential to alter study results. Design. Interlaboratory evaluation. Setting. Research department of a poison and drug center. Samples. Sixty-five serum samples collected from a previously published randomized clinical trial that were stored at -57°C for approximately 2 years. Intervention. Stored serum samples were divided and sent to two independent clinical laboratories (laboratory A and laboratory B) that had disparate ALT reference ranges. Measurements and Main Results. Samples were stratified by ALT levels measured during the primary study to provide a spectrum of ALT values. The ULRR for serum ALT level at laboratory A was 63 and 54 U/L for male and female subjects, respectively, and for laboratory B was 31 U/L for both male and female subjects. Each laboratory used different instruments and reagents. The primary outcome was the rate of ALT elevation (> 1 x ULRR and > 3 x ULRR) for each study laboratory. The overall mean ALT activity at laboratory A was 33.6 U/L (95% confidence interval [CI] 28.1-39.2 U/L) and at laboratory B was 47.92 U/L (95% CI 40.0-55.8 U/L). Although laboratory A had the higher ULRR (74% higher for female subjects, 103% higher for male subjects), it consistently reported lower ALT values. Laboratory B reported a significantly higher proportion of samples that had an ALT value greater than 1 time the ULRR and greater than 3 times the ULRR. Conclusion. Our findings suggest that laboratories systemically report different values for aminotransferase levels and that the choice of laboratory may alter the proportion of patients who have an elevation in ALT levels. Until standardized reference ranges are adopted, studies reporting an outcome that depends on the reference range (such as "abnormal" or > 3 x ULRR) will be subject to misclassification bias based on the laboratory performing the analysis. Key Words: alanine aminotransferase, ALT, liver, clinical laboratory techniques, systematic bias, upper limit of reference range, ULRR.