The Experts below are selected from a list of 10602 Experts worldwide ranked by ideXlab platform
Matthias Schwab - One of the best experts on this subject based on the ideXlab platform.
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Thiopurines in the Treatment of Childhood Acute Lymphoblastic Leukemia and Genetic Variants of the Thiopurine S-Methyltransferase Gene
Genomics and Pharmacogenomics in Anticancer Drug Development and Clinical Response, 2020Co-Authors: Martin Stanulla, Elke Schaeffeler, Matthias SchwabAbstract:The Thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are essential components of treatment protocols for childhood acute lymphoblastic leukemia (ALL). In the past 25 years, considerable insights into Thiopurine pharmacology have been gained through continuing research efforts which have led to the development of strategies for improving efficacy and reducing toxicity associated with 6-MP and 6-TG application. One important route of metabolism for Thiopurines is methylation by the enzyme Thiopurine S-methyltransferase (TPMT). The gene coding for TPMT is subject to phenotypically relevant genetic variation, with heterozygous individuals having intermediate TPMT activity, and homozygous variant individuals having low TPMT activity. In this chapter, we review the role of Thiopurines in the treatment of childhood ALL and provide an overview of strategies aimed at optimization of Thiopurine application by therapeutic drug monitoring of Thiopurine metabolites and geno- or phenotyping of TPMT.
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clinical pharmacogenetics implementation consortium guideline for Thiopurine dosing based on tpmt and nudt15 genotypes 2018 update
Clinical Pharmacology & Therapeutics, 2019Co-Authors: Mary V. Relling, William E Evans, C M Stein, Matthias Schwab, Teri E. Klein, Michelle Whirlcarrillo, Guilherme Suarezkurtz, Ann M Moyer, Federico Guillermo AntillonklussmannAbstract:: 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).
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clinical pharmacogenetics implementation consortium guidelines for Thiopurine methyltransferase genotype and Thiopurine dosing 2013 update
Clinical Pharmacology & Therapeutics, 2013Co-Authors: Mary V. Relling, William E Evans, Eric E Gardner, C M Stein, Michelle Whirl Carrillo, J K Hicks, Kjeld Schmiegelow, Matthias Schwab, William J Sandborn, Teri E. KleinAbstract:The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing was originally published in March 2011. We reviewed recent literature and concluded that although relevant new evidence has been generated, none of the evidence would change the primary dosing recommendations in the original guideline; therefore, the original publication remains clinically current. Up-to-date information on Thiopurine methyltransferase (TPMT) gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org). The CPIC of the Pharmacogenomics Research Network (http://www.pgrn.org) and the Pharmacogenomics Knowledge Base (PharmGKB, http://www.pharmgkb.org) provides peer-reviewed, updated, evidence-based, freely accessible guidelines for the translation of genetic laboratory tests into actionable prescribing recommendations for specific drugs.1 CPIC guidelines undergo continuous peer review, and information pertaining to gene-specific alleles and nomenclature is updated periodically on the PharmGKB website. Furthermore, approximately every 2 years, each published guideline and associated Supplementary Data online are reviewed and updated accordingly. The first guideline to be reviewed is the CPIC Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing originally published in March 2011.2 We have done a focused review of the literature between June 2010 and November 2012 on TPMT genotype and Thiopurine use (see Supplementary Data, Tables S1–S5, and Figure S1 online). At this time, there is no new evidence that would change our original recommendations in the published guideline; therefore, the original guideline publication remains current. Since the first CPIC guideline was published, the CPIC Steering Committee has recommended that authors address dosing in pediatrics or, at a minimum, comment that there is not enough supporting evidence to allow therapeutic recommendations in pediatrics. As Thiopurines are a staple of childhood acute lymphoblastic leukemia and inflammatory bowel disease treatment regimens, much of the evidence (summarized in Supplementary Table S5 online) used to support the original dosing recommendation was generated in children. Furthermore, the dosing recommendations in Table 2 of the main guideline are presented in units of mg/m2 and mg/kg. Therefore, our original guideline dosing recommendations can be used in both the adult and pediatric populations. Although we are not modifying the original main guideline, we have updated the Supplementary Data online to include additional studies that further support our original recommendations (see Supplementary Table S5 online and the Other Considerations subsection of the Supplementary Data online).3,4,5 In addition, we have added information for additional variant alleles not included in the original guideline (see Supplementary Tables S1 and S2 online). Up-to-date information on TPMT gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org).
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transporter mediated protection against Thiopurine induced hematopoietic toxicity
Cancer Research, 2008Co-Authors: Partha Krishnamurthy, Matthias Schwab, Kazumasa Takenaka, Deepa Nachagari, Jessica A Morgan, Mark Leslie, Weinan Du, Kelli L Boyd, Meyling Cheok, Hiromitsu NakauchiAbstract:Thiopurines are effective immunosuppressants and anticancer agents, but intracellular accumulation of their active metabolites (6-thioguanine nucleotides, 6-TGN) causes dose-limiting hematopoietic toxicity. Thiopurine S -methyltransferase deficiency is known to exacerbate Thiopurine toxicity. However, many patients are highly sensitive to Thiopurines for unknown reasons. We show that multidrug-resistance protein 4 (Mrp4) is abundant in myeloid progenitors and tested the role of the Mrp4, an ATP transporter of monophosphorylated nucleosides, in this unexplained Thiopurine sensitivity. Mrp4-deficient mice experienced Mrp4 gene dosage-dependent toxicity caused by accumulation of 6-TGNs in their myelopoietic cells. Therefore, Mrp4 protects against Thiopurine-induced hematopoietic toxicity by actively exporting Thiopurine nucleotides. We then identified a single-nucleotide polymorphism (SNP) in human MRP4 (rs3765534) that dramatically reduces MRP4 function by impairing its cell membrane localization. This SNP is common (>18%) in the Japanese population and indicates that the increased sensitivity of some Japanese patients to Thiopurines may reflect the greater frequency of this MRP4 SNP. [Cancer Res 2008;68(13):4983–9]
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adherence to Thiopurine treatment in out patients with crohn s disease
Alimentary Pharmacology & Therapeutics, 2007Co-Authors: B Bokemeyer, Elke Schaeffeler, Alexander Teml, C Roggel, P Hartmann, C Fischer, Matthias SchwabAbstract:Summary Background High frequency of incomplete or non-response to azathioprine (AZA) and/or mercaptopurine (MP) limit their use in Crohn’s disease (CD). Non-adherence is considered to be of relevance for ineffectiveness. Aim To assess adherence to Thiopurines in CD out-patients treated in a single gastroenterology practice. Methods Patients were eligible for inclusion if they received AZA/MP for at least 3 months. After follow-up of 3 months, adherence to AZA/MP was assessed by quantitation of relevant Thiopurine metabolite levels in red blood cells as well as by patients’ self-report using standardized questionnaire. Results Sixty-five patients were prospectively included. Six patients (9.2%) had metabolite profiles indicative of non-adherence. Self-assessed questionnaire revealed non-adherence in four of 56 patients (7.1%). Therapeutic drug monitoring (TDM) and self-assessment as two independent methods had a concordance rate of 75%. Metabolite levels and self-assessed adherence were not significantly different between patients in remission compared with those with active disease. Conclusions Out-patients with CD treated in a single gastroenterology practice had a satisfactory adherence (>90%) to Thiopurine therapy. Different measures of adherence (TDM and self-report) applied to the same patient suggest comparable levels. TDM appears to be a reliable tool to assess adherence to Thiopurines in clinical practice.
Mary V. Relling - One of the best experts on this subject based on the ideXlab platform.
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clinical pharmacogenetics implementation consortium guideline for Thiopurine dosing based on tpmt and nudt15 genotypes 2018 update
Clinical Pharmacology & Therapeutics, 2019Co-Authors: Mary V. Relling, William E Evans, C M Stein, Matthias Schwab, Teri E. Klein, Michelle Whirlcarrillo, Guilherme Suarezkurtz, Ann M Moyer, Federico Guillermo AntillonklussmannAbstract:: 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).
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clinical pharmacogenetics implementation consortium guidelines for Thiopurine methyltransferase genotype and Thiopurine dosing 2013 update
Clinical Pharmacology & Therapeutics, 2013Co-Authors: Mary V. Relling, William E Evans, Eric E Gardner, C M Stein, Michelle Whirl Carrillo, J K Hicks, Kjeld Schmiegelow, Matthias Schwab, William J Sandborn, Teri E. KleinAbstract:The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing was originally published in March 2011. We reviewed recent literature and concluded that although relevant new evidence has been generated, none of the evidence would change the primary dosing recommendations in the original guideline; therefore, the original publication remains clinically current. Up-to-date information on Thiopurine methyltransferase (TPMT) gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org). The CPIC of the Pharmacogenomics Research Network (http://www.pgrn.org) and the Pharmacogenomics Knowledge Base (PharmGKB, http://www.pharmgkb.org) provides peer-reviewed, updated, evidence-based, freely accessible guidelines for the translation of genetic laboratory tests into actionable prescribing recommendations for specific drugs.1 CPIC guidelines undergo continuous peer review, and information pertaining to gene-specific alleles and nomenclature is updated periodically on the PharmGKB website. Furthermore, approximately every 2 years, each published guideline and associated Supplementary Data online are reviewed and updated accordingly. The first guideline to be reviewed is the CPIC Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing originally published in March 2011.2 We have done a focused review of the literature between June 2010 and November 2012 on TPMT genotype and Thiopurine use (see Supplementary Data, Tables S1–S5, and Figure S1 online). At this time, there is no new evidence that would change our original recommendations in the published guideline; therefore, the original guideline publication remains current. Since the first CPIC guideline was published, the CPIC Steering Committee has recommended that authors address dosing in pediatrics or, at a minimum, comment that there is not enough supporting evidence to allow therapeutic recommendations in pediatrics. As Thiopurines are a staple of childhood acute lymphoblastic leukemia and inflammatory bowel disease treatment regimens, much of the evidence (summarized in Supplementary Table S5 online) used to support the original dosing recommendation was generated in children. Furthermore, the dosing recommendations in Table 2 of the main guideline are presented in units of mg/m2 and mg/kg. Therefore, our original guideline dosing recommendations can be used in both the adult and pediatric populations. Although we are not modifying the original main guideline, we have updated the Supplementary Data online to include additional studies that further support our original recommendations (see Supplementary Table S5 online and the Other Considerations subsection of the Supplementary Data online).3,4,5 In addition, we have added information for additional variant alleles not included in the original guideline (see Supplementary Tables S1 and S2 online). Up-to-date information on TPMT gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org).
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clinical pharmacogenetics implementation consortium guidelines for Thiopurine methyltransferase genotype and Thiopurine dosing
Clinical Pharmacology & Therapeutics, 2011Co-Authors: Mary V. Relling, William E Evans, Eric E Gardner, C M Stein, Michelle Whirl Carrillo, Kjeld Schmiegelow, William J Sandborn, Teri E. KleinAbstract:The purpose of this guideline is to provide information with which to interpret clinical Thiopurine methyltransferase (TPMT) genotype tests so that the results can be used successfully to guide the dosing of Thiopurines. Although most of the dosing recommendations have been generated from clinical studies in only a few diseases, we have extrapolated recommended doses to all conditions, given the pharmacokinetic characteristics of the genotype/phenotype associations. This is the first guideline developed by the Clinical Pharmacogenetics Implementation Consortium, which is part of the National Institutes of Health’s Pharmacogenomics Research Network.1 The consortium is a community-driven organization that is developing peer-reviewed, freely available gene/drug guidelines that are published in full at PharmGKB (http://www.pharmgkb.org). Guidelines for the use of phenotypic tests (i.e., TPMT activity and Thiopurine metabolite levels) and analyses of cost effectiveness are beyond the scope of this article.
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differential effects of targeted disruption of Thiopurine methyltransferase on mercaptopurine and thioguanine pharmacodynamics
Cancer Research, 2007Co-Authors: Christine Hartford, William E Evans, Matthias Schwab, Erick Vasquez, Mathew J Edick, Jerold E Rehg, Gerard Grosveld, Mary V. RellingAbstract:The recessive deficiency in Thiopurine methyltransferase (TPMT), caused by germ-line polymorphisms in TPMT , can cause severe toxicity after mercaptopurine. However, the significance of heterozygosity and the effect of the polymorphism on thioguanine or in the absence of Thiopurines is not known. To address these issues, we created a murine knockout of Tpmt . Pharmacokinetic and pharmacodynamic studies of mercaptopurine and thioguanine were done in Tpmt −/−, Tpmt +/−, and Tpmt +/+ mice and variables were compared among genotypes. Methylated Thiopurine and thioguanine nucleotide metabolites differed among genotypes after treatment with mercaptopurine ( P < 0.0001 and P = 0.044, respectively) and thioguanine ( P = 0.011 and P = 0.002, respectively). Differences in toxicity among genotypes were more pronounced following treatment with 10 daily doses of mercaptopurine at 100 mg/kg/d (0%, 68%, and 100% 50-day survival; P = 0.0003) than with thioguanine at 5 mg/kg/d (0%, 33%, and 50% 15-day survival; P = 0.07) in the Tpmt −/−, Tpmt +/−, and Tpmt +/+ genotypes, respectively. Myelosuppression and weight loss exhibited a haploinsufficient phenotype after mercaptopurine, whereas haploinsufficiency was less prominent with thioguanine. In the absence of drug challenge, there was no apparent phenotype. The murine model recapitulates many clinical features of the human polymorphism; indicates that mercaptopurine is more affected by the TPMT polymorphism than thioguanine; and provides a preclinical system for establishing safer regimens of genetically influenced antileukemic drug therapy. [Cancer Res 2007;67(10):4965–72]
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differing contribution of Thiopurine methyltransferase to mercaptopurine versus thioguanine effects in human leukemic cells
Cancer Research, 2001Co-Authors: Thierry Dervieux, Eugene Y Krynetski, Javier G Blanco, Elio F Vanin, Martine F Roussel, Mary V. RellingAbstract:Thioguanine and mercaptopurine are prodrugs requiring conversion into Thiopurine nucleotides to exert cytotoxicity. Thiopurine S -methyltransferase (TPMT), an enzyme subject to genetic polymorphism, catabolizes Thiopurines into inactive methylated bases, but also produces methylthioguanine nucleotides and methylmercaptopurine nucleotides from thioguanine and mercaptopurine nucleotides, respectively. To study the effect of TPMT on activation versus inactivation of mercaptopurine and thioguanine, we used a retroviral gene transfer technique to develop human CCRF-CEM cell lines that did (TPMT+) and did not (MOCK) overexpress TPMT. After transduction, TPMT activities were 14-fold higher in the TPMT+ versus the MOCK cell lines ( P 50 = 1.10± 0.12 μm versus 0.55 ± 0.19 μm; P = 0.02); in contrast, TPMT+ cells were more sensitive to mercaptopurine than MOCK cells (IC 50 = 0.52 ± 0.20 μm versus 1.50 ± 0.23 μm; P versus MOCK cells to thioguanine was associated with lower thioguanine nucleotide concentrations (917 ± 282 versus 1515 ± 183 pmol/5 × 10 6 cells; P = 0.01), higher methylthioguanine nucleotide concentrations (252 ± 34 versus 27 ± 10 pmol/5 × 10 6 cells; P = 0.01), less inhibition of de novo purine synthesis (13 versus 95%; P versus 7.2 ± 2.0%; P versus 174 ± 77 pmol/5 × 10 6 cells; P = 0.01) and greater inhibition of de novo purine synthesis (>99% versus 74%; P de novo purine synthesis by methylmercaptopurine nucleotides, whereas thioguanine is inactivated primarily by TPMT.
Teri E. Klein - One of the best experts on this subject based on the ideXlab platform.
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clinical pharmacogenetics implementation consortium guideline for Thiopurine dosing based on tpmt and nudt15 genotypes 2018 update
Clinical Pharmacology & Therapeutics, 2019Co-Authors: Mary V. Relling, William E Evans, C M Stein, Matthias Schwab, Teri E. Klein, Michelle Whirlcarrillo, Guilherme Suarezkurtz, Ann M Moyer, Federico Guillermo AntillonklussmannAbstract:: 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).
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clinical pharmacogenetics implementation consortium guidelines for Thiopurine methyltransferase genotype and Thiopurine dosing 2013 update
Clinical Pharmacology & Therapeutics, 2013Co-Authors: Mary V. Relling, William E Evans, Eric E Gardner, C M Stein, Michelle Whirl Carrillo, J K Hicks, Kjeld Schmiegelow, Matthias Schwab, William J Sandborn, Teri E. KleinAbstract:The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing was originally published in March 2011. We reviewed recent literature and concluded that although relevant new evidence has been generated, none of the evidence would change the primary dosing recommendations in the original guideline; therefore, the original publication remains clinically current. Up-to-date information on Thiopurine methyltransferase (TPMT) gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org). The CPIC of the Pharmacogenomics Research Network (http://www.pgrn.org) and the Pharmacogenomics Knowledge Base (PharmGKB, http://www.pharmgkb.org) provides peer-reviewed, updated, evidence-based, freely accessible guidelines for the translation of genetic laboratory tests into actionable prescribing recommendations for specific drugs.1 CPIC guidelines undergo continuous peer review, and information pertaining to gene-specific alleles and nomenclature is updated periodically on the PharmGKB website. Furthermore, approximately every 2 years, each published guideline and associated Supplementary Data online are reviewed and updated accordingly. The first guideline to be reviewed is the CPIC Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing originally published in March 2011.2 We have done a focused review of the literature between June 2010 and November 2012 on TPMT genotype and Thiopurine use (see Supplementary Data, Tables S1–S5, and Figure S1 online). At this time, there is no new evidence that would change our original recommendations in the published guideline; therefore, the original guideline publication remains current. Since the first CPIC guideline was published, the CPIC Steering Committee has recommended that authors address dosing in pediatrics or, at a minimum, comment that there is not enough supporting evidence to allow therapeutic recommendations in pediatrics. As Thiopurines are a staple of childhood acute lymphoblastic leukemia and inflammatory bowel disease treatment regimens, much of the evidence (summarized in Supplementary Table S5 online) used to support the original dosing recommendation was generated in children. Furthermore, the dosing recommendations in Table 2 of the main guideline are presented in units of mg/m2 and mg/kg. Therefore, our original guideline dosing recommendations can be used in both the adult and pediatric populations. Although we are not modifying the original main guideline, we have updated the Supplementary Data online to include additional studies that further support our original recommendations (see Supplementary Table S5 online and the Other Considerations subsection of the Supplementary Data online).3,4,5 In addition, we have added information for additional variant alleles not included in the original guideline (see Supplementary Tables S1 and S2 online). Up-to-date information on TPMT gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org).
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clinical pharmacogenetics implementation consortium guidelines for Thiopurine methyltransferase genotype and Thiopurine dosing
Clinical Pharmacology & Therapeutics, 2011Co-Authors: Mary V. Relling, William E Evans, Eric E Gardner, C M Stein, Michelle Whirl Carrillo, Kjeld Schmiegelow, William J Sandborn, Teri E. KleinAbstract:The purpose of this guideline is to provide information with which to interpret clinical Thiopurine methyltransferase (TPMT) genotype tests so that the results can be used successfully to guide the dosing of Thiopurines. Although most of the dosing recommendations have been generated from clinical studies in only a few diseases, we have extrapolated recommended doses to all conditions, given the pharmacokinetic characteristics of the genotype/phenotype associations. This is the first guideline developed by the Clinical Pharmacogenetics Implementation Consortium, which is part of the National Institutes of Health’s Pharmacogenomics Research Network.1 The consortium is a community-driven organization that is developing peer-reviewed, freely available gene/drug guidelines that are published in full at PharmGKB (http://www.pharmgkb.org). Guidelines for the use of phenotypic tests (i.e., TPMT activity and Thiopurine metabolite levels) and analyses of cost effectiveness are beyond the scope of this article.
Jeremy D Sanderson - One of the best experts on this subject based on the ideXlab platform.
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A practical guide to Thiopurine prescribing and monitoring in IBD.
Frontline Gastroenterology, 2016Co-Authors: Ben Warner, Peter M. Irving, El Johnston, Monica Arenas-hernandez, Anthony M. Marinaki, Jeremy D SandersonAbstract:Thiopurines are often the mainstay of treatment for many patients with inflammatory bowel disease. As such, a general understanding of the evidence behind their use and of their metabolism is extremely useful in clinical practice. This review gives a practical overview of Thiopurine metabolism, the importance of Thiopurine S-methyltransferase testing prior to the start of therapy and the monitoring of thioguanine nucleotide levels while on treatment, guiding a personalised approach to optimising Thiopurine therapy.
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Optimizing the use of Thiopurines in inflammatory bowel disease
Therapeutic Advances in Chronic Disease, 2015Co-Authors: Rishi M Goel, Anthony M. Marinaki, Paul Blaker, Alexander J. Mentzer, S Fong, Jeremy D SandersonAbstract:Immunomodulator drugs, of which Thiopurines can be considered the backbone, are widely used in the treatment of inflammatory bowel disease. They have been shown to be highly effective and safe; however, a significant proportion of patients are deemed to have a poor response or suffer adverse reactions. Knowing how to monitor and optimize Thiopurine therapy in these scenarios is crucial to effective management. We discuss the metabolism of Thiopurines, the use of enzyme/metabolite testing to guide treatment, as well as strategies to circumvent toxicity and side effects, such as allopurinol coprescription. The indications, use in pregnancy, safety profile and duration of Thiopurine therapy are also discussed.
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Getting the best out of Thiopurine therapy: Thiopurine S-methyltransferase and beyond.
Biomarkers in Medicine, 2015Co-Authors: Steven Chung Ming Fong, Anthony M. Marinaki, Monica Arenas-hernandez, Paul Blaker, Jeremy D SandersonAbstract:Thiopurines are the cornerstone of treatment for a wide variety of medical disorders, ranging from pediatric leukemia to inflammatory bowel disease. Because of their complex metabolism and potential toxicities, the use of biomarkers to predict risk and response is paramount. Thiopurine S-methyltransferase and Thiopurine metabolite levels have emerged as companion diagnostics with crucial roles in facilitating safe and effective treatment. This review serves to update the reader on how these tools are being developed and implemented in clinical practice. A useful paradigm in Thiopurine therapeutic strategy is presented, along with fresh insights into the mechanisms underlying these approaches. We elaborate on potential future developments in the optimization of Thiopurine therapy.
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A practical guide to the use of Thiopurines in oral medicine.
Journal of Oral Pathology & Medicine, 2014Co-Authors: E. Hullah, Anthony M. Marinaki, P. A. Blaker, Michael Escudier, Jeremy D SandersonAbstract:: Thiopurines are widely used as first-line immunosuppressive therapies in the management of chronic inflammatory oral disease. However, despite over half a century of clinical experience, the evidence base for their use is limited. The aims of this paper were to review the evidence for the use of Thiopurines in oral medicine and provide a contemporary model of Thiopurine metabolism and mechanism of action and a rationale for clinical use and safe practice.
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Sa1911 Calculating the “Missed Opportunity” of Thiopurine Monotherapy Overcome With Thiopurine and Allopurinol Combination Therapy
Gastroenterology, 2012Co-Authors: Melissa Smith, Peter M. Irving, Anthony M. Marinaki, Paul Blaker, Simon Anderson, Jeremy D SandersonAbstract:Introduction A proportion of patients preferentially methylate Thiopurines, resulting in high levels of methylated metabolites and low levels of thioguanine nucleotides. This can result in hepatotoxicity and treatment non-response. Co-prescription of Thiopurines (at 25%–50% of standard dose) with allopurinol, (which blocks xanthine oxidase) circumvents this problem, optimising metabolite profile and clinical outcome and additionally overcomes atypical side effects experienced on Thiopurine monotherapy. Using data from a large cohort of patients receiving combination therapy, we aimed to establish what proportion of all patients starting Thiopurines could benefit from combination treatment. Methods Using data from a cohort of 109 patients recruited retrospectively, all receiving combination therapy in our clinic, 1yr clinical response rates were calculated by indication. Using data from a published prospective cohort and side effect rates from meta-analysis, we calculated the proportion of all patients starting Thiopurines that could be salvaged from treatment failure to 1yr remission by combination therapy. Results 10/17 (59%) of hyper-methylating non-responders to Thiopurine monotherapy, 8/17 (47%) of those treated for atypical side effects and 11/15 (73%) switched for hepatotoxicity achieved remission at 1 year. Using these response rates, potential gain was calculated from a prospective cohort (n=207) from our centre. 60 patients discontinued Thiopurine monotherapy due to non-specific side effects, eight due to hepatitis and 32 were hyper-methylating non-responders, a total of 100 patients with clear indications for combination treatment. Our results predict that 53/100 could have achieved 1-year remission, representing 26% of the original cohort. Using a more conservative published side effect rate of 10% (Prefontaine et al 2010, Cochrane Database of Systematic Reviews, CD000545) and excluding 2.8% due to side effects unsuitable for combination therapy (pancreatitis and myelotoxicity), 12% of all patients started on azathioprine could have their outcome on Thiopurine therapy converted from treatment failure to 1-year remission by combination therapy. Conclusion 12%–26% represents the “missed opportunity” of patients starting Thiopurine monotherapy which can be realistically overcome by combination treatment with allopurinol, converting treatment failure to successful 1-year remission. Given that Thiopurines remain a key part of most IBD treatment paradigms, this is an important opportunity for improved treatment outcomes in IBD. Competing interests None declared.
William E Evans - One of the best experts on this subject based on the ideXlab platform.
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clinical pharmacogenetics implementation consortium guideline for Thiopurine dosing based on tpmt and nudt15 genotypes 2018 update
Clinical Pharmacology & Therapeutics, 2019Co-Authors: Mary V. Relling, William E Evans, C M Stein, Matthias Schwab, Teri E. Klein, Michelle Whirlcarrillo, Guilherme Suarezkurtz, Ann M Moyer, Federico Guillermo AntillonklussmannAbstract:: 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).
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novel variants in nudt15 and Thiopurine intolerance in children with acute lymphoblastic leukemia from diverse ancestry
Blood, 2017Co-Authors: Takaya Moriyama, William E Evans, Rina Nishii, Wenjian Yang, Yungli Yang, Hany Ariffin, Chihhsiang Yu, Shirley Kowyin Kham, Sima JehaAbstract:Prolonged exposure to Thiopurines (eg, mercaptopurine [MP]) is essential for curative therapy in acute lymphoblastic leukemia (ALL), but is also associated with frequent dose-limiting hematopoietic toxicities, which is partly explained by inherited genetic polymorphisms in drug metabolizing enzymes (eg, TPMT ). Recently, our group and others identified germ line genetic variants in NUDT15 as another major cause of Thiopurine-related myelosuppression, particularly in Asian and Hispanic people. In this article, we describe 3 novel NUDT15 coding variants (p.R34T, p.K35E, and p.G17_V18del) in 5 children with ALL enrolled in frontline protocols in Singapore, Taiwan, and at St. Jude Children’s Research Hospital. Patients carrying these variants experienced significant toxicity and reduced tolerance to MP across treatment protocols. Functionally, all 3 variants led to partial to complete loss of NUDT15 nucleotide diphosphatase activity and negatively influenced protein stability. In particular, the p.G17_V18del variant protein showed extremely low thermostability and was completely void of catalytic activity, thus likely to confer a high risk of Thiopurine intolerance. This in-frame deletion was only seen in African and European patients, and is the first NUDT15 risk variant identified in non-Asian, non-Hispanic populations. In conclusion, we discovered 3 novel loss-of-function variants in NUDT15 associated with MP toxicity, enabling more comprehensive pharmacogenetics-based Thiopurine dose adjustments across diverse populations.
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clinical pharmacogenetics implementation consortium guidelines for Thiopurine methyltransferase genotype and Thiopurine dosing 2013 update
Clinical Pharmacology & Therapeutics, 2013Co-Authors: Mary V. Relling, William E Evans, Eric E Gardner, C M Stein, Michelle Whirl Carrillo, J K Hicks, Kjeld Schmiegelow, Matthias Schwab, William J Sandborn, Teri E. KleinAbstract:The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing was originally published in March 2011. We reviewed recent literature and concluded that although relevant new evidence has been generated, none of the evidence would change the primary dosing recommendations in the original guideline; therefore, the original publication remains clinically current. Up-to-date information on Thiopurine methyltransferase (TPMT) gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org). The CPIC of the Pharmacogenomics Research Network (http://www.pgrn.org) and the Pharmacogenomics Knowledge Base (PharmGKB, http://www.pharmgkb.org) provides peer-reviewed, updated, evidence-based, freely accessible guidelines for the translation of genetic laboratory tests into actionable prescribing recommendations for specific drugs.1 CPIC guidelines undergo continuous peer review, and information pertaining to gene-specific alleles and nomenclature is updated periodically on the PharmGKB website. Furthermore, approximately every 2 years, each published guideline and associated Supplementary Data online are reviewed and updated accordingly. The first guideline to be reviewed is the CPIC Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing originally published in March 2011.2 We have done a focused review of the literature between June 2010 and November 2012 on TPMT genotype and Thiopurine use (see Supplementary Data, Tables S1–S5, and Figure S1 online). At this time, there is no new evidence that would change our original recommendations in the published guideline; therefore, the original guideline publication remains current. Since the first CPIC guideline was published, the CPIC Steering Committee has recommended that authors address dosing in pediatrics or, at a minimum, comment that there is not enough supporting evidence to allow therapeutic recommendations in pediatrics. As Thiopurines are a staple of childhood acute lymphoblastic leukemia and inflammatory bowel disease treatment regimens, much of the evidence (summarized in Supplementary Table S5 online) used to support the original dosing recommendation was generated in children. Furthermore, the dosing recommendations in Table 2 of the main guideline are presented in units of mg/m2 and mg/kg. Therefore, our original guideline dosing recommendations can be used in both the adult and pediatric populations. Although we are not modifying the original main guideline, we have updated the Supplementary Data online to include additional studies that further support our original recommendations (see Supplementary Table S5 online and the Other Considerations subsection of the Supplementary Data online).3,4,5 In addition, we have added information for additional variant alleles not included in the original guideline (see Supplementary Tables S1 and S2 online). Up-to-date information on TPMT gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org).
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clinical pharmacogenetics implementation consortium guidelines for Thiopurine methyltransferase genotype and Thiopurine dosing
Clinical Pharmacology & Therapeutics, 2011Co-Authors: Mary V. Relling, William E Evans, Eric E Gardner, C M Stein, Michelle Whirl Carrillo, Kjeld Schmiegelow, William J Sandborn, Teri E. KleinAbstract:The purpose of this guideline is to provide information with which to interpret clinical Thiopurine methyltransferase (TPMT) genotype tests so that the results can be used successfully to guide the dosing of Thiopurines. Although most of the dosing recommendations have been generated from clinical studies in only a few diseases, we have extrapolated recommended doses to all conditions, given the pharmacokinetic characteristics of the genotype/phenotype associations. This is the first guideline developed by the Clinical Pharmacogenetics Implementation Consortium, which is part of the National Institutes of Health’s Pharmacogenomics Research Network.1 The consortium is a community-driven organization that is developing peer-reviewed, freely available gene/drug guidelines that are published in full at PharmGKB (http://www.pharmgkb.org). Guidelines for the use of phenotypic tests (i.e., TPMT activity and Thiopurine metabolite levels) and analyses of cost effectiveness are beyond the scope of this article.
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differential effects of targeted disruption of Thiopurine methyltransferase on mercaptopurine and thioguanine pharmacodynamics
Cancer Research, 2007Co-Authors: Christine Hartford, William E Evans, Matthias Schwab, Erick Vasquez, Mathew J Edick, Jerold E Rehg, Gerard Grosveld, Mary V. RellingAbstract:The recessive deficiency in Thiopurine methyltransferase (TPMT), caused by germ-line polymorphisms in TPMT , can cause severe toxicity after mercaptopurine. However, the significance of heterozygosity and the effect of the polymorphism on thioguanine or in the absence of Thiopurines is not known. To address these issues, we created a murine knockout of Tpmt . Pharmacokinetic and pharmacodynamic studies of mercaptopurine and thioguanine were done in Tpmt −/−, Tpmt +/−, and Tpmt +/+ mice and variables were compared among genotypes. Methylated Thiopurine and thioguanine nucleotide metabolites differed among genotypes after treatment with mercaptopurine ( P < 0.0001 and P = 0.044, respectively) and thioguanine ( P = 0.011 and P = 0.002, respectively). Differences in toxicity among genotypes were more pronounced following treatment with 10 daily doses of mercaptopurine at 100 mg/kg/d (0%, 68%, and 100% 50-day survival; P = 0.0003) than with thioguanine at 5 mg/kg/d (0%, 33%, and 50% 15-day survival; P = 0.07) in the Tpmt −/−, Tpmt +/−, and Tpmt +/+ genotypes, respectively. Myelosuppression and weight loss exhibited a haploinsufficient phenotype after mercaptopurine, whereas haploinsufficiency was less prominent with thioguanine. In the absence of drug challenge, there was no apparent phenotype. The murine model recapitulates many clinical features of the human polymorphism; indicates that mercaptopurine is more affected by the TPMT polymorphism than thioguanine; and provides a preclinical system for establishing safer regimens of genetically influenced antileukemic drug therapy. [Cancer Res 2007;67(10):4965–72]
