Variantes genéticas de la tiopurina metiltransferasa e incidencia de eventos adversos en pacientes con indicación de azatioprina / Genetic polymorphisms of thiopurine methyltransferase and incidence of adverse events in patients with medical indication of azathioprine

La azatioprina es una tiopurina que presenta rango terapéutico estrecho y marcada toxicidad hematológica y hepática. La tiopurina S-metiltransferasa es una enzima que metaboliza ese grupo de drogas. Mutaciones en el gen que codifica dicha enzima aumentan el riesgo de presentar eventos adversos, por lo que su estudio farmacogenético permite contar con información para el diseño de la estrategia terapéutica. Sin embargo, su utilidad en el medio local no está completamente establecida. Fueron incluidos 45 sujetos (13 hombres) con indicación de azatioprina. Se determinó la presencia de las mutaciones *2, *3A, *3B y *3C de TMPT por PCR-RFLP y se analizó la relación entre el genotipo y la incidencia de eventos adversos relacionados al fármaco. Nueve portaban al menos un alelo no funcional, uno de ellos con genotipo *3A/*3A. Se detectó toxicidad en 3 de los 18 que iniciaron tratamiento con azatioprina: 2 pacientes con genotipo normal presentaron eventos adversos leves, y el único evento adverso de gravedad (aplasia medular) ocurrió en el sujeto con genotipo homocigota mutado. El único que presentó genotipo homocigota mutado desarrolló el más grave de los eventos adversos registrados, a pesar de estar en tratamiento con dosis bajas de azatioprina. Por este motivo, la determinación del genotipo de la tiopurina metiltransferasa pareciera ser de utilidad, pero no reemplaza la necesidad de seguimiento clínico y bioquímico en pacientes en tratamiento con tiopurinas.

Azathioprine is a thiopurine which has a narrow therapeutic index and marked hematological and hepatic toxicity. Thiopurine s-methyltransferase is an enzyme involved in the metabolism of thiopurines. Mutations in the gene that encodes the enzyme may augment the risk of adverse events. For that reason, pharmacogenetic determinations prior to the initiation of therapy can provide useful information for the future therapeutic strategy. Nevertheless, its utility in the local environment is not completely established. Forty-five subjects (13 men) who had been prescribed azathioprine were included. The presence of *2, *3A, *3B and *3C mutations were determined by PCR-RFLP, and the relationship between genotype and incidence of adverse events related to the drug was analyzed. Nine carried at least one non-functional allele, one of them with *3A/*3A genotype. Among the eighteen patients who initiated treatment with azathioprine, toxicity was detected in 3 cases: 2 mild events were observed in patients with normal genotype, and the only serious event (bone marrow suppression) occurred in the individual with homozygous mutant genotype. The only homozygous mutant patient developed the most severe of the registered events, in spite of being under treatment with low doses of azathioprine. This is the reason why enzymatic determination could be of utility, even though it does not replace clinical and biochemical follow-up in patients under thiopurine treatment.

Pharmacogenetic testing in oncology: a Brazilian perspective

Pharmacogenetics, a major component of individualized or precision medicine, relies on human genetic diversity. The remarkable developments in sequencing technologies have revealed that the number of genetic variants modulating drug action is much higher than previously thought and that a true personalized prediction of drug response requires attention to rare mutations (minor allele frequency, MAF<1%) in addition to polymorphisms (MAF>1%) in pharmacogenes. This has major implications for the conceptual development and clinical implementation of pharmacogenetics. Drugs used in cancer treatment have been major targets of pharmacogenetics studies, encompassing both germline polymorphisms and somatic variants in the tumor genome. The present overview, however, has a narrower scope and is focused on germline cancer pharmacogenetics, more specifically, on drug/gene pairs for which pharmacogenetics-informed prescription guidelines have been published by the Clinical Pharmacogenetics Implementation Consortium and/or the Dutch Pharmacogenetic Working Group, namely, thiopurines/TPMT, fluoropyrimidines/UGT1A1, irinotecan/UGT1A1 and tamoxifen/CYP2D6. I begin by reviewing the general principles of pharmacogenetics-informed prescription, pharmacogenetics testing and the perceived barriers to the adoption of routine pharmacogenetics testing in clinical practice. Then, I highlight aspects of the pharmacogenetics testing of the selected drug-gene pairs and finally present pharmacogenetics data from Brazilian studies pertinent to these drug-gene pairs. I conclude with the notion that pharmacogenetics testing has the potential to greatly benefit patients by enabling precision medicine applied to drug therapy, ensuring better efficacy and reducing the risk of adverse effects.

Pregnancy outcome in women with inflammatory bowel disease treated with anti-tumor necrosis factor and/or thiopurine therapy: a multicenter study from Japan

BACKGROUND/AIMS: Anti-tumor necrosis factor drugs (anti-TNF) and thiopurines are important treatment options in patients with inflammatory bowel disease (IBD), including during pregnancy. However, there are limited data on the benefit/risk profile of anti-TNF and thiopurines during pregnancy in Asia. The aim of this study was to analyze pregnancy outcomes of female Japanese IBD patients treated with anti-TNF and/or thiopurines. METHODS: This cross-sectional study assessed pregnancy outcomes in 72 women with IBD. Pregnancy outcomes were compared among 31 pregnancies without exposure to infliximab (IFX), adalimumab (ADA), or thiopurines; 24 pregnancies with exposure to anti-TNF treatment (23 IFX, 1 ADA); 7 pregnancies with exposure to thiopurines alone; and 10 pregnancies with exposure to both IFX and thiopurines. RESULTS: Thirty-five of the 41 pregnancies (85.3%) that were exposed to anti-TNF treatment and/or thiopurines resulted in live births after a median gestational period of 38 weeks. Of the 35 live births, 3 involved premature deliveries; 7, low birth weight; and 1, a congenital abnormality. There were 6 spontaneous abortions in pregnancies that were exposed to anti-TNF treatment (17.7%). Pregnancy outcomes among the 4 groups were similar, except for the rate of spontaneous abortions (P =0.037). CONCLUSIONS: Exposure to anti-TNF treatment or thiopurines during pregnancy was not related to a higher incidence of adverse pregnancy outcomes in Japanese IBD patients except for spontaneous abortion.

Progress in Genetic Polymorphism of Related Metabolic Enzymes Influencing Individualized Thiopurine Therapy / 中国药师

Thiopurines, one kind of immunosuppressants, represent an effective and widely prescribed therapy in clinic. Howev-er, the narrow therapeutic window and pharmacokinetic individual differences are always the problems in the clinical application of these drugs. Many factors can affect the metabolism and pharmacological effects of thiopurines, and the genetic polymorphisms of relat-ed metabolic enzymes involved in the metabolic process are considered to be the main factors. Recently, there is growing attention to the influence of the pharmacogenetics of related metabolic enzymes on the pharmacokinetics and pharmacodynamics of thiopurines. Therefore, based on the literature data, this review summarizes the correlation between the genetic polymorphisms of related metabolic enzymes ( TPMT, ITPA, GST, HPRT, XO, IMPDH and GMPS) and efficacy and side effects of thiopurines in order to provide guid-ance for the individualized thiopurine treatment in the clinical practice.

Use of Thiopurines in Inflammatory Bowel Disease: A Consensus Statement by the Korean Association for the Study of Intestinal Diseases (KASID)

BACKGROUND/AIMS: For decades, thiopurines have been the mainstay of inflammatory bowel disease (IBD) treatment and will play an important role in the future. However, complex metabolism and various side effects limit the use of these potent drugs in clinical practice. The Korean Association for the Study of Intestinal Diseases developed a set of consensus statements with the aim of guiding clinicians on the appropriate use of thiopurines in the management of IBD. METHODS: Sixteen statements were initially drafted by five committee members. The quality of evidence and classification of recommendation were assessed according to the Grading of Recommendations Assessment, Development and Evaluation system. The statements were then circulated to IBD experts in Korea for review, feedback, and then finalized and accepted by voting at the consensus meeting. RESULTS: The consensus statements comprised four parts: (1) pre-treatment evaluation and management strategy, including value of thiopurine S-methyltransferase screening, dosing schedule, and novel biomarkers for predicting thiopurine-induced leukopenia; (2) treatment with thiopurines with regards to optimal duration of thiopurine treatment and long-term outcomes of combination therapy with anti-tumor necrosis factors; (3) safety of thiopurines, especially during pregnancy and lactation; and (4) monitoring side effects or efficacy of therapy using biomarkers. CONCLUSIONS: Thiopurines are an effective treatment option for patients with IBD. Management decisions should be individualized according to the risk of relapse and adverse events.

Uso de azatioprina en enfermedad de Crohn ¿En qué estamos? / Current state of the use of azathioprine in Crohn’s disease

Crohn´s disease (CD) is an intestinal pathology that may have a torpid and disabling course. One of the purposes of the pharmalogical therapy is to prevent progression of the disease and keep the patient in clinical remission. Thiopurines (azathioprine (AZT)/6-mercaptopurine (6-MP)) correspond to a group of drugs so far recommended in all current consensus for maintaining remission of the disease. Recent publications have questioned its effectiveness as a maintenance treatment. We reviewed the literature to date and the aforementioned publications trying to clarify the current status of the use of AZT/6-MP in CD. We emphasize the importance of thiopurine therapy guided by levels of its metabolites, 6-thioguanines and 6-metilmercaptopurines and usefulness of Allopurinol in selected cases. It is still pending to determine whether thiopurines have the potential to modify the disease at an early stage. Further studies are needed before conclusions can modify our clinical behavior to continue using AZT/6-MP in patients with CD.

La enfermedad de Crohn (EC) es una enfermedad intestinal que puede tener un curso tórpido e invalidan. Uno de los objetivos del tratamiento farmacológico es evitar la progresión de la enfermedad y mantener al paciente en remisión. Las tiopurinas (azatioprina (AZT)/6-mercaptopurina (6-MP) corresponden a un grupo de fármacos hasta ahora recomendados en todos los consensos para mantener la remisión de esta enfermedad. Publicaciones recientes han cuestionado su efectividad como tratamiento de mantención. Revisamos la literatura disponible hasta la fecha y las mencionadas publicaciones, intentando esclarecer el estatus actual del uso de AZT/6-MP en EC. Recalcamos la importancia de realizar la terapia con tiopurinas guiada según los niveles de sus metabolitos 6-tioguaninas y 6-metilmercaptopurinas y la utilidad del uso de alopurinol en casos seleccionados. Conclusión: Está pendiente determinar si las tiopurinas tienen el potencial de modificar la enfermedad tempranamente. Se requieren mayores estudios antes de sacar conclusiones que modifiquen nuestra conducta clínica en lo que respecta a seguir usando AZT/6-MP en pacientes con EC.