RESUMEN
The conversion of azathioprine (AZA) to mercaptopurine (MP) is mediated by glutathione transferase Mu1 (GSTM1), alpha1 (GSTA1) and alpha2 (GSTA2). We designed a case-control study with data from the TOPIC trial to explore the effects of genetic variation on steady state 6-methylmercaptopurine ribonucleotide (6-MMPR) and 6-thioguanine nucleotide (6-TGN) metabolite levels. We included 199 patients with inflammatory bowel disease (126 on AZA and 73 on MP). GSTM1-null genotype carriers on AZA had two-fold lower 6-MMPR levels than AZA users carrying one or two copies of GSTM1 (2239 (1006-4587) versus 4371 (1897-7369) pmol/8 × 108 RBCs; P<0.01). In patients on MP (control group) 6-MMPR levels were comparable (6195 (1551-10712) versus 6544 (1717-11600) pmol/8 × 108 RBCs; P=0.84). The 6-TGN levels were not affected by the GSTM1 genotype. The presence of genetic variants in GSTA1 and GSTA2 was not related to the 6-MMPR and 6-TGN levels.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Azatioprina/uso terapéutico , Glutatión Transferasa/genética , Inmunosupresores/uso terapéutico , Tioinosina/análogos & derivados , Tionucleótidos/metabolismo , Adulto , Azatioprina/metabolismo , Estudios de Casos y Controles , Femenino , Genotipo , Nucleótidos de Guanina/genética , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/metabolismo , Isoenzimas/genética , Masculino , Mercaptopurina/metabolismo , Persona de Mediana Edad , Tioinosina/metabolismo , Tionucleótidos/genética , Adulto JovenRESUMEN
BACKGROUND: Leucopenia 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. AIM: To 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. METHODS: Post 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. RESULTS: Sixty 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]). CONCLUSIONS: Low baseline WBC count and mercaptopurine, due to a relatively higher dose, were risk factors for thiopurine-induced leucopenia in patients without a TPMT variant.
Asunto(s)
Azatioprina/efectos adversos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Mercaptopurina/efectos adversos , Metiltransferasas/genética , Adulto , Azatioprina/uso terapéutico , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Leucopenia/inducido químicamente , Masculino , Mercaptopurina/administración & dosificación , Persona de Mediana Edad , Polimorfismo Genético , Factores de RiesgoRESUMEN
We describe the case of a pediatric patient on azathioprine therapy with previously undiagnosed homozygote thiopurine S-methyltransferase (TPMT) deficiency, resulting in myelotoxic thiopurine metabolite levels. The patient was successfully treated with a very low azathioprine dose of 50 mg once a week (4% of standard dose), guided by frequent thiopurine metabolite measurement and a close clinical surveillance. We demonstrate that azathioprine therapy still might be an effective and safe therapeutic option in pediatric thiopurine S-methyltransferase-deficient IBD patients.
Asunto(s)
Azatioprina/uso terapéutico , Hipersensibilidad a las Drogas/complicaciones , Inmunosupresores/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Errores Innatos del Metabolismo de la Purina-Pirimidina/complicaciones , Adolescente , Azatioprina/administración & dosificación , Azatioprina/efectos adversos , Relación Dosis-Respuesta a Droga , Hipersensibilidad a las Drogas/diagnóstico , Monitoreo de Drogas/métodos , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Masculino , Errores Innatos del Metabolismo de la Purina-Pirimidina/diagnóstico , Resultado del TratamientoRESUMEN
BACKGROUND: Hepatotoxicity, gastrointestinal complaints and general malaise are common limiting adverse reactions of azathioprine and mercaptopurine in IBD patients, often related to high steady-state 6-methylmercaptopurine ribonucleotide (6-MMPR) metabolite concentrations. AIM: To determine the predictive value of 6-MMPR concentrations 1 week after treatment initiation (T1) for the development of these adverse reactions, especially hepatotoxicity, during the first 20 weeks of treatment. METHODS: The cohort study consisted of the first 270 IBD patients starting thiopurine treatment as part of the Dutch randomised-controlled trial evaluating pre-treatment thiopurine S-methyltransferase genotype testing (ClinicalTrials.gov NCT00521950). Blood samples for metabolite assessment were collected at T1. Hepatotoxicity was defined by alanine aminotransaminase elevations >2 times the upper normal limit or a ratio of alanine aminotransaminase/alkaline phosphatase ≥5. RESULTS: Forty-seven patients (17%) presented hepatotoxicity during the first 20 weeks of thiopurine treatment. A T1 6-MMPR threshold of 3615 pmol/8 × 108 erythrocytes was defined. Analysis of patients on stable thiopurine dose (n = 174) showed that those exceeding the 6-MMPR threshold were at increased risk of hepatotoxicity: OR = 3.8 (95% CI: 1.8-8.0). Age, male gender and BMI were significant determinants. A predictive algorithm was developed based on these determinants and the 6-MMPR threshold to assess hepatotoxicity risk [AUC = 0.83 (95% CI: 0.75-0.91)]. 6-MMPR concentrations above the threshold also correlated with gastrointestinal complaints: OR = 2.4 (95% CI: 1.4-4.3), and general malaise: OR = 2.0 (95% CI: 1.1-3.7). CONCLUSIONS: In more than 80% of patients, thiopurine-induced hepatotoxicity could be explained by elevated T1 6-MMPR concentrations and the independent risk factors age, gender and BMI, allowing personalised thiopurine treatment in IBD to prevent early failure.
Asunto(s)
Azatioprina/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Mercaptopurina/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Estudios de Cohortes , Diagnóstico Precoz , Femenino , Genotipo , Humanos , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/metabolismo , Masculino , Mercaptopurina/análogos & derivados , Metiltransferasas/metabolismo , Persona de Mediana Edad , Pronóstico , Factores de Riesgo , Tioinosina/análogos & derivados , Tioinosina/metabolismo , Tionucleótidos/metabolismo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND AND AIMS: A drug interaction between infliximab and azathioprine has previously been reported in Crohn's disease patients: the concentration of the main active thiopurine metabolites, the 6-thioguanine nucleotides (6-TGN), increased 1-3 weeks after the first infliximab infusion by 50% compared to baseline. The aim of this prospective study was to determine the effect of adalimumab on thiopurine metabolism in Crohn's disease patients, evaluated by 6-TGN and 6-methylmercaptopurine ribonucleotides (6-MMPR) concentration measurement. METHODS: Crohn's disease patients on azathioprine or mercaptopurine maintenance therapy starting with concomitant adalimumab treatment were included. 6-TGN and 6-MMPR concentrations were determined before initiation of adalimumab and after 2, 4, 6 and 12 weeks of combination therapy. The activity of three essential enzymes involving thiopurine metabolism, thiopurine S-methyltransferase (TPMT), hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and inosine-triphosphate pyrophosphatase (ITPase), was evaluated at baseline and week 4. Clinical outcome was evaluated by the Crohn's disease activity index and C-reactive protein concentrations at baseline, week 4 and week 12. RESULTS: Twelve Crohn's disease patients were analyzed. During the follow-up period of 12 weeks the median 6-TGN and 6-MMPR concentrations did not significantly change compared to baseline. TPMT, ITPase and HGPRT enzyme activity did not change either after 4 weeks. In two patients (17%) myelotoxicity was observed within 2-4 weeks, in whom both low therapeutic 6-TGN and 6-MMPR concentrations were found. CONCLUSIONS: In this study in Crohn's disease patients no pharmacokinetic interaction was shown between adalimumab and the conventional thiopurines, azathioprine and mercaptopurine.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Anticuerpos Monoclonales Humanizados/farmacología , Azatioprina/metabolismo , Enfermedad de Crohn/metabolismo , Inmunosupresores/metabolismo , Adalimumab , Adolescente , Adulto , Antiinflamatorios no Esteroideos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Azatioprina/farmacocinética , Azatioprina/uso terapéutico , Proteína C-Reactiva/metabolismo , Enfermedad de Crohn/tratamiento farmacológico , Interacciones Farmacológicas , Quimioterapia Combinada , Eritrocitos/enzimología , Femenino , Nucleótidos de Guanina/sangre , Humanos , Hipoxantina Fosforribosiltransferasa/sangre , Inmunosupresores/farmacocinética , Inmunosupresores/uso terapéutico , Masculino , Metiltransferasas/sangre , Persona de Mediana Edad , Estudios Prospectivos , Pirofosfatasas/sangre , Índice de Severidad de la Enfermedad , Tioinosina/análogos & derivados , Tioinosina/sangre , Tionucleótidos/sangre , Adulto Joven , Inosina TrifosfatasaAsunto(s)
Aneurisma Falso/diagnóstico por imagen , Anticoagulantes/efectos adversos , Enfermedades de la Aorta/diagnóstico por imagen , Procedimientos Quirúrgicos Vasculares/efectos adversos , Warfarina/efectos adversos , Anciano de 80 o más Años , Aneurisma Falso/terapia , Enfermedades de la Aorta/terapia , Ecocardiografía , Humanos , Masculino , Tomografía Computarizada por Rayos X/métodosRESUMEN
BACKGROUND AND PURPOSE: 5-aminosalicylate (5-ASA) raises levels of 6-thioguanine nucleotides (6-TGN), the active metabolites of thiopurines such as azathioprine (AZA). Changes in levels of each individual TGN - 6-thioguanosine mono-, di- and triphosphate (6-TGMP, 6-TGDP, 6-TGTP) - and of 6-methylmercaptopurine ribonucleotides (6-MMPR) after 5-ASA are not known. EXPERIMENTAL APPROACH: Effects of increasing 5-ASA doses on AZA metabolites were investigated prospectively in 22 patients with inflammatory bowel disease in 4-week study periods. Patients started with 2 g 5-ASA daily, and then were increased to 4 g daily and followed by a washout period. Thiopurine doses remained unchanged throughout the entire study. Levels of 6-TGMP, 6-TGDP, 6-TGTP and 6-MMPR as well as of 5-ASA and N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA) were determined each study period. KEY RESULTS: Median baseline levels in 17 patients of 6-TGDP, 6-TGTP and 6-MMPR were 52, 319 and 1676 pmol per 8 x 10(8) red blood cells respectively. After co-administration of 2 g 5-ASA daily, median 6-TGDP and 6-TGTP levels increased but median 6-MMPR levels were unchanged. Increasing 5-ASA to 4 g daily did not affect median 6-TGDP and 6-TGTP levels, but median 6-MMPR levels decreased. After discontinuation of 5-ASA, both 6-TGDP and 6-TGTP levels decreased and median 6-MMPR levels increased. The 6-TGTP/(6-TGDP+6-TGTP)-ratio did not change during the study, but 6-MMPR/6-TGN ratios decreased. CONCLUSIONS AND IMPLICATIONS: Individual 6-TGN metabolites increased after addition of 5-ASA, but 6-MMPR-levels and the 6-MMPR/6-TGN ratios decreased. Further studies are needed to decide whether this pharmacokinetic interaction would result in improvement of efficacy and/or increased risk of toxicity of AZA.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Azatioprina/farmacocinética , Inmunosupresores/farmacocinética , Enfermedades Inflamatorias del Intestino/metabolismo , Mesalamina/farmacología , Adulto , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacocinética , Azatioprina/uso terapéutico , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Masculino , Mercaptopurina/farmacocinética , Mercaptopurina/uso terapéutico , Mesalamina/administración & dosificación , Mesalamina/farmacocinética , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
The immunosuppressive thiopurines, azathioprine (AZA) and 6-mercaptopurine (6-MP), have proven efficacy in steroid-dependant or refractory inflammatory bowel disease (IBD). In case of TPMT deficiency serious myelosuppression may occur. 6-thioguanine (6-TG), has been suggested in case of AZA and 6-MP resistant or intolerant patients. Our case demonstrates that very low dose 6-TG under close clinical surveillance and frequent therapeutic drug monitoring, may be a rescue drug for IBD-patients with low or without functional TPMT activity.