thioinosine and Crohn-Disease

The conventional thiopurines azathioprine and mercaptopurine are considered maintenance immunosuppressive drugs of choice in the treatment of inflammatory bowel disease (IBD). Unfortunately, treatment is often discontinued because of adverse events (AEs) or refractoriness, retrospectively associated with the high levels of the thiopurine metabolites 6-methylmercaptopurine ribonucleotides (6-MMPR). Patients with a clinically "skewed" thiopurine metabolism may be particularly at risk for therapy failure. We determined the predictive value of this pharmacological phenomenon in patients with IBD during regular thiopurine therapy.. Clinical effectiveness and tolerability of weight-based thiopurine therapy were determined in all patients with IBD displaying a skewed metabolism [ratio 6-MMPR/6-thioguanine nucleotide (6-TGN) >20]. All samples were routinely assessed between 2008 and 2012, as part of standard clinical follow-up after initiation of conventional thiopurine therapy.. Forty-one (84%) of 49 included patients with IBD discontinued thiopurines (55% female, 53% with Crohn disease) with a median duration of 14 weeks (range, 7-155). The majority of patients with a skewed metabolism discontinued thiopurines because of adverse events (55%) or refractoriness (12%). The most commonly observed adverse event was hepatotoxicity (18 patients, 37%). Median 6-TGN level was 159 pmol/8 × 10 RBC (range, 46-419), median 6-MMPR level was 11,020 pmol/8 × 10 RBC (range, 3610-43,670), and the median 6-MMPR/6-TGN ratio was 72 (range, 29-367). Thiopurine therapy failure was associated with a ratio above 50 (P < 0.03). Hepatotoxicity occurred more frequently in patients with an extremely skewed metabolism (6-MMPR/6-TGN ratio >100) (P < 0.01).. This study demonstrates that a routinely established skewed metabolism is a major risk factor for future thiopurine failure in patients with IBD. These observations imply that routine thiopurine metabolite measurements may be used as a prognostic tool to identify those patients with an aberrant-skewed metabolism at an early stage, possibly benefitting from therapy adjustments.

Topics: Adolescent; Adult; Aged; Azathioprine; Cohort Studies; Colitis, Ulcerative; Crohn Disease; Female; Follow-Up Studies; Guanine Nucleotides; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Risk Factors; Thioinosine; Thionucleotides; Treatment Failure; Young Adult

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.. 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.. 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.. In this study in Crohn's disease patients no pharmacokinetic interaction was shown between adalimumab and the conventional thiopurines, azathioprine and mercaptopurine.

Topics: Adalimumab; Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal, Humanized; Azathioprine; C-Reactive Protein; Crohn Disease; Drug Interactions; Drug Therapy, Combination; Erythrocytes; Female; Guanine Nucleotides; Humans; Hypoxanthine Phosphoribosyltransferase; Immunosuppressive Agents; Inosine Triphosphatase; Male; Methyltransferases; Middle Aged; Prospective Studies; Pyrophosphatases; Severity of Illness Index; Thioinosine; Thionucleotides; Young Adult

The value of azathioprine metabolites (6-thioguanine nucleotides [6-TGN]) in monitoring clinical treatment response is still controversially discussed. Data regarding thiopurine metabolite levels and endoscopic improvement are lacking.. Data were analyzed post hoc from a 1-year, multicenter, double-blind, double-dummy, randomized trial comparing azathioprine 2.0 to 2.5 mg/kg per day versus mesalamine 4 g/d in a subset of 23 postoperative patients with Crohn's disease (CD) treated with azathioprine and having moderate-to-severe endoscopic recurrence according to a modified 6-grade score. Red blood cell (RBC) concentrations of 6-TGN, 6-methyl-mercaptopurine ribonucleotides (6-MMPR), and 6-methyl-thioguanine nucleotides (6-MTGN) were indicated as follows: area under the concentration-time curve, average concentration (C av), and concentration at the final study visit.. Overall, 74% of patients showed an improvement in the modified endoscopic score (P = 0.022). Median endoscopic score reduced from 4 at the baseline to 2 at the final visit. Patients with a high C av for 6-TGN (≥ 193 pmol/8 × 10(8) RBC; P = 0.017) or 6-MTGN (≥ 79.2 pmol/8 × 10(8) RBC; P = 0.035) significantly improved in endoscopic score, and the improvement in endoscopic score correlated with C av for 6-TGN (r = -0.51; P = 0.013). For concentration at the final visit, higher values for 6-TGN (≥ 142 pmol/8 × 10(8) RBC; P = 0.017) were associated with a better postoperative score. Sensitivity analysis revealed a significant correlation between 6-TGN (area under the concentration-time curve) and postoperative endoscopic improvement.. Our post hoc analysis from a double-blind, randomized trial suggests that higher RBC 6-TGN levels are associated with endoscopic improvement in patients with severe postoperative endoscopic recurrence of CD. Thus, our study provides first evidence on the utility of monitoring of thiopurine metabolites to achieve mucosal response in CD.

Topics: Adolescent; Adult; Aged; Azathioprine; Biomarkers; Crohn Disease; Drug Administration Schedule; Drug Monitoring; Endoscopy, Gastrointestinal; Female; Guanine Nucleotides; Humans; Immunosuppressive Agents; Intestinal Mucosa; Male; Middle Aged; Recurrence; ROC Curve; Severity of Illness Index; Thioguanine; Thioinosine; Thionucleotides; Treatment Outcome; Young Adult

In a 23-year-old female with colonic Crohn's disease 6-mercaptopurine 100 mg daily (1.7 mg/kg) was added to mesalamine and prednisolone therapy because of ongoing disease activity. One month later she had fever and a pancytopenia. 6-methylmercaptopurine ribonucleotides levels were extremely elevated (57,000 pmol/8x10(8) red blood cells) and 6-thioguanine nucleotides levels were subtherapeutically (126 pmol/8x10(8) red blood cells). Genotyping showed a wildtype thiopurine S-methyltransferase TPMT(H/H) (*1/*1) genotype and a wildtype inosine triphosphate pyrophosphatase gene. TPMT and inosine triphosphate pyrophosphatase activity were normal. The pancytopenia recovered spontaneously within a few weeks, parallel with decreasing 6-methylmercaptopurine ribonucleotides levels after interrupting 6-mercaptopurine treatment. Epstein-Barrvirus, Cytomegalovirus and Herpesvirus infections were excluded by serology. This is the first report of pancytopenia due to extremely high 6-methylmercaptopurine ribonucleotides levels. No relation was found with the genotype of TPMT and inosine triphosphate pyrophosphatase enzymes, which play key roles in the thiopurine metabolic pathway. Apparently, 6-methylmercaptopurine ribonucleotides metabolites can cause pancytopenia, as was already known for 6-thioguanine nucleotides.

Topics: Adult; Crohn Disease; Female; Humans; Mercaptopurine; Methyltransferases; Pancytopenia; Thioinosine; Thionucleotides