6-TGN Levels Research Articles

Relationship between azathioprine dosage, 6-thioguanine nucleotide levels, and therapeutic response in pediatric patients with IBD treated with azathioprine.

Azathioprine (AZA) is commonly used to treat IBD either alone or in combination with mesalazine. However, there are relatively few studies concerning the relationship between AZA dose, thiopurine metabolite levels, and therapeutic response in pediatric patients treated with both AZA and mesalazine. We retrospectively investigated the relationship between AZA dose, thiopurine metabolite levels, and therapeutic response in 137 pediatric patients with IBD treated with AZA using multilevel analysis. Additional factors affecting metabolite levels and therapeutic response were also analyzed. A positive correlation was observed between AZA dosage and 6-thioguanine nucleotide (6-TGN) level (P < 0.0001). Variant TPMT genotype (P < 0.001) and concomitant use of mesalazine (P < 0.001) were predictors of higher 6-TGN levels. Leukopenia (P = 0.025) and lymphopenia (P = 0.045) were associated with higher levels of 6-TGN. Poor AZA compliance affected median 6-TGN levels (P < 0.001). The frequency of patients with median 6-TGN levels >235 pmol per 8 × 10(8) red blood cells was the highest in the sustained therapeutic response group (P = 0.015). Age, sex, IBD type, and duration of AZA therapy did not influence 6-TGN levels or therapeutic effect. AZA dosage is positively correlated with 6-TGN level. Higher 6-TGN levels are related to leukopenia, lymphopenia, and concurrent use of mesalazine. These results provide the rationale for monitoring metabolites to optimize drug dosing and minimize drug-related toxicity. In addition, maintenance of 6-TGN levels within a beneficial therapeutic range by direct monitoring should be helpful in attaining therapeutic efficacy, although this possibility should be verified in prospective studies.

Tu1332 Exploring the Efficacy of Weight-Based Dosing of Thiopurine Therapy in Relation to Metabolite Levels at Week 12 in Patients With Inflammatory Bowel Disease

Introduction Traditionally patients commencing on thiopurine therapy in IBD have been dosed according to their body weight with data showing less than 70% achieve long term steroid free remission. 1 The ability to measure thiopurine metabolites has shown that 6-thioguanine nucleotide (6-TGN) levels inversely correlate with disease activity and patients with sub-therapeutic concentrations are less likely to achieve remission. Also very high 6-TGN concentrations risk myelotoxicity and hepatic nodular regernative hyperplasia whilst 6-methyl mercaptopurine (6-MMP) concentrations above 5700 pmol/8 × 10 8 correlate with hepatotoxicity. 2 Method The primary aim of this study was to assess how effective weight based dosing is in achieving therapeutic 6-TGN levels after 12 weeks of therapy, in patients with normal TPMT activity, when commencing thiopurines for the first time at our institution for both Crohn’s and Ulcerative Colitis between Oct 2013 and July 2014. The incidence of potentially toxic thiopurine levels was also assessed along with symptoms, MCV, LFTs and disease activity indicies. All patients with normal TMPT levels were dosed at 2.5 mg/kg (azathioprine) or 1.5 mg/kg (mercaptopurine) with any dose adjustments made clinically based on blood results and symptoms. Results From 37 patients with normal TPMT activity (19 male) at week 12 on stable thiopurine weight based therapy 15 (41%) did not achieve therapeutic 6-TGN concentrations. 7 (19%) were under-dosed, 6 (16%) were overdosed and 2 (6%) preferentially metabolised to excessive 6-MMP levels. Disease activity indices, faecal calprotectin, MCV and routine blood monitoring for leucopenia and abnormal LFTs did not consistently correlate with metabolite levels at week 12. Conclusion Weight-based dosing does not appear to be an accurate method for establishing patients on thiopurine maintenance therapy and this may explain the previous perceived lack of efficacy of thiopurines in a significant number of patients. MCV cannot be used as a surrogate for sufficient 6-TGN levels at week 12 and of the 2 “shunters” neither had significantly abnormal LFTs highlighting the need to identify these group using metabolite monitoring to enable allopurinol co-prescribing. The lack of correlation with disease activity indicies at week 12 likely reflects the patients having recently completed an induction course of steroids and that thiopurines themselves are not induction agents. Starting patients on weight-based dosing plus metabolite monitoring at week 12 to achieve therapeutic ranges may increase long term maintenance rates and increase the safety of treatment by preventing toxicity and a larger long term outcome study is warranted. Disclosure of interest None Declared. References D9Haens G, et al . 1999;50:667–71 Moreau AC, et al . 2014;20:464–71

Tu1328 Final Thiopurine Metabolite Levels and Shunter Status Can Be Predicted After Six Weeks of Thiopurine Therapy - Biochemical Outcomes From the EATME Study

Background: Dosing of thiopurines [azathioprine (AZA) and mercaptopurine (MP)] in the management of IBD has been based upon patient weight. However, this appears unreliable in predicting final levels of thiopurine metabolites, leading to suboptimal clinical outcomes because of underand over-dosing, and ‘shunting' in 15% where toxic 6-methylmercaptopurine (6MMP) is preferentially produced over the efficacious 6-thioguianine nucleotides (6TGN), with 6MMP:6TGN ratio ≥20. Aims: 1. To determine prospectively the clinical value of timing of measurement of thiopurine metabolites during dose-escalating regimen of thiopurine initiation in a consecutive cohort of IBD patients being initiated on a thiopurine. 2. To determine if the 6MMP:6TGN ratio changes during thiopurine dose escalation. Methods: In this single centre, prospective, open label study patients were commenced on either a daily dose of 50mg AZA or 25mg MP (physician discretion). Doses increased fortnightly by 50mg for AZA or 25mg for MP until target was achieved, aiming for 2-2.5mg/kg for AZA and 1-1.5mg/kg for MP. Hematology, CRP and liver function tests were performed fortnightly to monitor toxicity. Thiopurine metabolites were measured fortnightly until steady-state was achieved, but results were not used for dosing decisions. Clinical and biochemical outcomes were recorded. Landmark analyses of shunter status used logistic regression models. Metabolite levels were analysed using linear regression models. Results: 64 patients (52 Crohn's, 11 ulcerative colitis and 1 IBD-U) were enrolled. Final metabolite outcomes were: 11 (17%) patients were shunters, 27 (42%) were underdosed (6TGN level of 450) and 21 (33%) were therapeutic. 6MMP:6TGN ratios escalated over time in shunters, but not in others. After 2 weeks of therapy, a 6MMP:6TGN ratio above 9 (p=0.058) was suggestive of shunting, while after 6 weeks, a ratio ≥12 (95% CI 7-28, p=0.01) was predictive of shunting. 6TGN levels at week 2 (median 106, range 0-328) predicted final 6TGN outcomes (median282, range 50-746, r=0.681, p .10). Conclusions: 6MMP:6TGN ratios increase during dose escalation in shunters only. Patients with a 6MMP:6TGN ratio 12 or above after 6 weeks should be considered for optimisation with allopurinol rather than waiting until 12 weeks of therapy. Weight-based dosing of thiopurines should no longer be used in standard practice.

Concentrations of 6-Thioguanine Nucleotide Correlate With Trough Levels of Infliximab in Patients With Inflammatory Bowel Disease on Combination Therapy

In patients with inflammatory bowel diseases, the combination of infliximab and thiopurines (such as 6-thioguanine) is more effective treatment than monotherapy. We assessed the correlation between serum levels of 6-thioguanine (6-TGN) and infliximab levels or antibodies to infliximab (ATI). We performed a cross-sectional study of 72 patients receiving maintenance therapy with infliximab and a thiopurine for inflammatory bowel disease at the Crohn's and Colitis Center of the University of Miami, FL. We collected clinical, endoscopic, and biochemical data, and levels of thiopurine metabolites. The primary outcomes were trough level of infliximab and the presence of ATI. Levels of 6-TGN correlated with those of infliximab (ρ, 0.53; P < .0001). The cut-off point of 6-TGN that best predicted a higher level of infliximab was 125 pmol/8 × 10(8) red blood cells (RBCs) (area under receiver operating characteristic, 0.86; P < .001). Patients in the lowest quartile of 6-TGN had infliximab levels that were similar to patients on no thiopurines (4.3 vs. 4.8 mcg/mL, respectively; P = .8). An infliximab level of 8.3 mcg/mL or greater was associated with mucosal healing. Only 8 patients (11%) had detectable ATI. Patients with 6-TGN levels less than 125 pmol/8 × 10(8) RBCs were significantly more likely to have ATI (odds ratio, 1.3; 95% confidence interval, 2.3-72.5; P < .01). Although 6-TGN levels of greater than 230 pmol/8 × 10(8) RBCs have been associated with improved outcomes in patients on monotherapy, a level of 6-thioguanine of 125 pmol/8 × 10(8) RBCs or greater may be adequate to achieve therapeutic levels of infliximab. In the long term, this may minimize the toxicity for patients on combination therapy.

Hematologic Indices as Surrogate Markers for Monitoring Thiopurine Therapy in IBD

Clinical efficacy and risk of complications are associated with intracellular levels of thiopurine metabolites 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurines (6-MMP) in patients with Crohn's disease. Therapeutic monitoring of thiopurine metabolites is not widely available. Surrogate markers such as hematologic indices (MCV, leukopenia) have been proposed. To evaluate accuracy of hematologic indices for prediction of therapeutic levels of thiopurine metabolites. A retrospective cross-sectional study. We included patients treated with thiopurines for IBD between February 2008 and November 2013. Hematologic indices were correlated with thiopurine metabolites and compared to pre-treatment levels. A total of 168 patients with 608 measurements were included. Macrocytosis was observed in 4.5 % of the patients. On multivariate analysis, macrocytosis was associated with 6-TGN levels >235 pmol/8 × 10(8) erythrocytes and 6-mmp levels >5,700 pmol/8 × 10(8) erythrocytes. Therapeutic 6-TGN levels were associated with MCV, ΔMCV, macrocytosis and lymphocyte count. Sensitivity and Spearman's r correlation for prediction of therapeutic metabolite levels were poor for all hematologic indices. Although macrocytosis and an elevated MCV are associated with therapeutic 6-TGN levels, the correlation is weak. None of the evaluated hematologic indices is a reliable surrogate marker for thiopurine metabolite levels.

PWE-078 Mean Corpuscular Volume But Not Lymphocyte Count Is A Predictor Of Thiopurine Dose Adequacy And Toxicity

IntroductionThe thiopurines, azathioprine (AZA) and mercaptopurine (MP), commonly used in the treatment of inflammatory bowel diseases (IBD), are typically dosed according to patient’s body weight. A previous meta-analysis showed higher...

PWE-100 Increasing Weight And Body Mass Index Adversely Affect Thioguanine Nucleotide Levels In Inflammatory Bowel Disease

IntroductionInflammatory bowel disease (IBD) often requires long term immunosuppressive therapy with thiopurines such as azathioprine (AZA) or mercaptopurine (MP) and anti-tumour necrosis factor (TNF) agents. Despite the variable response to...

OC-059 Low Dose Azathioprine And Allopurinol In Azathioprine Intolerant Patients: Is It Tolerated And Is It Effective In Ibd?

IntroductionDespite the advancement and introduction of new biological therapies, thiopurines remain effective treatment options for the maintenance of remission for both ulcerative colitis (UC) and Crohn’s disease (CD). Once tolerated...

Sa1240 LéMann Index Assessment Overtime in Crohn's Disease Patients Treated With Anti TNFs: A Pilot Observational Cohort Study

completing the follow-up period of 8 weeks without any thiopurine dose adjustments. Results: Thirty-two patients with leukopenia and 162 patients without leukopenia were included. Patients with leukopenia were more frequently treated with 6MP than AZA: Odds Ratio (OR) = 7.3 (95%CI 3.1 17.0; p < 0.00001). Additionally, these patients were more often co-treated with anti-TNF agents: OR 5.1 (95%CI 1.6 16.4; p = 0.009). At T1 threshold values of ~213 pmol/8×108 red blood cells (RBC) for 6TGN and ~3525 pmol/8×108 RBC for 6MMPR, patients with elevated T1 6TGN or T1 6MMPR levels were at increased risk of leukopenia between week 1 8: Odds ratios were 6.2 (95%CI: 2.8 13.8; p < 0.001) and 5.9 (95%CI: 2.7 13.3; p < 0.001), respectively. Finally, a logistic regression model was designed including the T1 6TGN and 6MMPR threshold parameters, thiopurine type and concurrent anti-TNF therapy at baseline. The predictive performance measured by Receiver Operating Characteristic (ROC) analysis revealed an area under the curve (AUC) of 0.70 (95%CI: 0.59 0.81; p < 0.001), when either T1 6TGN or 6MMPR threshold values were evaluated. Including all parameters, the AUC was 0.84 (95%CI: 0.76 0.92; p < 0.000001). Conclusions: Both 6TGN and 6MMPR metabolites were independently associated with the occurrence of leukopenia during the first 8 weeks of thiopurine therapy. Assessment of 6TGN and 6MMPR metabolite concentrations one week after thiopurine initiation helps to identify patients at risk of developing leukopenia.

Letter: metabolite monitoring for thiopurines in Crohn's disease – still not fully understood

We read with great interest the study by Dassopoulos et al. comparing individualised vs. weight-based dosing of azathioprine in Crohn's disease.1 Publication of such negative results is welcome, as it avoids publication bias and provides independent data. Great interest has been focused on the metabolism of thiopurines, related to a supposed capability to predict, monitor, individualise and optimise azathioprine treatment as it represents a pharmacogenetic model that seems to be a matter of therapeutic intervention. However, we are still far from fully understanding the metabolism of thiopurines, and this randomised trial is another example of that. The observed results cannot be fully explained by current knowledge. Surprisingly, and despite very different azathioprine doses, both groups (individualised and weight-based) achieved similar 6-tioguanine-nucleotide (6TGN) levels. Regardless of that, the proportion of patients who achieved clinical remission in each arm was different, although this was not statistically significant. As 6TGN levels were similar in both groups, it is difficult to understand whether these differences, if true, could be related to the azathioprine dose adjustments based on 6TGN levels. The authors, however, found a trend favouring the individualised strategy. Some important limitations of the study, pointed out by the authors themselves, should also question this finding.1 Despite this, the trial confirms the results of a prior meta-analysis showing a relationship between 6TGN levels and clinical remission.2, 3 Previous attempts to develop a tailored thiopurine treatment were also unsuccessful. Reinshagen et al. failed to demonstrate the usefulness of 6TGN-adapted azathioprine therapy.4 A Spanish study, including 113 steroid-refractory patients whose 6TGN blood levels were periodically determined during 6 months of follow-up after steroid withdrawal, also failed to identify therapeutic threshold levels of 6TGN.5 Systematic determinations of thiopurine methyltransferase or 6TGN levels are expensive and not always available. Strong evidence of their usefulness is still needed before recommending such an individualised approach. Declaration of personal and funding interests: None.

Febuxostat as a Novel Option to Optimize Thiopurines’ Metabolism in Patients With Inadequate Metabolite Levels

To report the use of febuxostat in order to potentiate thiopurines' metabolism in a patient on azathioprine (AZA) therapy with low metabolite 6-thioguanine nucleotides (6-TGN) levels and elevated metabolite 6-methylmercaptopurine (6-MMP) levels. A 44-year-old woman with a history of anti-signal recognition particle necrotizing myopathy was treated with AZA-allopurinol combination therapy. When she developed an atypical drug-induced hypersensitivity syndrome, allopurinol was replaced by the new xanthine oxidase (XO) inhibitor febuxostat, at a daily dose of 40 mg. Febuxostat-AZA combination was successful with 6-TGN reaching therapeutic levels while 6-MMP levels remained low. After 5 months, she developed similar manifestations that she had presented on AZA-allopurinol combination. Febuxostat and AZA were then stopped. AZA and 6-MP are both inactive pro-drugs that undergo a complex metabolic transformation leading to active 6-TGN and potentially hepatotoxic 6-MMP. Some patients with unfavorable thiopurine metabolism might benefit from addition of XO inhibitor allopurinol in order to potentiate 6-TGN and reduce 6-MMP levels. It is likely that febuxostat, via its XO inhibition, would exhibit the same effect on thiopurines' metabolism. It has been shown that low dose of febuxostat was able to prevent hypermethylation and to potentiate 6-TGN levels in an AZA-treated patient. Thus, febuxostat could be useful in optimizing thiopurines' metabolism, but more data are needed before this practice can be recommended. The mechanisms by which febuxostat optimizes thiopurines' metabolism remain to be confirmed. Also, the optimal dose of febuxostat for this use remains to be determined.

P526 Correlation of 6-TGN levels with clinical remission in patients with ulcerative colitis treated with azathioprine

P526 Correlation of 6-TGN levels with clinical remission in patients with ulcerative colitis treated with azathioprine

P344 Short and medium term efficacy of adalimumab in ulcerative colitis – a multicentre, prospective observational study

are particularly at risk for therapy failure. We determined the predictive value of this pharmacological phenomenon in IBD patients. Methods: Clinical effectiveness and tolerability of regular weight-based thiopurine therapy were determined in all IBD patients displaying a skewed metabolism [ratio 6-MMPR/ 6-thioguaninenucleotide (6-TGN) >20]. All samples were routinely assessed between 2008 2012, being part of standard clinical follow-up after initiation of conventional thiopurines. Results: Fourty-one (84%) out of 49 included IBD patients discontinued thiopurines (55% female, 53% with Crohn’s disease and 47% with ulcerative colitis) with a median duration of 14 weeks (IQR 10 29). The majority of patients discontinued thiopurines due to adverse events (55%) or refractoriness (12%). The most commonly observed adverse event was thiopurine induced hepatotoxicity (18 patients, 37%). Median 6-TGN level was 159 pmol/10e8RBC (IQR 113 218 pmol/10e8RBC), median 6-MMPR level was 11020 pmol/10e8RBC (IQR 721

Commentary: individual vs. weight‐based dosing of azathioprine in Crohn's disease

This study illustrates the difficulties of running a clinical study. There were several attempts to change the protocol, but low enrolment numbers resulted in an underpowered negative study. The primary end point of this study was clinical remission at 16 weeks. There was no difference in remission rates at 16 weeks, although the per-protocol analysis showed a trend towards better results in the individualised group (clinical remission in 3/12 in weight-based vs. 9/15 in the individualised group). These remission rates were below predicted levels, partly because a high proportion of patients had steroid dependency or steroid-refractory disease. The secondary outcomes were remission at 28 and 52 weeks, but only 4 patients were still in the study at week 52. This study shows that dose escalation does not always achieve the target concentration. For the individualised group, the mean 6-tioguanine (thioguanine) (6TGN) concentrations among normal thiopurine methyltransferase (TPMT) metabolisers was 198 pmol/8 9 10 red blood cells (significantly below the therapeutic target of 250, and not different from the mean 6TGN for the weight-based arm). These disappointingly low 6TGN levels may also explain the low remission rates. This study adds to the data showing the clinical benefit of achieving higher 6TGN levels and is consistent with a meta-analysis of 6TGN and IBD activity. There was a significant difference in 6TGN between patients achieving remission and those not achieving remission (216 vs. 149), although a wide range and significant overlap in values were observed. The study showed a modest difference in dose between individualised and weight-based groups (3.4 compared with 2.3 mg/kg for normal TPMT and 1.5 compared with 2.4 mg/kg for intermediate levels), but the trial was not long enough to observe a more significant divergence. A study by Gardiner et al. showed a two-fold divergence in dosing after 9 months of monitoring and dose change, although they predicted that a three-fold difference was likely to be more appropriate. The most useful test may be the initial TMPT activity with reduction of starting dose to 1.0 – 1.5 mg/kg for patients with intermediate TPMT (in this study, the numbers with intermediate TMPT were low and it is difficult to reach any conclusions). The only similar study is a randomised, open-label study where dose adjustment was based on 6TGN alone. Recruitment was also difficult, and the numbers in each group were small. Similar to this study, mean concentrations of 6TGN were below target in the dose-adjusted group and not different from the weightbased group. It is difficult to see this study being repeated. The concept of dose optimisation of azathioprine dose is now well accepted, and there will be reluctance among clinicians to enrol patients into a weight-based arm. There is a strong body of data, including studies with azathioprine/allopurinol combination, supporting this approach. Dose optimisation may be a slow process and not easy to replicate in a clinical trial. However, the disappointing remission rates in this study should not discourage use of azathioprine for an extended period with dose optimisation.

Use of allopurinol in children with acute lymphoblastic leukemia to reduce skewed thiopurine metabolism

Mercaptopurine (6-MP), a critical component of acute lymphoblastic leukemia (ALL) therapy, is metabolized to 6-thioguanine (6-TGN) which is responsible for its anti-leukemic effect, and to 6-methylmercaptopurine nucleotides (6-MMPN/6-MMP) which can be hepatotoxic. Some patients preferentially metabolize 6-MP to 6-MMPN which may increase the risk of liver injury, reduce serum levels of 6-TGN and potentially increase the risk of relapse. The addition of allopurinol to oral 6-MP has been shown to optimize metabolism towards 6-TGN in patients with inflammatory bowel disease (IBD); however, this use has not been reported in patients undergoing treatment for ALL.

The role of thiopurine metabolites in inflammatory bowel disease and rheumatological disorders

Thiopurines have been a cornerstone of medical management of patients with inflammatory bowel disease(IBD) and many rheumatological disorders. The thiopurines are metabolized to their end products, 6-methymercaptopurine (6MMP) and the 6-thioguanine nucleotides (6TGN), with 6TGN being responsible for thiopurine efficacy by causing apoptosis and preventing activation and proliferation of T-lymphocytes. In IBD, conventional weight-based dosing with thiopurines leads to an inadequate response in many patients. Utilizing measurement of these metabolites and then employing dose optimization strategies has led to markedly improved outcomes in IBD. Switching between thiopurines as well as the addition of low-dose allopurinol can overcome adverse events and elevate 6TGN levels into the therapeutic window. There is a paucity of data on thiopurine metabolites in rheumatological diseases and further research is required.

6-Thioguanine Levels in Pediatric IBD Patients

Thiopurine immunosuppressants such as 6-mercaptopurine (6-MP) are widely used to maintain remission in children with both Crohn's disease and ulcerative colitis. Therapeutic efficacy is associated with higher red blood cell levels of the thiopurine metabolite 6-thioguanine (6-TGN). Studies in both children and adults have inexplicably failed to demonstrate a significant correlation between prescribed dose and level of 6-TGN. We aimed to quantify the relationship between 6-TGN levels and adherence. We used electronic monitoring devices to assess adherence in children and adolescents with inflammatory bowel diseases who were prescribed 6-MP. During 3230 days of monitoring in 19 subjects, adherence to 6-MP was 74.2%. Due to the generally low adherence to the prescribed dose of 6-MP, the 6-TGN level was not correlated with the prescribed dose. The 6-TGN level was significantly correlated with the adherence-adjusted dose (R(2) = 0.395). It was also significantly correlated to adherence alone (R(2) = 0.478). Adherence to 5-aminosalicylic acid and 6-MP were significantly positively correlated (r(s)(9) = 0.82, P = 0.00), and a significant relationship was found between 5-aminosalicylic acid adherence and 6-TGN levels independent of 6-MP adherence. Furthermore, low adherence to 6-MP was associated with increased likelihood of escalation of medical therapy. Red blood cell 6-TGN levels are strongly correlated with the dose, when the dose is actually taken. Lack of efficacy of thiopurines may often be the result of poor adherence. Novel ways of assessing and improving adherence are necessary. Future trials should assess adherence in study participants. Intake of 5-aminosalicylic acid positively influences 6-TGN levels.

PP219—Thiopurine metabolites are useful in predicting azathioprine resistance in pediatric ibd patients

Azathioprine (AZA) is an immunosuppressive drug widely used in inflammatory bowel disease (IBD). Few data on azathioprine (AZA) therapy IBD exist for children. We evaluated whether the 6-thioguanine nucleotides (6-TGN) level predicts AZA refractoriness in children with IBD and whether children benefit an AZA dose escalation. Seventy-eight children with IBD initially treated with an AZA dose of 1.5 to 2.5 mg/kg/d were retrospectively included. The dose was adjusted based on the clinical status. 6-TGN and Me6-MPN thiopurine metabolites were determined by HPLC. The receiver operating characteristic curve and logistic regression were used to determine predictors for AZA resistance. Initially, 18 of 40 (45%) patients receiving a dose below 2 mg/kg/d and 11 of 38 (28.9%) patients receiving a dose of 2 to 2.5 mg/kg/d achieved remission. The 6-TGN level above 250 pmol/8.108 RBCs was associated with a higher remission rate, although nonsignificant. Among 35 patients with a dose escalation due to treatment failure, 12 (34.3%) achieved remission (the median 6-TGN level increased from 260 to 394 pmol/8.108 RBCs (P = 0.002)), 23 (67.6%) were AZA refractory. A 6-TGN level above 405 pmol/8.108 RBCs was the only predictor for AZA resistance (sensitivity, 78.3%; specificity, 75%; OR, 10.8 [95% CI, 2.1–55.7], P = 0.004)). Drug monitoring of thiopurine metabolites is useful to identify children with IBD resistant to AZA. Children who cannot achieve remission despite a 6-TGN level above 405 pmol/8.108 RBCs should receive alternative therapies.

Usefulness of Thiopurine Metabolites in Predicting Azathioprine Resistance in Pediatric IBD Patients

Few data on azathioprine (AZA) therapy for inflammatory bowel disease (IBD) exist for children. We evaluated whether the 6-thioguanine nucleotides (6-TGN) level predicts AZA refractoriness in children with IBD and whether children benefit an AZA dose escalation. Seventy-eight children with IBD initially treated with an AZA dose of 1.5-2.5 mg/kg/day were retrospectively included. The dose was adjusted based on the clinical status. The receiver operating characteristic curve and logistic regression were used to determine predictors for AZA resistance. Initially, 18 of 40 (45%) patients receiving a dose of <2 mg/kg/day and 11 of 38 (28.9%) patients receiving a dose of 2-2.5 mg/kg/day achieved remission. The 6-TGN level above 250 pmol/8.10(8) RBCs was associated with a higher remission rate, though non-significant. Among 35 patients with a dose escalation due to treatment failure, 12 (34.3%) achieved remission (the median 6-TGN level increased from 260 to 394 pmol/8.10(8) RBCs [P = .002]), 23 (67.6%) were AZA refractory. A 6-TGN level above 405 pmol/8.10(8) RBCs was the only predictor for AZA resistance (sensitivity 78.3%, specificity 75%, OR 10.8 [95% CI: 2.1-55.7, P = .004]). Serial metabolite monitoring is useful to identify children with IBD resistant to AZA. Children who cannot achieve remission despite a 6-TGN level above 405 pmol/8.10(8) RBCs should receive alternative therapies than dose increase.

PTH-104 The Routine Measurement of Thiopurine Metabolite Levels Results in Dose Optimisation in One Third of IBD Patients; Results from a District General Hospital

IntroductionMeasuring azathioprine or mercaptopurine (AZA) metabolite levels 6-TGN and 6-MMPN allows identification of patients who are: 1. Non compliant with their medication, 2. On a sub-optimal doe, 3. On a...