Thiopurine metabolite testing in inflammatory bowel disease

Goldberg, Rimma; Moore, Gregory Thomas Charles; Cunningham, Georgina; Schulberg, Julien; Marsh, Philip; Brown, Steven J; Connell, William; Lust, Mark; Kamm, Michael A.; Bell, Sally

doi:10.1111/jgh.13210

Cited by 15 publications

(23 citation statements)

References 32 publications

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“… 29 , 30 A recent study in IBD patients followed at tertiary care centers showed that 52% did not achieve therapeutic 6-TGN levels. 31 Our higher endoscopic remission and healing rates are in accordance with other prospective studies using AZA. In UC, 60% of patients have complete mucosal healing (Mayo score 0).…”

Section: Discussionsupporting

confidence: 92%

Allopurinol in combination with thiopurine induces mucosal healing and improves clinical and metabolic outcomes in IBD

Moreau

Clément²,

Théôret

et al. 2017

Therap Adv Gastroenterol

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Background:Thiopurines, azathioprine (AZA) and 6-mercaptopurine (6-MP) are common maintenance medications for inflammatory bowel disease (IBD). Excessive methylation via thiopurine methyltransferase (TPMT) frequently causes therapeutic failure. Allopurinol reduces excessive 6-methyl-mercaptopurine (6-MMP) while enhancing 6-thioguanine (6-TGN) levels. The aim of this study was to evaluate clinical, metabolic and endoscopic impact of allopurinol in combination with low-dose thiopurine in IBD.Methods:Retrospective review of consecutive cases treated with allopurinol. Metabolites and their ratios (6-MMP/6-TGN) were compared pre- and post-allopurinol. Clinical and endoscopic remission were assessed.Results:Allopurinol (n = 66) reduced mean dose of AZA by 70% (p < 0.01). Baseline levels (SD) 6-TGN, 6-MMP and 6-MMP/6-TGN were 165 (64), 9388 (5234) and 59.8 (30.3), respectively. These values improved on allopurinol to 297 (102), 896 (1031) and 3.4 (4.0), respectively (p < 0.0001). Therapeutic 6-TGN level (>235) was achieved in 49/58 cases on allopurinol combination therapy, versus 9/58 monotherapy (p = 0.0001). Among the thiopurine failure group (40 patients), clinical remission or response was observed in 65% and 22% of patients, respectively. In the asymptomatic group with excessive 6-MMP, 11/14 achieved sustained remission on allopurinol. Repeat colonoscopy (n = 28) showed mostly endoscopic remission (67.9%) or improvement (17.8%). Few had unimproved lesions (14.3%). Importantly, 46% of cases had complete mucosal healing. Two patients had cancer on combination therapy (de novo pancreatic cancer and fatal recurrence of metastatic testicular cancer). Elevated transaminases were reduced on allopurinol (48.2 versus 6.9%) (p < 0.001); no change in leukopenic or infectious events occurred.Conclusion:Allopurinol in combination with low-dose thiopurine corrected excessive 6-MMP levels, resulting in clinical remission and mucosal healing in the majority of cases. The potential cancer risk of allopurinol and thiopurine combination therapy needs further research.

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Section: Discussionsupporting

confidence: 92%

Allopurinol in combination with thiopurine induces mucosal healing and improves clinical and metabolic outcomes in IBD

Moreau

Clément²,

Théôret

et al. 2017

Therap Adv Gastroenterol

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“…Four noncomparative, retrospective studies have reported the efficacy of reactive TDM, which had been initiated in thiopurine-treated patients because of active IBD despite thiopurine therapy, suspicion of lack of adherence, or adverse events thought to be related to thiopurine therapy. [79][80][81][82] The end points for the evaluation of a successful reactive TDM in the individual patients in these studies varied and included change in disease management (adaption of drug dosing, switch to another drug, or surgery), improved clinical outcome or remission based on physician assessment or resolution of side effects thought to be thiopurine related; however, none of these studies reported outcomes with empiric treatment changes and did not contribute to summary estimates. None of the studies used established diseases activity scores, such as the Mayo or the Harvey Bradshaw score, or assessed for mucosal healing.…”

Section: Quality Of Evidencementioning

confidence: 99%

American Gastroenterological Association Institute Technical Review on the Role of Therapeutic Drug Monitoring in the Management of Inflammatory Bowel Diseases

et al. 2017

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Therapeutic drug monitoring (TDM), which involves measurement of drug or active metabolite levels and anti-drug antibodies, is a promising strategy that can be used to optimize inflammatory bowel disease therapeutics. It is based on the premise that there is a relationship between drug exposure and outcomes, and that considerable inter-individual variability exists in how patients metabolize the drug (pharmacokinetics) and the magnitude and duration of response to therapy (pharmacodynamics). Therefore, the American Gastroenterological Association has prioritized clinical guidelines on the role of TDM in the management of inflammatory bowel disease. To inform these clinical guidelines, this technical review was developed in accordance with the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework for interventional and prognostic studies, and focused on the application of TDM for biologic therapy, specifically anti-tumor necrosis factor-α agents, and for thiopurines. Focused questions address the benefits and risks of a strategy of reactive TDM (in patients with active inflammatory bowel disease) to guide treatment changes compared with empiric treatment changes, and the benefits and risks of a strategy of routine proactive TDM (during routine clinical care in patients with quiescent disease) compared with no routine TDM. Additionally, the review addresses the benefits and risks of routine measurement of thiopurine methyltransferase enzyme activity or genotype before starting thiopurine therapy compared with empiric weight-based dosing and explores the performance of different trough drug concentrations for anti-tumor necrosis factor agents and thiopurines to inform clinical decision making when applying TDM in a reactive setting. Due to a paucity of data, this review does not address the role of TDM for more recently approved biologic agents, such as vedolizumab or ustekinumab.

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“…In both these studies, 52% and 72% were in subtherapeutic range 28, 30. In one of these studies by Goldberg et al .,28 mean 6‐TGN level was 273 pmol/8 × 10 8 RBCs.…”

Section: Discussionmentioning

confidence: 86%

“…In both these studies, 52% and 72% were in subtherapeutic range 28, 30. In one of these studies by Goldberg et al .,28 mean 6‐TGN level was 273 pmol/8 × 10 8 RBCs. In a study from USA by Dassopoulos et al ., the mean dose in patients with normal TPMT activity was 2.5 mg/kg and the mean 6‐TGN level was 230 pmol/8 × 10 8 RBCs 35.…”

Section: Discussionmentioning

confidence: 86%

“…At this dose, a high 6‐TGN level was obtained in 23% of patients, 49% had subtherapeutic level while 28% had a therapeutic level. The other studies in literature where measurement of thiopurine metabolites has been performed are shown in Table 2 27, 28, 29, 30, 31, 32, 33, 34, 35. The comparison of different studies is complicated by the fact that some have used mean, whereas others have used median dose and drug levels.…”

Section: Discussionmentioning

confidence: 99%

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Thiopurine metabolite level and toxicity in Indians with inflammatory bowel disease

et al. 2017

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Background and AimA lower dose requirement and higher toxicity of thiopurine is reported in Asian patients with inflammatory bowel disease (IBD) as compared with Caucasian patients. These reports are based on thiopurine methyltransferase measurement studies rather than metabolite estimation.We studied the utility of thiopurine metabolite estimation in Indian patients with IBD and compared dose and toxicity with Asian and Caucasian patients.MethodsIn this prospective study, 6‐thioguanine nucleotide (6‐TGN) and 6‐methylmercaptopurine levels were determined by HPLC in 76 IBD patients treated with thiopurines. The levels were correlated with dose, disease activity, and toxicity. The dose‐related metabolite levels and toxicity were compared with Caucasian and Asian patients reported in literature.ResultsOf the 76 patients (32 women, mean age: 35.9 [SD: 14.54] years, 36 Crohn's disease and 40 ulcerative colitis), 1 non‐compliant patient had undetectable level of metabolites. Of the 75 patients, 21(28%) had therapeutic level of 6‐TGN, 37(49%) had subtherapeutic level and 17(23%) had supratherapeutic level. The 6‐methylmercaptopurine levels ranged up to 4971 pmol/8 × 108 red blood cells. Six (8%) patients showed toxicity. Thiopurine dose was optimized in 20 (26.31%) patients. Dose‐based metabolite levels were comparable to Asian and Caucasian patients. The toxicity (8%) observed in our patients was less than that reported (12–39%).ConclusionHalf of the patients in this study had low and a quarter had high 6‐TGN levels. One‐fourth of the patients needed dose modification. The dose‐based metabolite levels were comparable and the toxicity was less than that reported in Asian and Caucasian patients.

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Thiopurine metabolite testing in inflammatory bowel disease

Abstract: Metabolite testing resulted in a change in management in most patients not responding to thiopurines or experiencing adverse events. Weight-based dosing did not increase rates of therapeutic levels but was associated with increased 6MMP shunting.

Cited by 15 publications

References 32 publications

Allopurinol in combination with thiopurine induces mucosal healing and improves clinical and metabolic outcomes in IBD

Allopurinol in combination with thiopurine induces mucosal healing and improves clinical and metabolic outcomes in IBD

American Gastroenterological Association Institute Technical Review on the Role of Therapeutic Drug Monitoring in the Management of Inflammatory Bowel Diseases

Thiopurine metabolite level and toxicity in Indians with inflammatory bowel disease

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