Introduction Clinical response to thiopurines is dependent on the concentration of its active metabolite, 6-thioguanine nucleotide (6-TGN).1 Dosing is, however, unpredictable because the concentration of 6-TGN is dependent on thiopurine methyl transferase (TPMT) activity, an enzyme with common genetic polymorphisms. Because metabolite monitoring is not commonplace in the UK, some clinicians use proxy measures to assess response to thiopurines. We aim to evaluate how measuring thioguanine metabolites measurement influences clinical practice.
Methods Thiopurine metabolites were measured in children who had been on medication for 3 months or more. For each measurement, data were collected on dosage, disease severity, concomitant use of 5-ASA, haematological and biochemical indices, and changes to management. Therapeutic 6-TGN levels were defined as 235–400 pmol/8×108 RBCs. Toxicity is defined as WBC <4×10 mm, neutrophils <2×10 mm, and AST/ALT >2× elevated.
Result 64 individuals studied, median age 14 years. Underlying diagnoses were “IBD” (54/64) and “other” (10/64). 59 treated with AZA, 5 with 6-MP. 95 separate measurements were made. TPMT phenotype was measured in 51/64 patients,40/51 had “normal” phenotype, and 11/51 had heterozygous TPMT mutations. Initial 6-TGN levels were higher in heterozygotes (median levels 836 vs 328, p=0.001) at comparable doses of thiopurine (median 1.9 vs 2.2 mg/kg, p=0.11). On first measurement, only 30% patients had 6-TGN levels within therapeutic levels. 30% were subtherapeutic and 40% were supra-therapeutic. 9% had 6-TGN levels >800. Toxicity occurred in 8 cases (9%). Leucopaenia (WBC<4) had a sensitivity of 12.5% in predicting supra-therapeutic 6-TGN levels. Concomitant use of 5-ASA did not significantly affect 6-TGN levels at comparable doses (median (6-TGN) “5-ASA” 393 vs 451 “no 5-ASA”, p=0.26). In total, management was changed in 39 cases (41%). 6 cases of total non-compliance were exposed. 33/39 of these changes were adjudged to be exclusively or predominantly influenced by knowledge of the 6-TGN level.
Conclusion Based on standard dosing regimens, clinicians can expect to achieve therapeutic levels of 6-TGN in a minority of cases. Measuring Thiopurine metabolites aids therapeutic dose alteration, detects potential toxicity, and identifies issues of non-compliance that cannot be detected on routine blood monitoring.
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