Background and importance Azathioprine (AZA) is an analogue of purines used in inflammatory bowel disease (IBD) treatment. AZA is transformed by thiopurine methyltransferase (TPMT) into its metabolites,including 6-methylmercaptopurine (6-MMP) and 6-thioguanine (6-TGN).
Aim and objectives (1) Compare the maximum recommended dose of AZA according to TPMT activity and the maximum tolerated dose (MTD), (2) evaluate the MTD and 6-TGN levels and (3) analyse the prevalence of each activity of TPMT.
Material and methods Retrospective observational study in patients with IBD treated with AZA and determination of TPMT activity between February 2017 and May 2021. Demographic, clinical data, metabolites (6-TGN (target 300–550 pmol/0.2 mL) and 6-MMP) and phenotype (activity of TPMT (IU/mL), determined by HPLC) were collected. AZA dosage was adjusted according to TPMT activity: treatment not recommended (poor; TPMT <5.0 IU/mL)), 0.5 mg/kg (low; TPMT 5.1–13.7 IU/mL), 5 mg/kg (intermediate; TPMT 13.8–18 IU/mL), 2.5 mg/kg (moderate; TPMT 18.1–26.0 IU/mL) and 3.0 mg/kg (high activity; TPMT 26.1–40.0 IU/mL).
Results 131 patients were included, 61 (46.6%) women, mean age 34.7(SD 17.4) years. TPMT phenotype: low activity in 19 (14.5%) patients, intermediate activity 54 (41.2%) and moderate activity 58 (44.3%).
When analysing the dosage, in 30 (22.9%) patients the dosage according MTD was higher than according to the activity of TPMT, in 43 (32.8%) it was lower and in 58 (44.3%) it was within the range.
6-TGN levels in the patients receiving the MTD were higher than recommended in 35 (26.7%) patients, lower in 24 (18.3%) and within range in 72 (54.9%). Median 6-MMP/6-TGN ratio was 1.57 (SD1.7) in patients with 6-TGN levels <300 pmol/0.2 mL and only 3 (2.3%) had a ratio >4.
Mean serum creatinine was 0.70 (SD 0.35) mg/dL. Patients’ renal function did not interfere in the elimination of AZA metabolites.
AZA posology was decreased in 31 (23.7%) patients and withdrawn in 22 (16.8%) due to adverse events. Most frequent adverse events detected were: digestive intolerance in 10 (7.6%) patients, leukopenia 7 (5.3%), lymphopenia 5 (3.8%), hypertransaminasaemia 4 (3.1%) and nausea 3 (2.3%).
Conclusion and relevance The phenotypes of intermediate and moderate activity of TPMT were the most prevalent. 6-TGN levels were high in almost a quarter of patients, increasing the risk of toxicity. In half the patients, the recommended dose based on TPMT activity was not coincident with MTD, suggesting the need to analyse other genetic factors that might influence AZA metabolism.
Conflict of interest No conflict of interest
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