TY - JOUR
T1 - Normal Ranges of Thiopurine Methyltransferase Activity Do Not Affect Thioguanine Nucleotide Concentrations with Azathioprine Therapy in Inflammatory Bowel Disease
AU - Jonason, David E.
AU - Sievers, Tyson
AU - Trocke, Lindsay
AU - Abraham, James M.
AU - Vaughn, Byron P.
N1 - Publisher Copyright:
© 2020 Crohn’s & Colitis Foundation.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - Background: Thiopurine methyltransferase (TPMT) activity influences azathioprine conversion into active metabolite 6-thioguanine nucleotide (6-TGN). Low TPMT activity correlates with high 6-TGN and risk for myelosuppression. Conversely, normal-to-high TPMT activity may be associated with low 6-TGN and drug resistance, the so-called hypermetabolizers. Our aim was to identify the effect of normal-to-high TPMT activity on 6-TGN concentrations in an inflammatory bowel disease population. Methods: A retrospective chart review of patients aged ≥18 with inflammatory bowel disease, on azathioprine, with documented TPMT activity and 6-TGN concentration was performed. Correlations were evaluated via the Spearman rho correlation coefficient. Linear regression was used to determine the effect of TPMT activity on 6-TGN accounting for confounders. Relationships between TPMT activity, drug dose, and 6-TGN levels were defined via average causal mediation effects. Results: One hundred patients were included. No correlation was observed between TPMT activity, azathioprine dosing, and metabolite concentrations. Overall, 39% of the cohort had a therapeutic 6-TGN level of >230 pmol/8 × 108 red blood cells (RBCs). No patient under 1 mg/kg achieved a therapeutic 6-TGN level, whereas 42% of patients taking 2.5 mg/kg did. The median 6-TGN concentration was higher for those in remission (254 pmol/8 × 108 RBCs, interquartile range: 174, 309) versus those not in remission (177 pmol/8 × 108 RBCs, interquartile range: 94.3, 287.8), though not significantly (P = 0.08). Smoking was the only clinical factor associated with 6-TGN level. On multivariate linear regression, only age, azathioprine dose, and obese body mass index were predictive of metabolite concentration. Conclusions: Variations within the normal range of TPMT activity do not affect 6-TGN concentration. Lay Summary Thiopurine methyltransferase (TPMT) activity in the normal or high range does not affect 6-thioguanine nucleotide concentration in patients with inflammatory bowel disease treated with azathioprine. Providers should not make assumptions about 6-thioguanine nucleotide concentration based on normal TPMT activity.
AB - Background: Thiopurine methyltransferase (TPMT) activity influences azathioprine conversion into active metabolite 6-thioguanine nucleotide (6-TGN). Low TPMT activity correlates with high 6-TGN and risk for myelosuppression. Conversely, normal-to-high TPMT activity may be associated with low 6-TGN and drug resistance, the so-called hypermetabolizers. Our aim was to identify the effect of normal-to-high TPMT activity on 6-TGN concentrations in an inflammatory bowel disease population. Methods: A retrospective chart review of patients aged ≥18 with inflammatory bowel disease, on azathioprine, with documented TPMT activity and 6-TGN concentration was performed. Correlations were evaluated via the Spearman rho correlation coefficient. Linear regression was used to determine the effect of TPMT activity on 6-TGN accounting for confounders. Relationships between TPMT activity, drug dose, and 6-TGN levels were defined via average causal mediation effects. Results: One hundred patients were included. No correlation was observed between TPMT activity, azathioprine dosing, and metabolite concentrations. Overall, 39% of the cohort had a therapeutic 6-TGN level of >230 pmol/8 × 108 red blood cells (RBCs). No patient under 1 mg/kg achieved a therapeutic 6-TGN level, whereas 42% of patients taking 2.5 mg/kg did. The median 6-TGN concentration was higher for those in remission (254 pmol/8 × 108 RBCs, interquartile range: 174, 309) versus those not in remission (177 pmol/8 × 108 RBCs, interquartile range: 94.3, 287.8), though not significantly (P = 0.08). Smoking was the only clinical factor associated with 6-TGN level. On multivariate linear regression, only age, azathioprine dose, and obese body mass index were predictive of metabolite concentration. Conclusions: Variations within the normal range of TPMT activity do not affect 6-TGN concentration. Lay Summary Thiopurine methyltransferase (TPMT) activity in the normal or high range does not affect 6-thioguanine nucleotide concentration in patients with inflammatory bowel disease treated with azathioprine. Providers should not make assumptions about 6-thioguanine nucleotide concentration based on normal TPMT activity.
KW - 6-thioguanine nucleotide
KW - Azathioprine
KW - Inflammatory bowel disease
KW - Therapeutic drug monitoring
KW - Thiopurine methyltransferase
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U2 - 10.1093/crocol/otaa058
DO - 10.1093/crocol/otaa058
M3 - Article
AN - SCOPUS:85103800698
SN - 2631-827X
VL - 2
SP - 1
EP - 7
JO - Crohn's and Colitis 360
JF - Crohn's and Colitis 360
IS - 3
ER -