We thank Stocco et al. for their letter about the influence of age on thiopurine S-methyltransferase (TPMT) activity, with respect to our review on thiopurine pharmacogenetics for inflammatory bowel disease (IBD).[1, 2] Influence of age has been shown for many drug-metabolising enzymes. Several confounding factors such as treatment (by thiopurine or methotrexate) or analytical variations can affect TPMT activity measurement.[4, 5]
Although some articles conclude that there is a higher TPMT activity in children, Ganiere-Monteil et al., in a population of 147 children and 304 healthy adult blood donors, showed a slight, but significantly, lower TPMT activity in children than in adults (18.62 ± 4.14 vs. 19.34 ± 4.09 nmol/h/mL; P = 0.033). However, this minor difference is almost certainly not clinically relevant during thiopurine therapy.
Globally, in two large-scale cohort studies, TPMT activity did not appear to be modified by age.[7, 8] In addition, based on our own 8-year laboratory experience (n = 3771 patients) in a French University hospital, we measured TPMT activity in 244 wild-type children (median: 11.0 years; range: 0.3–15). We did not find any impact of age on TPMT activity (r2 = 0.06) (Figure 1; unpublished personal data from L. Chouchana, C. Narjoz, M.-A. Loriot and P. Beaune).
It is a known fact that higher doses of azathioprine (2.5 mg/kg/day) are more effective than lower doses (1.0–2.0 mg/kg/day) in IBD. Interestingly, Grossman et al. showed that 6-year-old, or younger, IBD patients might require azathioprine doses >3.0 mg/kg/day. However, many pharmacokinetic parameters (e.g. absorption, hepatic clearance) or metabolic enzymes, probably more significant than TPMT activity, could account for this difference between adults and children.
To conclude, we think that even if it exists, TPMT activity difference between children and adults is very small and clinically irrelevant in terms of any effect on thiopurine response, considering the inter-individual variability in thiopurine metabolism and the lack of a standardised method to assay TPMT activity.