. 2011 Jan 26;89(3):387–391. doi: 10.1038/clpt.2010.320

Table 2.

Recommended dosing of thiopurines by thiopurine methyltransferase phenotype

Phenotype	MP			Azathioprine		TG
Phenotype	Implications for MP and azathioprine pharmacologic measures	Dosing recommendations for MP	Classification of recommen- dations^a	Dosing recommendations for azathioprine	Classification of recommen- dations^a	Implications for pharmacologic measures after TG	Dosing recommendations for TG	Classification of recommen- dations^a
Homozygous wild-type or normal, high activity	Lower concentrations of TGN metabolites, higher methylTIMP, this is the “normal” pattern	Start with normal starting dose (e.g., 75 mg/m²/d or 1.5 mg/kg/d) and adjust doses of MP (and of any other myelosuppressive therapy) without any special emphasis on MP compared to other agents. Allow 2 weeks to reach steady state after each dose adjustment.^4,25,29	Strong	Start with normal starting dose (e.g., 2–3 mg/kg/d) and adjust doses of azathioprine based on disease-specific guidelines. Allow 2 weeks to reach steady state after each dose adjustment.^4,27,29	Strong	Lower concentrations of TGN metabolites, but note that TGN after TG are 5–10× higher than TGN after MP or azathioprine	Start with normal starting dose. Adjust doses of TG and of other myelosuppressive therapy without any special emphasis on TG. Allow 2 weeks to reach steady state after each dose adjustment.^4,16	Strong

Heterozygote or intermediate activity	Moderate to high concentrations of TGN metabolites; low concentrations of methylTIMP	Start with reduced doses (start at 30–70% of full dose: e.g., at 50 mg/m²/d or 0.75 mg/kg/d) and adjust doses of MP based on degree of myelosuppression and disease-specific guidelines. Allow 2–4 weeks to reach steady state after each dose adjustment. In those who require a dosage reduction based on myelosuppression, the median dose may be ~40% lower (44 mg/m²) than that tolerated in wild-type patients (75 mg/m²).^6,12 In setting of myelosuppression, and depending on other therapy, emphasis should be on reducing MP over other agents.^{4,13,15,21,23,25,29,31,32}	Strong	If disease treatment normally starts at the “full dose”, consider starting at 30–70% of target dose (e.g., 1–1.5 mg/kg/d), and titrate based on tolerance. Allow 2–4 weeks to reach steady state after each dose adjustment.^4,27,29,31	Strong	Moderate to high concentrations of TGN metabolites; but note that TGN after TG are 5–10× higher than TGN after MP or azathioprine	Start with reduced doses (reduce by 30–50%) and adjust doses of TG based on degree of myelosuppression and disease-specific guidelines. Allow 2–4 weeks to reach steady state after each dose adjustment. In setting of myelosuppression, and depending on other therapy, emphasis should be on reducing TG over other agents.^4,16	Moderate

Homozygous variant, mutant, low, or deficient activity	Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease; no methylTIMP metabolites	For malignancy, start with drastically reduced doses (reduce daily dose by 10-fold and reduce frequency to thrice weekly instead of daily, e.g., 10 mg/m²/d given just 3 days/week) and adjust doses of MP based on degree of myelosuppression and disease-specific guidelines. Allow 4–6 weeks to reach steady state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing MP over other agents. For nonmalignant conditions, consider alternative nonthiopurine immunosuppressant therapy.^4,24,29,31	Strong	Consider alternative agents. If using azathioprine start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 4–6 weeks to reach steady state after each dose adjustment. Azathioprine is the likely cause of myelosuppression.^{27,29–31,33}	Strong	Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease	Start with drastically reduced doses¹⁶ (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of TG based on degree of myelosuppression and disease-specific guidelines. Allow 4–6 weeks to reach steady state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing TG over other agents. For nonmalignant conditions, consider alternative nonthiopurine immunosuppressant therapy.⁴	Strong

MP, mercaptopurine; TG, thioguanine; TGN, thioguanine nucleotide; TIMP, secondary metabolite of MP.

Rating scheme is described in Supplementary Data online.