Start with reduced doses of thioguanine for patients with one nonfunctional TPMT allele, or drastically reduced doses for patients with malignancy and two nonfunctional alleles; adjust dose based on degree of myelosuppression and disease-specific guidelines. Consider alternative nonthiopurine immunosuppressant therapy for patients with nonmalignant conditions and two nonfunctional alleles.
These guidelines apply to adults and pediatrics. Please see below for full details of these guidelines, with supporting evidence and disclaimers.
Guidelines regarding the use of pharmacogenomic tests in dosing for azothioprine, thioguanine and mercaptopurine were published March 2011 in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).
Conclusions of the CPIC guidelines update 2013, accepted for publication by Clinical Pharmacology and Therapeutics and available online Jan 2013: Literature published between June 2010-November 2012 was reviewed and there is no new evidence that would change the original guidelines. Therefore, the dosing recommendations in the original publication remain clinically current. As much of the evidence used to support the guidelines was generated in children, and the dosing recommendations are in units mg/m2 and mg/kg (see table below), they are applicable to both pediatric and adult patients.
Read the Clinical Pharmacology and Therapeutics Updated Article and supplement
Excerpt from the original thiopurine dosing guidelines:
Thiopurines are most commonly used to treat nonmalignant conditions but are also critical anticancer agents. The approach to dosing adjustments based on TPMT status may differ depending on the clinical indication and the propensity to initiate therapy at higher vs. lower starting doses. We and others advocate testing for TPMT status prior to initiating thiopurine therapy, so that starting dosages can be adjusted accordingly.
Recommended dosing of thioguanine by TPMT phenotype
|Phenotype (Genotype)||Examples of diplotypes||Implications for pharmacologic measures after thioguanine||Dosing recommendations for thioguanine||Classification of recommendations|
|Homozygous wild-type or normal, high activity (two functional *1 alleles)||*1/*1||Lower concentrations of TGN metabolites, but note that TGN after thioguanine are 5-10x higher than TGN after mercaptopurine or azathioprine||Start with normal starting dose. Adjust doses of thioguanine and of other myelosuppressive therapy without any special emphasis on thioguanine . Allow 2 weeks to reach steady state after each dose adjustment.||Strong|
|Heterozygote or intermediate activity (one functional allele - *1, plus one nonfunctional allele - *2, *3A, *3B, *3C, or *4)||*1/*2, *1/*3A, *1/*3B, *1/*3C, *1/*4||Moderate to high concentrations of TGN metabolites; but note that TGN after thioguanine are 5-10x higher than TGN after mercaptopurine or azathioprine||Start with reduced doses (reduce by 30-50%) and adjust doses of thioguanine 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 thioguanine over other agents.||Medium|
|Homozygous variant, mutant, low, or deficient activity (two nonfunctional alleles - *2, *3A, *3B, *3C, or *4)||*3A/*3A, *2/*3A, *3C/*3A, *3C/*4, *3C/*2, *3A/*4||Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease||Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of thioguanine 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 thioguanine over other agents. For nonmalignant conditions, consider alternative nonthiopurine immunosuppressant therapy.||Strong|