Mercaptopurine (brand names Purinethol, Purixan) is an immunosuppressant and anti-neoplastic agent that belongs to the drug class of thiopurines. It is used with other drugs to treat acute lymphoblastic leukemia, which is the most common form of cancer in children (1). Common off-label uses include the treatment of inflammatory bowel disease (IBD).
Mercaptopurine is a prodrug that must first be activated to form thioguanine nucleotides (TGNs), of which 6-thioguanine triphosphate (6-TGTP) is the major active metabolite. Two of the enzymes involved in the complex pathway of these metabolites are thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15). Individuals with reduced activity of either enzyme will be exposed to higher levels of active metabolites, like 6-TGTP, and will be at a higher risk of side effects, such as severe bone marrow suppression (myelosuppression).
The FDA-approved drug label states that the initial dose of mercaptopurine should be reduced in individuals who are known to lack TPMT or NUDT15 activity (“homozygous deficiency”) and that these individuals typically require 10% or less of the standard dose. In individuals who have reduced enzyme activity (“heterozygous deficiency”), the label states that the dose of mercaptopurine should be reduced based on tolerability. A more substantial dose reduction may be required in individuals who have reduced activity of both enzymes (Table 1) (1).
Dosing recommendations for mercaptopurine based on TPMT and NUDT15 genotype have also been published by the Clinical Pharmacogenetics Implementation Consortium (CPIC, Table 2, Table 3) and the Dutch Pharmacogenetics Working Group (DPWG). These recommendations include specific dose reductions for individuals who have low or deficient enzyme activity, including starting dose and more information on how and when to adjust the dose for example, the time allowed to reach steady-state after each dose adjustment (2, 3).