Pharmacokinetics, dose adjustments, and 6‐mercaptopurine/ methotrexate drug interactions in two patients with thiopurine methyltransferase deficiency

Two children with acute lymphoblastic leukaemia (ALL) were found to be thiopurine methyltransferase (TPMT)‐deficient by both genotype and phenotype. They were monitored with haematological parameters and red blood cell concentrations of 6‐thioguanine nucleotides (E‐6TGN) and methotrexate (E‐MTX, including MTX polyglutamates), in relation to the doses of 6‐mercaptopurine (6MP) and methotrexate (MTX), during their maintenance chemotherapy. Both patients developed severe pancytopenia at the standard protocol dose of 6MP. Even at 25% and 5%, respectively, of the protocol dose of 6MP, they achieved E‐6TGN values several‐fold above the population median, but without unacceptable bone‐marrow toxicity. Their high E‐6TGN values had only a minor influence on their E‐MTX values and their tolerance to oral MTX, but severe pancytopenia followed high‐dose MTX infusions. Due to the risk of fatal myelo‐suppression we recommend up‐front determination of TPMT activity in patients treated with 6MP or azathioprine.