Tanya R Yakushi*, Yong Qu,Mike M Moradian,Ruan T Ramjit
Purine analogs, 6-mercaptopurine (6-MP) and the prodrug azathioprine (Aza) are used as immunosuppressants in the treatment of many diseases including cancer, autoimmune disorders and inflammatory diseases ofthe digestive tract. Treatment with thiopurines is complicated by the high variability in response observed in a patient population. The need to titrate treatment to adequate therapeutic levels is exacerbated by the cytotoxicity that can result from overdosing patients. In this comprehensive study, we evaluated the response of 946 individuals, with known thiopurine S-methyltransferase (TPMT) genotypes, to treatment with 6-MP and Aza. We determined the allelic frequencies of the most common TPMT alleles in a diverse cohort of individuals. The TPMT*1/TPMT*1 genotype was found to occur in 92.1% of the patient population, while the TPMT*1/TPMT*3A, TPMT*1/ TPMT*3C, and TPMT*1/TPMT*2 genotypes were found to occurin 6.0%, 1.8%, and 0.1% of the patient population, respectively. We evaluated how genotype affected therapeutic response and make safe dosing recommendation based on genotype. The observations made in thisstudy,strongly suggests a need to prescribe patients with the TPMT*1/TPMT*3A genotype ~50% of the dose prescribed to wild type individuals and ~25% of the TPMT*1/TPMT*1 dosage to individuals encoding the TPMT*1/TPMT*3C genotype. The results presented are intended to serve as a guide to better understand the complex relationship between genotype and pharmaceutical response to thiopurine drugs.
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