Howard L. McLeod, PharmD; Kim L. Isaacs, MD, PhD
Grant Support: By grants U01 GM63340, UL1RR025747, and P30 DK34987 from the National Institutes of Health.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-1137.
Requests for Single Reprints: Howard L. McLeod, PharmD, University of North Carolina Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, 120 Mason Farm Road, Genetic Medicine Building, Campus Box 7361, Chapel Hill, NC 27599-7361; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. McLeod: University of North Carolina Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, 120 Mason Farm Road, Genetic Medicine Building, Campus Box 7361, Chapel Hill, NC 27599-7361.
Dr. Isaacs: Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, 130 Mason Farm Road, Bioinformatics Building, Campus Box 7080, Chapel Hill, NC 27599-7080.
McLeod HL, Isaacs KL. Preemptive Pharmacogenetic Testing: Insufficient Data Equal Unsatisfactory Guidance. Ann Intern Med. 2011;154:842-843. doi: 10.7326/0003-4819-154-12-201106210-00016
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Published: Ann Intern Med. 2011;154(12):842-843.
The past decade has seen the emergence of tools for tailoring care to individual patients. Under the guise of personalized medicine, a host of drug-level assays and DNA, RNA, protein, and imaging tests promise to enhance clinical benefit by enabling clinicians to determine optimal therapies and dosages (1). These tools come at an opportune time, when health systems are under pressure to improve returns on the therapeutic investment. However, evidence on the clinical effectiveness and cost-effectiveness of preemptive testing is lacking.
In this issue, Booth and colleagues (2) systematically review evidence (54 observational studies and 1 randomized trial) on a particularly promising situation for preemptive testing: thiopurine S-methyltransferase (TPMT) enzymatic activity before thiopurine therapy. Azathioprine and 6-mercaptopurine are thiopurine agents used for nearly 50 years to treat lymphocyte cancer and various autoimmune diseases, including inflammatory bowel disease, rheumatoid arthritis, and pemphigus (3). Thiopurine S-methyltransferase was found to be part of a thiopurine inactivation pathway, and its clinical relevance first became apparent in case reports of severe or fatal hematopoietic toxicity in patients who were subsequently found to have low or undetectable TPMT activity (4, 5). The predominant molecular basis for TPMT deficiency was found to be nonsynonymous (amino acid–changing) single nucleotide polymorphisms, which result in an inability to properly degrade the drug (6). Patients with TPMT deficiency often require one tenth of a standard dose to achieve erythrocyte activity metabolite levels in the therapeutic range (3). Patients with a heterozygous TPMT genotype are also at heightened risk for neutropenia from thiopurine agents, although this is rarely fatal (7, 8). Some practices routinely assess TPMT status (by genotype or erythrocyte enzyme activity) before prescribing a thiopurine or measure metabolite levels of erythrocyte activity shortly after initiating thiopurine therapy (9).
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Print ISSN: 0003-4819 | Online ISSN: 1539-3704
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