Optimizing immunomodulator therapy for inflammatory bowel disease.
6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) remain the mainstay of immunomodulator therapy for the maintenance of steroid-free remission in patients with inflammatory bowel disease (IBD). Traditional dosing strategies for initiation of thiopurines are often based on weight or empirically chosen. Dosing based on an understanding of an inherited difference in drug disposition and metabolism may provide a safer alternative. The thiopurine methyltransferase (TPMT) enzyme plays a pivotal role in the metabolism of 6-MP and AZA and is critical to the determination of thiopurine toxicity. The therapeutic benefits of thiopurines correlate best with concentration of the active 6-thioguanine (6-TGN) metabolites. Reports suggest that therapeutic response can be maximized when patients achieve therapeutic 6-TGN levels. Pharmacogenetic dosing based on TPMT and pharmacokinetic dosing based on 6-TGN levels may offer a safety and efficacy advantage over traditional dosing strategies and provide a novel mechanism for optimizing immunomodulator therapy in IBD.
Pediatric IBD Center, Cedars-Sinai Medical Center, 8635 West 3rd Street, Suite 1165W, Los Angeles, CA 90048, USA. dubinskym@csmc.edu
Marla C
MC
Dubinsky
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D001379:Azathioprine / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D015122:Mercaptopurine / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D008780:Methyltransferases / Q000502:physiology; D016896:Treatment Outcome
D000276:Adjuvants, Immunologic; D007166:Immunosuppressive Agents; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine