Optimizing immunomodulator therapy for inflammatory bowel disease

Abstract

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.

Current use of immunosuppressive agents in inflammatory bowel disease patients in East China

“…Experience abroad has shown that AZA can be safely used for treatment of IBD [22][23][24] . Recently, TPMT and its genotype have been applied to predict the efficacy and toxicity of drugs, which can provide some guidance for clinicians and reduce the incidence of drug toxicity in Western countries [25][26][27][28][29] . Meanwhile, studies have shown that examining TPMT enzyme activity may decrease the overall medical cost in Europe and America [30,31] .…”

Clinical usefulness of therapeutic drug monitoring of thiopurines in patients with inadequately controlled inflammatory bowel disease

“…10,11 The evidence supporting an upper limit of >450 pmol/8 Â 10 8 RBC is not so strong. The cutoff concentration above 450 pmol/8 Â 10 8 RBC is based on an increased risk of side effects (myelotoxicity 12 and nodular regenerative hyperplasia of the liver 15 ) without an increase in efficacy. Patients with erythrocyte 6-MMP concentrations above 5700 pmol/8 Â 10…”

Measurement of Erythrocyte Inosine Triphosphate Pyrophosphohydrolase (ITPA) Activity by HPLC and Correlation of ITPA Genotype-Phenotype in a Caucasian Population

“…Patients with high TPMT activity may experience treatment failure (9,10 ) or hepatotoxicity (11 ), but the situation is much less clear than for the TPMT deficiencies (12)(13)(14). In addition, an estimated 10% to 30% of patients cannot tolerate AZA therapy because of nonmyelosuppression adverse reactions, such as influenzalike symptoms, nausea, vomiting, hepatotoxicity, pancreatitis, fever, or rash (1,12,15,16 ). Two recent studies with patients suffering from chronic inflammatory disease, a retrospective study by Marinaki et al (17 ) and a prospective one by von Ahsen et al (16 ), have provided evidence that deficiency in another polymorphic enzyme-inosine triphosphate (ITP) pyrophosphohydrolase (ITPA; EC 3.6.1.19)-could represent a further pathomechanism for thiopurine side effects in addition to TPMT.…”