Prospective Evaluation of the Pharmacogenetics of Azathioprine in the Treatment of Inflammatory Bowel Disease

A. Ansari; M. Arenas; S. M. Greenfield; D. Morris; J. Lindsay; K. Gilshenan; M. Smith; C. Lewis; A. Marinaki; J. Duley; J. Sanderson

Disclosures

Aliment Pharmacol Ther. 2008;28(8):973-983. 

In This Article

Abstract and Introduction

Abstract

Background: One-third of patients with inflammatory bowel disease (IBD) receiving azathioprine (AZA) withdraw treatment due to side effects or lack of clinical response.
Aim: To investigate whether pharmacogenetic loci or metabolite concentrations explain clinical response or side effects to AZA.
Methods: Patients with IBD were given 2 mg/kg of AZA without dose escalation or adjustment. Serial clinical response, thiopurine methyl transferase (TPMT) activity and thioguanine nucleotide (TGN) concentrations were measured over 6 months. All patients were genotyped for inosine triphosphatase (ITPase) and TPMT. Clinical response and side effects were compared to these variables.
Results: Two hundred and seven patients were analysed. Thirty-nine per cent withdrew due to adverse effects. Heterozygous TPMT genotype strongly predicted adverse effects (79% heterozygous vs. 35% wild-type TPMT, P< 0.001). The ITPA 94C>A mutation was associated with withdrawal due to flu-like symptoms (P= 0.014). A baseline TPMT activity below 35 pmol/h/mg/Hb was associated with a greater chance of clinical response compared with a TPMT above 35 pmol/h/mg/Hb (81% vs. 43% respectively, P< 0.001). Patients achieving a mean TGN level above 100 were significantly more likely to respond (P= 0.0017).
Conclusions: TPMT testing predicts adverse effects and reduced chance of clinical response (TPMT >35 pmol/h/mg/Hb). ITPase deficiency is a predictor of adverse effects and TGN concentrations above 100 correlate with clinical response.

Introduction

The thiopurine drugs, azathioprine (AZA) and mercaptopurine (MP) are an important mainstay in the effective treatment of Crohn's disease (CD) and ulcerative colitis (UC) with efficacy rates of 55-70%.[1,2,3,4] Indeed, with greater emphasis now placed on reduction to steroid exposure, usage of these drugs for inflammatory bowel disease (IBD) has steadily increased in recent years.[5] In general, thiopurines are well tolerated and safe. However, as many as one-third of patients may suffer adverse effects[2,6,7] prompting drug withdrawal and a switch to alternative treatments. The metabolism of AZA and pharmacogenetic influences are represented in Figure 1 (Data S1 and S2).

Figure 1.

Individuals with high TPMT can generate greater methylated metabolites of MP as opposed to cytotoxic TGNs. Those with ITPA deficiency will trap TITP also a possible cause for toxicity. AZA, azathioprine; MP, mercaptopurine; 6-TU, 6-thiouric acid; TITP, 6-thioinosine triphosphate; 6-TGNs, 6-thioguanine nucleotides; HPRT, hypoxanthine phosphoribosyltransferase; ITPA, inosine triphosphate pyrophosphohydrolase; TPMT, thiopurine S-methyltransferase; XOD, xanthine oxidase.

Considerable interest has focused on the metabolism of thiopurines as a means of identifying ways of individualizing therapy to minimize adverse effects and maximize clinical response. Genetic variation of the activity of thiopurine methyl transferase (TPMT) and its influence on how an individual metabolizes AZA is an important pharmacogenetic model. Individuals with TPMT deficiency who receive standard doses of thiopurines are at significant risk of toxicity, primarily as a result of unchecked production of thioguanine nucleotides (TGNs).[8,9,10,11]

The majority of our understanding of thiopurine biology stems from work in acute lymphocytic leukaemia in which TPMT activity has been found to be inversely proportional to TGNs and a positive clinical response.[8,12] The opinion about the influence of these two parameters in IBD therapy is still divided, probably due to a lack of prospective data. However, some studies which are also supported by a meta-analysis of retrospective and cross-sectional studies have confirmed a strong association between TGN concentrations and induction of remission.[13] These indicate that a TGN level consistently above 230-260 pmol/8 × 108 RBC [14,15] is associated with a favourable response. Considering TPMT, only retrospective studies in IBD have addressed (and confirmed) that pretreatment measurement of TPMT might predict clinical response to AZA.[11,16] The majority of the remaining studies have looked for a correlation between adverse reactions and TPMT activity with a recent prospective study confirming a fourfold risk of myelotoxicity in patients with intermediate TPMT activity.[17] However, variation in TPMT activity accounts for no more than 10% of overall thiopurine toxicity [18] and perhaps around one-third of myelotoxicity.[19] Whilst other factors account for much of the remaining toxicity (e.g. hypersensitivity), genetic variation of other enzymes metabolizing thiopurines is also likely to be important.

Inosine triphosphopyrohydrolase (ITPase) catalyses the breakdown of inosine triphosphate (ITP) as part of a futile cycle in the purine metabolic pathway.[20] Genetic ITPase deficiency is thought to be a benign disorder of no known detriment to health under normal circumstances. However, following exposure to thiopurines, ITPase deficiency results in the cellular accumulation of thio-inosine triphosphate (thioITP) [Arenas, personal communication], a 'rogue nucleotide' with the potential of cell toxicity.[21] Indeed, three studies, one prospective, have reported association of thiopurine toxicity with the presence of the ITPA 94C>A mutant allele.[22,23] However, no consistent pattern of toxicity has been reported, with three retrospective studies reporting no association.[24,25,26]

The value of pretreatment assessment of TPMT in avoiding potentially life-threatening toxicity in patients with zero activity is well proved and increasingly taken up in clinical practice.[27] However, the true clinical value of prior knowledge of the more frequent heterozygous TPMT state is less well defined. Furthermore, whether TPMT activity can provide useful information about likely clinical response has only been addressed retrospectively. Finally, the role of ITPase deficiency as an additional pharmacogenetic marker in thiopurine therapy remains unclear.

We therefore sought to study the role of TGNs, TPMT and ITPase as predictors of adverse effects and clinical response to AZA, using a well-powered prospective study of patients with IBD. To our knowledge, the cohort presented here constitutes the largest prospective analysis of thiopurine pharmacogenetic and pharmacokinetic parameters in IBD.

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