INFLAMMATORY BOWEL DISEASE

Pharmacogenetics during standardised initiation of thiopurine treatment in inflammatory bowel disease

U Hindorf^1,*, M Lindqvist^2,*, C Peterson², P Söderkvist³, M Ström⁴, H Hjortswang⁴, A Pousette⁵, S Almer⁴

¹ Department of Clinical Sciences, Division of Gastroenterology, Faculty of Medicine, Lund University, Lund, Sweden
² Department of Medicine and Care, Division of Clinical Pharmacology, Faculty of Health Sciences, Linköping University, Linköping, Sweden
³ Department of Biomedicine and Surgery, Division of Cell Biology, Faculty of Health Sciences, Linköping University
⁴ Department of Molecular and Clinical Medicine, Division of Gastroenterology and Hepatology, Faculty of Health Sciences, Linköping University
⁵ Department of Internal Medicine, Vrinnevi Hospital, Norrköping, Sweden

Correspondence to:
Dr Ulf Hindorf
Department of Clinical Sciences, Division of Gastroenterology, Faculty of Medicine, Lund University, 22185 Lund, Sweden; Ulf.Hindorf{at}med.lu.se

Background: Firm recommendations about the way thiopurine drugs are introduced and the use of thiopurine methyltransferase (TPMT) and metabolite measurements during treatment in inflammatory bowel disease (IBD) are lacking.

Aim: To evaluate pharmacokinetics and tolerance after initiation of thiopurine treatment with a fixed dosing schedule in patients with IBD.

Patients: 60 consecutive patients with Crohn’s disease (n = 33) or ulcerative colitis (n = 27) were included in a 20 week open, prospective study.

Methods: Thiopurine treatment was introduced using a predefined dose escalation schedule, reaching a daily target dose at week 3 of 2.5 mg azathioprine or 1.25 mg 6-mercaptopurine per kg body weight. TPMT and ITPA genotypes, TPMT activity, TPMT gene expression, and thiopurine metabolites were determined. Clinical outcome and occurrence of adverse events were monitored.

Results: 27 patients completed the study per protocol, while 33 were withdrawn (early protocol violation (n = 5), TPMT deficiency (n = 1), thiopurine related adverse events (n = 27)); 67% of patients with adverse events tolerated long term treatment on a lower dose (median 1.32 mg azathioprine/kg body weight). TPMT activity did not change during the 20 week course of the study but a significant decrease in TPMT gene expression was found (TPMT/huCYC ratio; p = 0.02). Patients with meTIMP concentrations >11 450 pmol/8x10⁸ red blood cells during steady state at week 5 had an increased risk of developing myelotoxicity (odds ratio = 45.0; p = 0.015).

Conclusions: After initiation of thiopurine treatment using a fixed dosing schedule, no general induction of TPMT enzyme activity occurred, though TPMT gene expression decreased. The development of different types of toxicity was unpredictable, but we found that measurement of meTIMP early in the steady state phase helped to identify patients at risk of developing myelotoxicity.

Abbreviations: HBI, Harvey-Bradshaw index; HPRT, hypoxanthine phosphoribosyl transferase; IBD, inflammatory bowel disease; IQR, interquartile range; ITPA, inosine triphosphate pyrophosphohydrolase; ITPase, inosine triphosphate pyrophosphatase; meTIMP, methylthioinosine monophosphate; purine de novo synthesis, ; pRBC, packed red blood cells; TGN, thioguanine nucleotide; TIMP, thioinosine monophosphate; TPMT, thiopurine methyltransferase

Keywords: inflammatory bowel disease; thiopurine methyltransferase; thioguanine nucleotides; methylated metabolites

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