Abstract | BACKGROUND: AIM: To evaluate pharmacokinetics and tolerance after initiation of thiopurine treatment with a fixed dosing schedule in patients with IBD. PATIENTS: 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 RESULTS: 27 patients completed the study per protocol, while 33 were withdrawn (early protocol violation (n = 5), TPMT deficiency (n = 1), thiopurine related adverse events (n = 27)); 67% of patients with adverse events tolerated long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/8 x 10(8) 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.
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Authors | U Hindorf, M Lindqvist, C Peterson, P Söderkvist, M Ström, H Hjortswang, A Pousette, S Almer |
Journal | Gut
(Gut)
Vol. 55
Issue 10
Pg. 1423-31
(Oct 2006)
ISSN: 1468-3288 [Electronic] England |
PMID | 16543290
(Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antimetabolites
- Mercaptopurine
- Methyltransferases
- thiopurine methyltransferase
- Pyrophosphatases
- inosine triphosphatase
- Azathioprine
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Topics |
- Adolescent
- Adult
- Aged
- Antimetabolites
(administration & dosage, adverse effects, pharmacokinetics)
- Azathioprine
(administration & dosage, adverse effects, pharmacokinetics)
- Colitis, Ulcerative
(drug therapy, enzymology)
- Crohn Disease
(drug therapy, enzymology)
- Dose-Response Relationship, Drug
- Female
- Gene Expression
- Genotype
- Humans
- Male
- Mercaptopurine
(administration & dosage, adverse effects, pharmacokinetics)
- Methyltransferases
(genetics, metabolism)
- Middle Aged
- Phenotype
- Polymorphism, Genetic
- Prospective Studies
- Pyrophosphatases
(genetics, metabolism)
- Treatment Outcome
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