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Clinical Drug Investigation

, Volume 24, Issue 8, pp 479–486 | Cite as

Therapeutic Drug Monitoring in Patients with Inflammatory Bowel Disease and Established Azathioprine Therapy

  • L. P. L. Gilissen
  • L. J. J. Derijks
  • L. P. Bos
  • P. J. Bus
  • P. M. Hooymans
  • L. G. J. B. Engels
Original Research Article

Abstract

Background and objective

Azathioprine is widely used in the treatment of corticosteroid-dependent and refractory inflammatory bowel disease (IBD). The efficacy of this treatment is based on the production of 6-thioguanine nucleotides, but extremely elevated levels may cause bone marrow suppression. Other azathioprine metabolites, 6-methylmercaptopurine ribonucleotides, are associated with hepatotoxicity. Therapeutic drug monitoring (TDM) may be of help in optimising azathioprine treatment, but data on TDM in established azathioprine therapy are lacking. We therefore measured metabolite levels in a small cohort of patients established on azathioprine therapy.

Patients and methods

6-Thioguanine (6-TGN) and 6-methylmercaptopurine (6-MMP) levels in erythrocytes were measured in 15 IBD outpatients established on azathioprine therapy for at least 3 months at baseline and 1, 4 and 8 weeks after inclusion (mean duration of treatment 28 months; range 7–67 months). Disease activity was evaluated by the Crohn’s Disease Activity Index (Crohn’s disease) or Truelove-Witts (ulcerative colitis) scores. Metabolite levels were measured by modified high-performance liquid chromatography assay (HPLC). Primary outcome measures were 6-TGN and 6-MMP metabolite levels and 95% confidence intervals (CIs). Secondary outcomes were correlations between metabolite levels, drug dose, disease activity and laboratory parameters and compliance.

Results

One patient had active disease during the study period. Eleven of 15 patients (73%) completed the 8-week study period. Dropout reasons were noncompliance in three patients (20%) and intolerance in one patient (7%).

Primary outcomes

At baseline mean 6-TGN levels were 158 (95% CI 113, 203) pmo1/8·108 RBC (red blood cells), steadily increasing over the 8-week study period, but not significantly. Two patients had zero levels. Another two had significantly increasing levels also suggesting noncompliance. Mean 6-MMP levels showed almost a similar pattern. At baseline, levels were 2213 (95% CI 722, 3704) mo1/8·108 RBC.

Secondary outcomes

A correlation was found between all RBC 6-MMP levels and azathioprine dose (mg/kg bodyweight) [r = 0.43, p = 0.001] and also between the 6-MMP/6-TGN ratio and azathioprine dose (mg/kg) [r = 0.36, p = 0.010). There was no correlation between RBC 6-TGN or 6-MMP levels and haematological parameters or disease activity scores. No hepatic, pancreatic or myelotoxicity occurred.

Thirteen of 15 patients (87%) had baseline steady-state 6-TGN levels below the therapeutic threshold of 235 pmol/8·108 RBC. Forty percent (6/15) of our patients were noncompliant; TDM revealed this noncompliance in four of the six patients (27% of all patients).

Conclusion

Our small study demonstrates that TDM may provide insight into individual pharmacokinetics. However, TDM does not seem to be useful in patients with IBD established on azathioprine therapy and without disease activity, although it may be helpful in cases of worsening IBD activity to elucidate noncompliance or inefficient treatment.

Keywords

Inflammatory Bowel Disease Therapeutic Drug Monitoring Inflammatory Bowel Disease Patient Thiopurine Azathioprine Therapy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

This study received no external funding. The authors have no potential conflicts of interest directly relevant to the contents of this article.

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Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • L. P. L. Gilissen
    • 1
  • L. J. J. Derijks
    • 2
  • L. P. Bos
    • 3
  • P. J. Bus
    • 4
  • P. M. Hooymans
    • 5
  • L. G. J. B. Engels
    • 3
  1. 1.Department of Internal Medicine and GastroenterologyAcademic Hospital Maastricht (azM)MaastrichtThe Netherlands
  2. 2.Department of Clinical PharmacyMaxima Medical CentreVeldhovenThe Netherlands
  3. 3.Department of GastroenterologyMaasland Hospital SittardSittardThe Netherlands
  4. 4.Department of GastroenterologySt Laurentius Hospital RoermondRoermondThe Netherlands
  5. 5.Department of Clinical PharmacyMaasland Hospital SittardSittardThe Netherlands

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