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P629 The initial trough concentration at 36 h after starting tacrolimus is important for the personalised medicine strategy in patients with ulcerative colitis

N. Hida*1, K. Watanabe2, T. Miyazaki1, Y. Yokoyama2, M. Kawai1, T. Takagawa1, K. Kamikozuru1, T. Sato2, K. Fujimoto1, R. Koshiba1, K. Kojima1, S. Nakamura1

1Hyogo College of Medicine, Department of Inflammatory Bowel Disease, Nishinomiya, Hyogo, Japan, 2Hyogo College of Medicine, Department of Intestinal Inflammation Research, Nishinomiya, Hyogo, Japan

Background

Oral tacrolimus (TAC) is effective for inducing clinical remission in patients with refractory ulcerative colitis (UC). Therapeutic drug monitoring of TAC to achieve a high trough level as soon as possible is essential for demonstrating maximum effectiveness especially in patients with severe UC. However, high interindividual pharmacokinetics variability due to CYP3A5 genetic polymorphism may affect the efficacy of TAC therapy. Since it is difficult to examine genetic polymorphisms before TAC administration in clinical settings, an easy and practical strategy to predict optimal dose of TAC is required.

Methods

Seventy-one hospitalised patients with moderate to severe UC who received oral TAC were retrospectively analysed. The initial dose of TAC was 6 mg/day (0.08–0.15 mg/kg/day) twice daily and was administrated in a fasting condition. The initial trough concentration of TAC was measured at 36 h after starting therapy and each patient was classified as a poor metaboliser (PM; trough >20 μg/ml), intermediate metaboliser (IM; 10–20 μg/ml), rapid metaboliser (RM; 5–10 μg/ml), or ultra-rapid metaboliser (UM; <5 μg/ml). Dosage of TAC was adjusted as follows: reduce to 2–4 mg/day for PM, continue with 5–6 mg for IM, increase to 8–10 mg/day for RM, increase to 12 mg/day with coadministration of proton pump inhibitor for UM. After the first dose adjustment of TAC, trough concentration was measured once every 2 days to maintain a high trough level for 2 to 3 weeks. All responding patients were followed by tapered trough level of 5–10 μg/ml for 3 months.

Results

Proportion of metabolising phenotypes of TAC depending on the initial trough concentration was as follows: PM 13%, IM 39%, RM 24%, and UM 24%. Final required average dose of TAC for maintaining high trough level was 3.9 ± 1 mg/day for PM, 4.8 ± 1.6 mg/day for IM, 7.9 ± 2.2 mg/day for RM, and 11.5 ± 3.3 mg/day for UM. All cases reached a high trough level within a week. Time required for reaching a high trough level was 2.9 days on average. After 3 months from the treatment initiation, the response rate was 76% and clinical remission was achieved in 65% of patients. Patients with severely active compared with moderate UC had equivalent rate of clinical response (72% vs. 88%; p = 0.15) and clinical remission (59% vs. 82%; p = 0.07). Frequency of RM or UM did not differ between non-responder and responder (38% vs. 60%; p = 0.15, chi-squared test). The incidence of adverse events did not differ between metabolising phenotypes of TAC.

Conclusion

Personalised medicine strategy based on predicted metabolising phenotype from the initial trough level would make TAC therapy safer, easier and more effective. The influence of genetic polymorphism could be eliminated by our rapid induction method of TAC.