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P446 Effects of CYP3A5 genotype on efficacy and safety of tacrolimus in refractory ulcerative colitis: experience from a tertiary referral centre

E. Saito*, T. Kobayashi, M. Nakano, T. Toyonaga, S. Kuronuma, O. Takeuchi, H. Serizawa, N. Watanabe, T. Hibi

Kitasato University Kitasato Institute Hospital, Centre for Advanced IBD Research and Treatment, Tokyo, Japan

Background

A calcineurin inhibitor, tacrolimus (TAC), is widely used as an induction therapy for steroid-refractory ulcerative colitis (UC) patients in Japan. Its efficacy, as well as toxicity, depends on the blood trough level, which requires frequent monitoring of blood concentration. TAC is metabolised by CYP3A5 and its single nucleotide polymorphism (SNP) is reported to influence the blood concentration of TAC. We retrospectively tried to examine the association of SNPs of CYP3A5 with the dosing, short- and long-term efficacy, and incidence of renal dysfunction by TAC for UC in our institution.

Methods

Medical records of 29 patients with UC who were treated with TAC were retrospectively reviewed (M:F = 20:9). CYP3A5*3 (A6986G, rs776746) was genotyped using the TaqMan real-time polymerase chain reaction assays. Mean duration of TAC treatment was 39.0 weeks (0.91–78.3). Dose of TAC required to reach the therapeutic level (10 μg/ml), short- and long-term clinical efficacy outcomes, and incidence of renal dysfunction, were examined in combination of CYP3A5 SNP genotypes. Renal dysfunction was defined by the 25% increase of serum creatinine (Cr). All analyses were conducted under the approval of Institutional Review Board of Kitasato Institute Hospital.

Results

CYP3A5*3 genotypes were *3/*3 in 16; *1/*3 in 10; and *1/*1 in 3 patients. Overall remission rate at week 4 was 67.9%. The dose of TAC required to reach the therapeutic trough level was significantly lower in non-expressors (*3/*3) compared with expressors (*1/*3 and *1/*1). There was no significant difference in short- and long-term outcomes between the non-expressor group and expressor group. During the follow-up period, 14 out of 29 patients (48.3%) suffered from renal dysfunction, which was not associated with CYP3A5 genotype.

Conclusion

CYP3A5 genotype seemed useful to optimise the dosing of TAC, but was not associated with the incidence of side effects and efficacy. Incidence of renal dysfunction was increased because of the continuous use of TAC for maintenance therapy.