Effects of CYP3A5 Genotype on Efficacy and Safety of Tacrolimus in Refractory Ulcerative Colitis: An Experience From a Tertiary Referral Center in Japan

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Introduction: A calcineurin inhibitor, tacrolimus (TAC), is widely used as an induction therapy for steroid-refractory ulcerative colitis (UC) patients in Japan. Although its efficacy in inducing remission is comparable with other treatment options such as anti-tumor necrosis factor antibodies, its longterm efficacy is not well studied. Its long-term use may lead to an increased incidence of side effects including renal dysfunction. Furthermore, its efficacy as well as toxicity depends on the blood trough level, which requires the frequent monitoring of blood concentration. Both patients and physicians may want to avoid using Tac due to these factors. Here we retrospectively tried to examine the association of genotyping the single nucleotide polymorphism of CYP3A5, the metabolizing enzyme of tacrolimus, with the dosing, long-term efficacy, and incidence of renal dysfunction by TAC for UC in our institution. Methods: Medical records of 21 patients with UC who were treated with TAC for more than 2 weeks were retrospectively reviewed (M:F=13:8). Mean duration of TAC treatment was 308 +/- 284 days. CYP3A5*3(A6986G) was genotyped using the TaqMan real-time polymerase chain reaction assays. 1) Dose of TAC required to reach the therapeutic level (10 ug/ml) 2) incidence of renal dysfunction 3) short- and long-term clinical efficacy outcome was examined in combination of CYP3A5 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 10, *1/*3 in 9, and *1/*1 in 2 patients. 1) The dose required to reach the therapeutic trough level was significantly lower in non-expressor (*3/*3) compared with expressor (*1/*3 and *1/*1). 2) 13 out of 21patients (62%) suffered from renal dysfunction, which was not associated with CYP3A5 genotype but with the trough concentration during the treatment. Most cases recovered after discontinuing or switching Tac to thiopurines. 3) Short- and long-term efficacy outcome was not affected by the genotype. Conclusion: CYP3A5 genotype seemed useful for determining the initial dose of TAC, but was not associated with the incidence of side effects and efficacy. There was a significant proportion of patients who were maintained for longer than 3 months by TAC in combination with thiopurines, however, the incidence of gradual decrease of renal function was frequent.