Impact of CYP3A5 Genetic Polymorphisms on the Pharmacokinetics and Short-term Remission in Patients With Ulcerative Colitis Treated With Tacrolimus

Fumihito Hirai; Noritaka Takatsu; Yutaka Yano; Yuhou Satou; Haruhiko Takahashi; Satoshi Ishikawa; Kozue Tsurumi; Takashi Hisabe; Toshiyuki Matsui

Disclosures

J Gastroenterol Hepatol. 2014;29(1):60-66. 

In This Article

Results

The subjects in this study were 25 men and 21 women with a mean age of 40.9 ± 13.8 years and a mean duration of disease of 4.9 ± 5.2 years. The DAI score on day 0 of Tac was 10.9 ± 1.2, and the pDAI score was 7.8 ± 1.2.

Pretreatments involved steroid therapy in 35 patients, accounting for 78% of all cases. Of these 35 patients, 25 received intravenous steroids, and the remaining 10 took oral steroids. Other treatments were cytapheresis in six patients, cyclosporine A (CyA) and infliximab in one patient each, and 5-aminosalicylic acid with an immunomodulator in two patients. Fasting management with total parenteral nutrition was selected in 22 patients, which corresponded to about half of the 45 patients in this study. Hydrocortisone was administered intravenously in 20 of these 22 patients, the large majority. The treatments given the subjects prior to starting Tac are summarized in Figure 1.

Figure 1.

This figure shows the clinical courses and treatments of the subjects prior to starting tacrolimus. Severe or fulminant ulcerative colitis was seen in 39 (86.7%) of 45 subjects. The other six patients (13.3%) showed an acute exacerbation in a chronic steroid-dependent course. *Dose at starting tacrolimus (mg/day, mean ± SD); period before starting tacrolimus from initial treatment (days, mean ± SD); initial dose (mg/day, mean ± SD); §period before starting tacrolimus from admission (days, mean ± SD). AZA, azathioprine; CyA, cyclosporine A; IFX, infliximab; IV, intravenous; PSL, prednisolone.

CYP3A4, CYP3A5, and ABCB1 Genotypes and Patient Profiles

The CYP3A4 genotype was *1*1 in 44 of 45 subjects (97.8%) and *1/*1B in only one subject (2.2%).

The CYP3A5 genotype was *1*1 in four subjects (8.9%), *1*3 in 20 subjects (44.4%), and *3*3 in 21 subjects (46.7%). Thus, 24 of 45 subjects (53.3%) were Exp with *1, and 21 of 45 (46.7%) were Non-Exp without *1. No obvious differences were seen in the baseline characteristics of patients in the Exp group and the Non-Exp group before starting Tac (Table 1).

The genotype of ABCB1 2677G/A/T was G/T in 16 patients (35.6%), G/A in 11 patients (24.4%), G/G in 9 patients (20.0%), T/A in 4 patients (8.9%), and T/T in 5 patients (11.1%). The genotype of ABCB1 3435C/T was C/T in 24 patients (53.3%), C/C in 17 patients (37.8%), and T/T in 4 patients (8.9%).

CYP3A5 and ABCB1 Genotypes and Pharmacokinetics of Tac

All patients who needed fasting to control their severe symptoms were continued on fasting status until at least day 12 of Tac therapy. Therefore, their fasting status did not affect the analysis of Tac pharmacokinetics on days 2–5 and 7–10.

On days 2–5, there was no difference in the Tac dose between the CYP3A5 Non-Exp group and the Exp group, but the Non-Exp group had a significantly higher trough level (10.16 ± 5.84 vs 4.47 ± 2.50 ng/mL, P < 0.0001) and dose-adjusted trough level (139.36 ± 77.43 vs 61.37 ± 41.55 ng/mL per mg/kg/day, P < 0.0001). On days 2–5, the Non-Exp group had a significantly higher percentage of patients achieving the optimal trough level than the Exp group (40.0% vs 4.3%, P = 0.01). On days 7–10, the Tac dose was significantly higher in the Exp group because of dose adjustment (0.156 ± 0.036 vs 0.112 ± 0.044 mg/kg, P = 0.001), but the Non-Exp group had significantly higher trough levels (16.81 ± 5.70 vs 9.76 ± 2.90 ng/mL, P < 0.0001) and dose-adjusted trough levels (185.19 ± 109.55 vs 66.52 ± 28.00 ng/mL per mg/kg/day, P < 0.0001) than the Exp group. On days 7–10, the Non-Exp group had a significantly higher percentage of patients achieving the optimal trough level than the Exp group (84.2% vs 45.5%, P = 0.04) (Table 2).

For ABCB1, the trough level and dose-adjusted trough level were compared on days 2–5 and 7–10 between the TT type and all other types in C3435T and between the TT type and all other types in G2677A/T, but no significant differences were seen (data not shown).

Achieving Optimal Trough Level

1. Percentage of patients achieving the optimal trough level on days 2–5 and associated factors

Nine patients (20.9%) achieved the optimal trough levels on the initial measurement. Univariate analysis was done with a total of 28 items, including CYP3A4, ABCB1, CYP3A5 genotype, patient background, pretreatment, activity index, endoscopic severity, and laboratory data (erythrocyte sedimentation rate, white blood cell count, hemoglobin, platelet count, C-reactive protein, albumin) to determine whether an appropriate trough level was achieved (Table 3).

Items with P < 0.25 on the univariate analysis (CYP3A5 genotype, food intake/non-intake, BMI<20 kg/m2, PSL dose at baseline) were taken as explanatory variables on multivariate analysis. Food non-intake (OR 36.7, 95% CI 2.9–471.7) and CYP3A5 Non-Exp (odds ratio [OR] 40.3, 95% confidence interval [CI] 3.2–515.5) were significantly associated with achievement of the optimal trough level on days 2–5 (Table 4).

2. Percentage of patients achieving the optimal trough level on days 7–10 and associated factors

Twenty-six patients achieved high trough levels on the second measurement. As on days 2–5, a univariate analysis was done with a total of 28 items to determine whether an appropriate trough level was achieved (Table 3).

Items with P < 0.25 on the univariate analysis (CYP3A5 genotype, food intake/non-intake, disease type, duration of disease < 40 months) were taken as explanatory variables on multivariate analysis. Only CYP3A5 Non-Exp (OR 5.9, 95% CI 1.3–26.3) was significantly associated with achievement of the optimal trough level on days 7–10 (Table 4).

Short-term Clinical Remission

The pDAI score 4 weeks after the start of Tac showed a significant difference between the Exp group and the Non-Exp group (3.9 ± 2.8 vs 2.6 ± 1.9, P = 0.045). The remission rate was significantly higher in the Non-Exp group (47.6%) than in the Exp group (16.7%) (P = 0.046). Four patients required surgery within 4 weeks, all of whom were in the Non-Exp group (P = 0.078) (Table 5).

Adverse Effects

Two patients (4.0%) had severe adverse effects that necessitated discontinuation of Tac. One of them had renal dysfunction, and one had PCP. The CYP3A5 gene type was *1*1 in both of these patients. Amelioration of adverse effects with conservative treatment and observation only, without discontinuation of Tac, was seen in 34 of 45 patients (75.6%). These adverse effects included magnesium deficiency in 27 patients, tremor in 18 patients, facial flush in 5 patients, and glucose intolerance in 2 patients. There was no difference in these frequencies between the Exp group and the Non-Exp group (70.8% vs 81.0%, P = 0.66).

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