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

Discussion

To produce a sufficient effect with Tac, the trough level needs to be controlled to a target level, for which TDM is necessary.[6] This target trough level differs depending on the disease being treated. In the case of UC, placebo-controlled, blinded trials have shown that 10–15 ng/mL is the optimal trough level to induce remission.[2,3] Especially in cases of severe UC, control to the optimal trough level as early as possible from the start of therapy is necessary to obtain a therapeutic effect. The trough level is frequently measured in the early period of therapy and the dose is adjusted, but the dose is difficult to estimate because of the large individual differences in Tac blood levels. Many reports have examined the relationships between Tac pharmacokinetics and CYP3A4, CYP3A5, and ABCB1 genetic polymorphisms in the fields of kidney and liver transplantation, and they have concluded that CYP3A5 has a large effect.[13,14,17–19] CYP3A5 genetic polymorphisms are identified prior to transplantation, and setting doses separately for Exp and Non-Exp patients is effective. In a prospective study, Thervet et al. divided kidney transplantation patients into groups that did and did not have the initial Tac dose set based on CYP3A5 polymorphism and studied the subsequent pharmacokinetics.[20] The percentage of patients achieving the optimal trough level after six oral administrations, which was the primary end-point, was significantly higher in the group with the initial Tac dose set based on CYP3A5 polymorphism than in the group with the dose not set based on CYP3A5 polymorphism (43.2% vs 29.1%). There have been no such studies in the field of IBD; this is the first such report. In the present study, the trough and dose-adjusted trough levels were significantly higher on days 2–5 and 7–10 in the CYP3A5 Non-Exp group than in the CYP3A5 Exp group. Moreover, on both days 2–5 and 7–10, the percentage of patients achieving the optimal trough level was significantly higher in the Non-Exp group than in the Exp group. Higher trough levels were also obtained with low Tac doses in the Non-Exp group than in the Exp group among UC patients, and the optimal trough level was shown to be achieved at an early time.

In an analysis of factors involved in achieving the optimal trough level on days 2–5, CYP3A5 genetic polymorphisms and food intake/non-intake were significant factors on multivariate analysis. Only CYP3A5 genetic polymorphisms were significant on days 7–10. Although the effects of both CYP3A5 and fasting became weak with time, CYP3A5 polymorphism was the only significant factor because of its strong impact. Thus, the results showed that consideration of CYP3A5 genetic polymorphisms is important for early induction of the optimal trough level. ABCB1 is also reported to be associated with Tac pharmacokinetics, although its effect is smaller than that of CYP3A5 genetic polymorphisms.[21] However, involvement of ABCB1 and CYP3A4 genetic polymorphisms in the trough level was not seen in the present study.

Clinical remission was evaluated 4 weeks after the start of therapy in the present study using the pDAI score, which excluded the endoscopy score. The partial Mayo score has also been used to determine clinical efficacy in recent large-scale studies.[22,23] Judging clinical efficacy with an activity index that excludes the endoscopy score is thought to have a certain level of validity.[24] Because the Mayo score and DAI are essentially the same score, in this study, DAI, which can be determined in a single day, was adopted.[25] The remission rate was significantly higher in the Non-Exp group than in the Exp group. All four patients who underwent surgery within 4 weeks after the start of therapy were in the Exp group. These results are interpreted as showing a higher likelihood of achieving the optimal trough level, resulting in a tendency for a better therapeutic response, in the Non-Exp group. Herrlinger et al. reported a relationship between Tac therapy results and CYP3A4, CYP3A5, and ABCB1 genetic polymorphisms in 89 UC patients.[12] In that study, the therapeutic effect was determined 6 weeks after the start of Tac, and it was effective in 75% of cases (61% remission and 14% improvement). It was found that CYP3A4 and CYP3A5 genetic polymorphisms were not associated with efficacy and that the presence or absence of TT type in the 1236C/T, 2677G/T/A, and 3435C/T of ABCB1 was related to the clinical effect. Several differences are thought to be causative factors in this difference from the present study. One major difference is the racial difference in genetic polymorphisms of CYP3A4, CYP3A5, and ABCB1.[9–11] There is a large difference in CYP3A5 Non-Exp in particular at 35–65% in Asians and 85–90% in Caucasians.[9–11] In fact, CYP3A5 Non-Exp accounted for 89.9% in the report by Herrlinger et al.,[12] clearly higher than the 46.7% in the present study. Nearly 90% of patients were Non-Exp, and this is thought to be why CYP3A5 genetic polymorphisms did not affect the percentage of patients achieving the optimal trough level and the clinical effect. It may be inferred that the high remission rate of 61% is attributable to the fact that the subjects were Caucasians, a population susceptible to the effects of Tac.

As for adverse effects, the results of the current study were similar to other reports.[3,26] There were no differences in the frequencies of adverse effects between the Exp group and the Non-Exp group.

A limitation of this study is that the analysis was done with a small number of UC patients in a single institution. However, the results of genetic polymorphisms of CYP3A4, CYP3A5, and ABCB1 were nearly the same as in previously reported analyses of Asian patients.[14,17] The pharmacokinetics and therapeutic effect of Tac were investigated in IBD patients, and interesting new findings were obtained, namely that CYP3A5 Non-Exp is associated with achieving the optimal Tac trough level and short-term clinical remission. These findings suggest that understanding the genetic polymorphisms of CYP3A5 in UC patients is useful in controlling the dosage, such as establishing higher initial dosages in Exp than in Non-Exp and establishing greater increases when changing the dose after confirming the trough level. Thus, it may be possible to implement tailor-made medicine suited to the individual case in the therapy of UC patients. Interestingly, there is some doubt as to a relationship between the pharmacokinetics of cyclosporine, also a calcineurin inhibitor, and CYP3A5 genetic polymorphisms.[27–30] Cyclosporine is also used in treating UC, but unlike Tac, no advantages can be expected from confirming the CYP3A5 genetic polymorphisms.

In conclusion, this study showed that CYP3A5 genetic polymorphisms affect the pharmacokinetics of Tac and short-term clinical remission, at least in Asian patients. Various factors are thought to be related to the individual differences in Tac treatment effect. We conclude that CYP3A5 genetic polymorphisms are important as a major factor in the early stage of treatment. When Tac is used in the therapy of UC patients, it is desirable to confirm the genetic polymorphisms of CYP3A5 in patients if possible. At the very least, it is necessary to understand that the percentage of patients achieving the optimal trough level in the early period of therapy and the short-term clinical outcome will differ in CYP3A5 Exp and Non-Exp cases.

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