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The effect of CYP3A5 genetic polymorphisms on adverse events in patients with ulcerative colitis treated with tacrolimus
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Alimentary Tract
The effect of CYP3A5 genetic polymorphisms on adverse events in patients with ulcerative colitis treated with tacrolimus Ayumi Asada, Shigeki Bamba ∗ , Yukihiro Morita, Kenichiro Takahashi, Hirotsugu Imaeda, Atsushi Nishida, Osamu Inatomi, Mitsushige Sugimoto, Masaya Sasaki, Akira Andoh Department of Medicine, Shiga University of Medical Science, Otsu, Japan
a r t i c l e
i n f o
Article history: Received 19 June 2016 Accepted 11 September 2016 Available online xxx Keywords: Adverse events Nephrotoxicity Single nucleotide polymorphism
a b s t r a c t Background: Tacrolimus is an immunosuppressive agent, used in the remission induction therapy of ulcerative colitis (UC). Aims: We investigated the correlation between CYP3A5 genetic polymorphisms and the adverse events in patients with UC. The pharmacokinetics of tacrolimus after oral administration were also analyzed. Methods: We enrolled 29 hospitalized patients with UC received oral tacrolimus. Genotyping for CYP3A5 A6986G (rs776746) was performed using Custom TaqMan® SNP genotyping assays. Adverse events, concentration and dose (C/D) ratios and clinical outcomes were investigated. Results: CYP3A5 expressers and non-expressers were 16 and 13, respectively. C/D ratios of CYP3A5 expressers were significantly lower compared to non-expressers. The response rate in CYP3A5 nonexpressers was relatively higher in the early phase of treatment compared to expressers, but not statistically significant. The incidence of overall adverse events was significantly higher in CYP3A5 expressers than in non-expressers (P = 0.034, chi-squared test). In particular, the incidence of nephrotoxicity was significantly higher in CYP3A5 expressers compared to non-expressers (P = 0.027, chi-squared test). All of the nephrotoxicity were reversible and resolved by discontinuation or dose reduction of tacrolimus. Conclusion: The adverse events especially nephrotoxicity were frequently observed in CYP3A5 expressers. CYP3A5 expressers should be paid attention to the onset of nephrotoxicity. © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Ulcerative colitis (UC) is a chronic inflammatory disease of unknown etiology that occurs in the large bowel [1]. Patients who have no response to 5-aminosalicylic acid (5-ASA) or corticosteroids administered as remission induction therapy are considered for second-line therapy with calcineurin inhibitors or biologics [2]. Based on the results of randomized, double-blind controlled studies, tacrolimus was approved for steroid-resistant UC under the national health insurance in July 2009 [3]. Tacrolimus has the similar pharmacological mechanism as cyclosporine A and is widely used in the field of organ transplantation [2]. The pharmacological effect of tacrolimus depends on its trough level in blood. Because tacrolimus has a narrow therapeutic window of 5–15 ng/ml, therapeutic drug monitoring (TDM) is important for
∗ Corresponding author at: Department of Medicine, Shiga University of Medical Science, Seta−Tsukinowa, Otsu 520-2192, Japan. Fax: +81 77 548 2219. E-mail address: [email protected] (S. Bamba).
ensuring maximum efficacy while minimizing the risk of adverse effects such as nephrotoxicity [3]. Tacrolimus is a substrate of cytochrome P-450 (CYP) 3A and the majority of its metabolites are secreted into bile. CYP3A5, which is present in the liver and intestinal epithelium, is responsible for the metabolism of tacrolimus [4]. The tacrolimus metabolism is largely affected by CYP3A5 genetic polymorphisms. A single nucleotide polymorphism (SNP) in the CYP3A5 gene involving an A–G transition at position 6986 within intron 3 (rs776746) was found strongly associated with CYP3A5 protein expression. CYP3A5*3/*3 genotypes are considered to be CYP3A5 non-expressers, while CYP3A5 expressers carry at least one CYP3A5*1 allele [5–7]. When tacrolimus is administered orally, it is circulated throughout the body after being excreted into stool (approximately 15%), being transferred to the portal vein after being metabolized in the intestinal epithelium (approximately 50%), and undergoing first-pass metabolism (approximately 10%) in the liver. It is thought that approximately 25% of the amount ingested orally remains in the blood [4]. Many studies of organ transplantation patients have investigated the correlation between CYP3A5 genetic polymorphisms and
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Please cite this article in press as: Asada A, et al. The effect of CYP3A5 genetic polymorphisms on adverse events in patients with ulcerative colitis treated with tacrolimus. Dig Liver Dis (2016), http://dx.doi.org/10.1016/j.dld.2016.09.008
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nephrotoxicity, which is the frequent adverse drug effect associated with tacrolimus. However, there is no established view on the issue [8]. This is because some studies [9,10] have reported that many CYP3A5 expressers experience nephrotoxicity, some other studies [11,12] have shown the lack of correlation between the two, and yet some other studies [13–15] have indicated that nephrotoxicity is more frequent in CYP3A5 non-expressers. Recently, a systematic review and meta-analysis investigating the relationships between CYP3A5 genetic polymorphisms and nephrotoxicity in kidney transplant recipients was published. In the paper, Rojas et al. concluded that compared with CYP3A5 non-expressers, CYP3A5 expressers probably have a higher risk of tacrolimus-related chronic nephrotoxicity, but without a statistical significance [16]. As far as we know, the matter of adverse effects and CYP3A5 genetic polymorphisms in UC patients has never been investigated. Hirai et al. reported on the influence of CYP3A5 polymorphisms on tacrolimus pharmacokinetics and therapeutic outcomes in patients with UC [17]. According to their study, at 2–5 days after therapy initiation CYP3A5 non-expressers had higher tacrolimus trough levels than CYP3A5 expressers and CYP3A5 non-expressers had a significantly higher clinical remission rate than CYP3A5 expressers. In this study, we investigated the correlation between CYP3A5 genetic polymorphisms and adverse events of tacrolimus in UC patients. We also investigated the relationships between CYP3A5 genetic polymorphisms and the pharmacokinetics of tacrolimus or clinical outcomes.
Mononuclear cells were isolated from heparinized blood using a Ficoll density gradient. The genomic DNA was isolated by a DNA extraction kit purchased from QIAGEN (Valencia, CA). Genotyping for CYP3A5 A6986G (rs776746) was performed using Custom TaqMan® SNP genotyping assays (ID: C 26201809 30; Applied Biosystems, Inc., Foster City, CA) in accordance with information on the Applied Biosystems website (http://www.appliedbiosystems. com).
2. Methods
2.6. Hardy–Weinberg equilibrium (HWE)
2.1. Study population and clinical datas
HWE analysis was performed for the research subjects by comparing the detected distribution of allele frequencies with the theoretical distribution estimated on the basis of the SNP allele frequencies. P > 0.05 (chi-squared test) was considered to indicate equilibrium.
This study was conducted with the approval of the Ethics Committee of the Shiga University of Medical Science. The subjects were a consecutive series of 29 patients with moderate to severe refractory UC who underwent remission induction therapy with tacrolimus on an inpatient basis between April 2010 and March 2015. All subjects were of Japanese ethnicity. Clinical background factors, type of UC, concomitant medication, blood biochemistry findings, and other clinical data were collected retrospectively. 2.2. Tacrolimus treatment and nephrotoxicity When tacrolimus was administered orally, the initial dose was 0.05 mg/kg twice per day, 1 h before meals, every 12 h. Blood tacrolimus levels were measured three times per week for the first 2 weeks of remission induction therapy. Doses were adjusted to achieve a high target trough level of 10–15 ng/ml for both oral and intravenous administration. After maintaining high trough levels for 2 weeks, the dose was decreased so as to achieve a low trough level target of 5–10 ng/ml. The concentration and dose ratio (C/D ratio) was calculated as an index of the drug metabolism of tacrolimus using the formula shown below. C/D ratio [(ng/ml)/(mg/kg)] =
[tacrolimus trough level (ng/ml) × body weight (kg)] [tacrolimus dose (mg)]
2.3. Safety The adverse effects of tacrolimus were investigated. In this study, adverse effects of ≥grade 2 according to the Common Terminology Criteria for Adverse Events (CTCAE) were included. Nephrotoxicity was defined as a ≥grade 2 of “Creatinine increased” (an increase of >1.5-fold over the baseline creatinine level or an
increase of >1.5-fold over the upper limit of normal). To prevent Pneumocystis jiroveci pneumonia, sulfamethoxazole-trimethoprim were used for all cases treated with tacrolimus as prophylactic administration. The dose of prophylaxis was sulfamethoxazoletrimethoprim 400–80 mg once daily. 2.4. Clinical disease activity Clinical disease activity was assessed using the partial Mayo score at 1, 2, and 4 weeks. “Responders” were defined as having a decrease of ≥2 points in the partial Mayo score, ≥30% decrease from the partial Mayo score measured prior to the start of treatment, and a decrease of ≥1 point in the rectal bleeding score or a rectal bleeding score of ≤1. “Non-responders” were defined as patients who did not meet the above definition or those whose therapeutic strategy was changed prior to achieving remission. 2.5. Genotyping of CYP3A5 A6986G (rs776746)
2.7. Statistical analyses All statistical analyses were performed using Prism version 6.05 (GraphPad, San Diego, CA). The chi-squared test and Mann–Whitney U test were used appropriately. A P value of <0.05 was regarded as statistically significant. 3. Results The allele frequency of the CYP3A5*1 in our subjects was 27.6% and the frequency of the CYP3A5*3 allele was 72.1%. This result agrees with previous reports on CYP3A5 polymorphism analysis in the Japanese population [18–20]. HWE exact test showed a significant deviation from equilibrium (P = 0.040), which could be a result of small sample size or might be a result of genotyping error. No differences were noted in our comparison of the background factors between CYP3A5 expressers and non-expressers (Table 1). The C/D ratios of CYP3A5 expressers and non-expressers who received tacrolimus orally indicated that CYP3A5 expressers had significantly lower C/D ratios at all measurement points (Fig. 1). Fig. 2(a) shows the period required for achieving the target trough level (≥10 ng/ml). The periods required for achieving the trough levels of 10 ng/ml tended to be shorter in CYP3A5 non-expressers than in expressers; however, without reaching statistical significance. With regard to the required tacrolimus dose, CYP3A5 non-expressers were able to achieve the target trough level (≥10 ng/ml) with a smaller dose than CYP3A5 expressers (Fig. 2(b)). As for concomitant medications, we found the prescription of loxoprofen which may affect the renal function in four patients. Loxoprofen was only used episodically and the total amount of
Please cite this article in press as: Asada A, et al. The effect of CYP3A5 genetic polymorphisms on adverse events in patients with ulcerative colitis treated with tacrolimus. Dig Liver Dis (2016), http://dx.doi.org/10.1016/j.dld.2016.09.008
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Table 1 Clinical backgrounds before the administration of tacrolimus. CYP3A5 expressers (n = 16)
CYP3A5 non-expressers (n = 13)
P value
Male/female Body mass index (kg/m2 ) Food intake (yes/no) Hemoglobin (g/dl) Albumin (g/dl) Creatinine (mg/dl) C-reactive protein (mg/dl) Partial Mayo score before starting tacrolimus therapy, mean ± SD Disease duration before starting tacrolimus therapy (month)
12/4 21.2 ± 4.5 10/6 12.1 ± 2.0 3.3 ± 0.7 0.62 ± 0.14 2.8 ± 4.5 7.1 ± 1.5 56.3 ± 54.4
6/7 22.5 ± 5.4 11/2 12.5 ± 1.9 3.5 ± 0.5 0.59 ± 0.16 0.8 ± 0.8 7.8 ± 1.0 89.1 ± 55.6
0.11a 0.44b 0.19a 0.51b 0.49b 0.38b 0.28b 0.30b 0.17b
Disease location Left-sided colitis Pancolitis
7 9
4 9
0.47a
Response to steroid therapy Steroid-dependent Steroid-resistant
8 5
7 4
0.92a
Concomitant medication starting tacrolimus (%) 5-ASA Prednisolone (intravenous or oral) Cytapheresis Azathioprine/6-mercaptopurine
14 (87.2) 9 (56.3) 3 (18.8) 5 (31.3)
11 (84.6) 9 (69.3) 3 (23.1) 8 (50.0)
0.82a 0.47a 0.77a 0.10a
a b
Chi-squared test. Mann–Whitney U test.
(ng/ml)/(mg/kg)
**
C/D ratio
200
* n=15
**
*
** CYP3A5 expressers
n=14
n=15
n=14
150
n=13
CYP3A5 non-expressers
n=16 n=12
100
*
n=12 n=12
n=12
n=10
n=13
50 0
Fig. 1. Changes in C/D ratio: oral administration. Numbers of cases noted at each measurement point. * P < 0.05, **P < 0.01.
(a)
(b) P = 0.27
Days to high trough
6 4 2
n=16
P = 0.0074
(mg/kg)
8
n=13
0
Daily dose when reached high trough
(Days)
0.20 0.15 0.10 0.05
n=16
n=13
0.00
Fig. 2. (a) Days required to achieve target trough level (≥10 ng/ml). (b) Tacrolimus dose required to achieve target trough level (≥10 ng/ml). The Mann–Whitney U test was used to test for significant differences. Error bar represents standard error of the mean.
loxoprofen during the tacrolimus treatment was 60–180 mg. Therefore the relevance between loxoprofen and nephrotoxicity was not observed. In addition, there were total three patients prescribed medicine which can be metabolized by CYP3A5. One each
for amlodipine, clarithromycin and loratadine. These drugs are supposed to affect the C/D ratio. Even if excluding these three cases, the results of Fig. 1 were consistent.
Please cite this article in press as: Asada A, et al. The effect of CYP3A5 genetic polymorphisms on adverse events in patients with ulcerative colitis treated with tacrolimus. Dig Liver Dis (2016), http://dx.doi.org/10.1016/j.dld.2016.09.008
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Table 2 Comparison of CYP3A5 genetic polymorphisms and therapeutic effect.
Response rate at 1 week after the start of tacrolimus Response rate at 2 weeks after the start of tacrolimus Response rate at 4 weeks after the start of tacrolimus a
CYP3A5 expressers (n = 16)
CYP3A5 non-expressers (n = 13)
P value
25.0% (4/16) 56.3% (9/16) 81.3% (13/16)
53.8% (7/13) 76.9% (10/13) 92.3% (12/13)
0.11a 0.24a 0.39a
Chi-squared test.
Table 3 Adverse events in 37 patients treated with tacrolimus. Total period of administration
Number of patients with adverse events Nephrotoxicity Hyperkalemia Elevated alanine aminotransferase Headache Tremors Hyperglycemia Skin infection (candidiasis) Varicella Hypocalcemia Hypophosphatemia
CYP3A5 non-expressers (n = 13)
P value
10 5 2 2 1 1 1 1 0 0 0
3 0 0 0 1 0 0 0 1 1 1
0.034a 0.027a 0.19a 0.19a 0.88a 0.36a 0.36a 0.36a 0.26a 0.26a 0.26a
Chi-squared test.
Cumulative colectomy-free survival (%)
a
CYP3A5 expressers (n = 16)
100
P = 0.26 (Log-rank test)
50
CYP3A5 expressers CYP3A5 non-expressers
0 0
500
1000
1500
2000
Days Fig. 3. Cumulative colectomy-free survival rate.
As for the short-term outcome, we compared the therapeutic responses between CYP3A5 expressers and non-expressers at 1, 2, and 4 weeks (Table 2). The response rate in CYP3A5 non-expressers was relatively higher in the early phase of treatment compared to expressers, but not statistically significant. Long-term outcome was also evaluated based on the cumulative colectomy-free survival (Fig. 3). There was no significant difference in the response rate and colectomy-free survival between two groups. The adverse events experienced during the administration of tacrolimus were shown in Table 3. The incidence of overall adverse events was significantly higher in CYP3A5 expressers than in non-expressers. In particular, there was a significant increase of nephrotoxicity in CYP3A5 expressers compared to nonexpressers. The period from starting tacrolimus to nephrotoxicity were 6–52 days (18 days in average). The trough levels at the time of nephrotoxicity were 10.2–13.6 ng/ml (11.8 ng/ml in average). All of the nephrotoxicity were reversible and resolved by discontinuation or dose reduction of tacrolimus. 4. Discussion This study elucidated the fact that adverse events especially nephrotoxicity was frequently observed in CYP3A5 expressers as compared to non-expressers. In addition, the dose of tacrolimus is influenced by CYP3A5 genetic polymorphisms when administered orally in patients with UC.
It has been reported that in addition to CYP3A5 genetic polymorphisms, other factors that influence tacrolimus levels in the blood include age, sex, body mass index (BMI), steroid dose, and drugs that are metabolized by CYP3A5 (proton pump inhibitors, etc.) [21,22]. In the present study, when we compared patients with a BMI of ≥20 with those with a BMI of <20, we found that those with a BMI of ≥20 had a significantly higher C/D ratio during days 7–10 of treatment, but no significant differences for any other measurement period or factors (data not shown). Thus, we believe that CYP3A5 genetic polymorphism is the factor that has the greatest influence over tacrolimus levels in the blood. The C/D ratio is significantly low in CYP3A5 expressers, which means that they require a larger dose of tacrolimus to achieve effective blood levels. At our hospital, the initial dose of tacrolimus is set at 0.1 mg/kg/day. According to our results shown in Fig. 2(b), the dose requirement for reaching target trough of ≥10 ng/ml is 0.17 mg/kg/day for CYP3A5 expressers, whereas non-expressers required a dose of 0.11 mg/kg/day. Thus, the initial dose at our hospital is an optimal initial dose for CYP3A5 non-expressers. Because CYP3A5 expressers require a higher dose of tacrolimus, dosage adjustment is necessary. Therefore, CYP3A5 expressers tended to require longer to achieve a blood level of 10 ng/ml. We investigated if CYP3A5 genetic polymorphisms correlate with therapeutic response or colectomy rate as an indicator of longterm prognosis, but found no correlation between these factors. Hirai et al. [17] reported that CYP3A5 non-expressers experienced a higher rate of effectiveness. The higher rate of effectiveness is supposed to originate from a higher trough level during the early period of administration in CYP3A5 non-expressers. Therefore, rapid dose adjustment of CYP3A5 expressers should enable the achievement of the same efficacy for CYP3A5 expressers as non-expressers. The results of this study indicated that many CYP3A5 expressers experienced nephrotoxicity. In addition, the trough levels at the time of nephrotoxicity were within a high trough level of 10–15 ng/ml. The reason for this was the fact that the peak levels of tacrolimus concentration are thought to be higher in CYP3A5 expressers than non-expressers if you set equivalent trough levels for both CYP3A5 expressers and non-expressers. When a high trough level of 10–15 ng/ml is targeted in cases of oral administration, the blood level immediately after administration is likely to exceed 20 ng/ml [23]. In addition, it has been reported that
Please cite this article in press as: Asada A, et al. The effect of CYP3A5 genetic polymorphisms on adverse events in patients with ulcerative colitis treated with tacrolimus. Dig Liver Dis (2016), http://dx.doi.org/10.1016/j.dld.2016.09.008
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nephrotoxicity becomes more prevalent when blood levels exceed 20 ng/ml [24]. These data support our results. It should be noted that the all of the nephrotoxicity were reversible and resolved by discontinuation or dose reduction of tacrolimus. The limitations of this study were the fact that it was a retrospective single-center study and included a small number of subjects. It remains necessary to conduct further prospective studies whether CYP3A5 genotyping before starting tacrolimus enables the rapid and safe induction of tacrolimus in UC. In conclusion, we found that the adverse events especially nephrotoxicity were frequently observed in CYP3A5 expressers. In addition, tacrolimus dose requirements are influenced by CYP3A5 genetic polymorphisms. CYP3A5 expressers require that particular attention should be paid to the onset of nephrotoxicity. Prior genotyping for CYP3A5 genetic polymorphisms allows individualized care to be practiced. Specifically, it allows drug doses to be set in accordance with each patient’s individual metabolism, which we believe will allow tacrolimus blood levels to achieve the therapeutic range more quickly. Conflict of interest All authors, except Akira Andoh, have no conflicts of interest to declare. Akira Andoh reports speaker fees from AbbVie and Eisai Pharmaceutical. Acknowledgement This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (15K08967), a grant for the Intractable Diseases from the Ministry of Health, Labor and Welfare of Japan, a grant from the Practical Research Project for Rare/Intractable Diseases from Japan Agency for Medical Research and development, AMED, and a grant from Smoking Research Foundation. References [1] Engel MA, Neurath MF. New pathophysiological insights and modern treatment of IBD. Journal of Gastroenterology 2010;45:571–83. [2] Naganuma M, Fujii T, Watanabe M. The use of traditional and newer calcineurin inhibitors in inflammatory bowel disease. Journal of Gastroenterology 2011;46:129–37. [3] Ogata H, Matsui T, Nakamura M, et al. A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis. Gut 2006;55:1255–62. [4] Cervelli M, Russ G. Specialty practice series: intrapatient variability with tacrolimus. The Australian Journal of Pharmacy 2012;93:83–6. [5] Hesselink DA, Bouamar R, Elens L, et al. The role of pharmacogenetics in the disposition of and response to tacrolimus in solid organ transplantation. Clinical Pharmacokinetics 2014;53:123–39. [6] Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nature Genetics 2001;27:383–91.
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[7] Chen YK, Han LZ, Xue F, et al. Personalized tacrolimus dose requirement by CYP3A5 but not ABCB1 or ACE genotyping in both recipient and donor after pediatric liver transplantation. PLoS One 2014;9:e109464. [8] Gijsen VM, Madadi P, Dube MP, et al. Tacrolimus-induced nephrotoxicity and genetic variability: a review. Annals of Transplantation 2012;17:111–21. [9] Kuypers DR, Naesens M, de Jonge H, et al. Tacrolimus dose requirements and CYP3A5 genotype and the development of calcineurin inhibitor-associated nephrotoxicity in renal allograft recipients. Therapeutic Drug Monitoring 2010;32:394–404. [10] Kuypers DR, de Jonge H, Naesens M, et al. CYP3A5 and CYP3A4 but not MDR1 single-nucleotide polymorphisms determine long-term tacrolimus disposition and drug-related nephrotoxicity in renal recipients. Clinical Pharmacology and Therapeutics 2007;82:711–25. [11] Klauke B, Wirth A, Zittermann A, et al. No association between single nucleotide polymorphisms and the development of nephrotoxicity after orthotopic heart transplantation. The Journal of Heart and Lung Transplantation 2008;27:741–5. [12] Naesens M, Lerut E, de Jonge H, et al. Donor age and renal P-glycoprotein expression associate with chronic histological damage in renal allografts. Journal of the American Society of Nephrology 2009;20:2468–80. [13] Chen JS, Li LS, Cheng DR, et al. Effect of CYP3A5 genotype on renal allograft recipients treated with tacrolimus. Transplantation Proceedings 2009;41:1557–61. [14] Quteineh L, Verstuyft C, Furlan V, et al. Influence of CYP3A5 genetic polymorphism on tacrolimus daily dose requirements and acute rejection in renal graft recipients. Basic & Clinical Pharmacology & Toxicology 2008;103:546–52. [15] Fukudo M, Yano I, Yoshimura A, et al. Impact of MDR1 and CYP3A5 on the oral clearance of tacrolimus and tacrolimus-related renal dysfunction in adult living-donor liver transplant patients. Pharmacogenetics and Genomics 2008;18:413–23. [16] Rojas L, Neumann I, Herrero MJ, et al. Effect of CYP3A5*3 on kidney transplant recipients treated with tacrolimus: a systematic review and meta-analysis of observational studies. The Pharmacogenomics Journal 2015;15:38–48. [17] Hirai F, Takatsu N, Yano Y, et al. Impact of CYP3A5 genetic polymorphisms on the pharmacokinetics and short-term remission in patients with ulcerative colitis treated with tacrolimus. Journal of Gastroenterology and Hepatology 2014;29:60–6. [18] Niwa T, Shiraga T, Omura M, et al. Effect of genetic polymorphism of cytochrome P450 3A and transporter gene on pharmacokinetics of tacrolimus, a calcineurin inhibitor. Folia Pharmacologica Japonica 2006;128:395–404. [19] Myrand SP, Sekiguchi K, Man MZ, et al. Pharmacokinetics/genotype associations for major cytochrome P450 enzymes in native and first- and third-generation Japanese populations: comparison with Korean, Chinese, and Caucasian populations. Clinical Pharmacology and Therapeutics 2008;84:347–61. [20] Ota T, Kamada Y, Hayashida M, et al. Combination analysis in genetic polymorphisms of drug-metabolizing enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A5 in the Japanese population. International Journal of Medical Sciences 2015;12:78–82. [21] Iwamoto T, Monma F, Fujieda A, et al. Hepatic drug interaction between tacrolimus and lansoprazole in a bone marrow transplant patient receiving voriconazole and harboring CYP2C19 and CYP3A5 heterozygous mutations. Clinical Therapeutics 2011;33:1077–80. [22] Stratta P, Quaglia M, Cena T, et al. The interactions of age, sex, body mass index, genetics, and steroid weight-based doses on tacrolimus dosing requirement after adult kidney transplantation. European Journal of Clinical Pharmacology 2012;68:671–80. [23] Storset E, Holford N, Hennig S, et al. Improved prediction of tacrolimus concentrations early after kidney transplantation using theory-based pharmacokinetic modelling. British Journal of Clinical Pharmacology 2014;78:509–23. [24] Ratanatharathorn V, Nash RA, Przepiorka D, et al. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood 1998;92:2303–14.
Please cite this article in press as: Asada A, et al. The effect of CYP3A5 genetic polymorphisms on adverse events in patients with ulcerative colitis treated with tacrolimus. Dig Liver Dis (2016), http://dx.doi.org/10.1016/j.dld.2016.09.008
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Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Alimentary Tract
The effect of CYP3A5 genetic polymorphisms on adverse events in patients with ulcerative colitis treated with tacrolimus Ayumi Asada, Shigeki Bamba ∗ , Yukihiro Morita, Kenichiro Takahashi, Hirotsugu Imaeda, Atsushi Nishida, Osamu Inatomi, Mitsushige Sugimoto, Masaya Sasaki, Akira Andoh Department of Medicine, Shiga University of Medical Science, Otsu, Japan
a r t i c l e
i n f o
Article history: Received 19 June 2016 Accepted 11 September 2016 Available online xxx Keywords: Adverse events Nephrotoxicity Single nucleotide polymorphism
a b s t r a c t Background: Tacrolimus is an immunosuppressive agent, used in the remission induction therapy of ulcerative colitis (UC). Aims: We investigated the correlation between CYP3A5 genetic polymorphisms and the adverse events in patients with UC. The pharmacokinetics of tacrolimus after oral administration were also analyzed. Methods: We enrolled 29 hospitalized patients with UC received oral tacrolimus. Genotyping for CYP3A5 A6986G (rs776746) was performed using Custom TaqMan® SNP genotyping assays. Adverse events, concentration and dose (C/D) ratios and clinical outcomes were investigated. Results: CYP3A5 expressers and non-expressers were 16 and 13, respectively. C/D ratios of CYP3A5 expressers were significantly lower compared to non-expressers. The response rate in CYP3A5 nonexpressers was relatively higher in the early phase of treatment compared to expressers, but not statistically significant. The incidence of overall adverse events was significantly higher in CYP3A5 expressers than in non-expressers (P = 0.034, chi-squared test). In particular, the incidence of nephrotoxicity was significantly higher in CYP3A5 expressers compared to non-expressers (P = 0.027, chi-squared test). All of the nephrotoxicity were reversible and resolved by discontinuation or dose reduction of tacrolimus. Conclusion: The adverse events especially nephrotoxicity were frequently observed in CYP3A5 expressers. CYP3A5 expressers should be paid attention to the onset of nephrotoxicity. © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Ulcerative colitis (UC) is a chronic inflammatory disease of unknown etiology that occurs in the large bowel [1]. Patients who have no response to 5-aminosalicylic acid (5-ASA) or corticosteroids administered as remission induction therapy are considered for second-line therapy with calcineurin inhibitors or biologics [2]. Based on the results of randomized, double-blind controlled studies, tacrolimus was approved for steroid-resistant UC under the national health insurance in July 2009 [3]. Tacrolimus has the similar pharmacological mechanism as cyclosporine A and is widely used in the field of organ transplantation [2]. The pharmacological effect of tacrolimus depends on its trough level in blood. Because tacrolimus has a narrow therapeutic window of 5–15 ng/ml, therapeutic drug monitoring (TDM) is important for
∗ Corresponding author at: Department of Medicine, Shiga University of Medical Science, Seta−Tsukinowa, Otsu 520-2192, Japan. Fax: +81 77 548 2219. E-mail address: [email protected] (S. Bamba).
ensuring maximum efficacy while minimizing the risk of adverse effects such as nephrotoxicity [3]. Tacrolimus is a substrate of cytochrome P-450 (CYP) 3A and the majority of its metabolites are secreted into bile. CYP3A5, which is present in the liver and intestinal epithelium, is responsible for the metabolism of tacrolimus [4]. The tacrolimus metabolism is largely affected by CYP3A5 genetic polymorphisms. A single nucleotide polymorphism (SNP) in the CYP3A5 gene involving an A–G transition at position 6986 within intron 3 (rs776746) was found strongly associated with CYP3A5 protein expression. CYP3A5*3/*3 genotypes are considered to be CYP3A5 non-expressers, while CYP3A5 expressers carry at least one CYP3A5*1 allele [5–7]. When tacrolimus is administered orally, it is circulated throughout the body after being excreted into stool (approximately 15%), being transferred to the portal vein after being metabolized in the intestinal epithelium (approximately 50%), and undergoing first-pass metabolism (approximately 10%) in the liver. It is thought that approximately 25% of the amount ingested orally remains in the blood [4]. Many studies of organ transplantation patients have investigated the correlation between CYP3A5 genetic polymorphisms and
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nephrotoxicity, which is the frequent adverse drug effect associated with tacrolimus. However, there is no established view on the issue [8]. This is because some studies [9,10] have reported that many CYP3A5 expressers experience nephrotoxicity, some other studies [11,12] have shown the lack of correlation between the two, and yet some other studies [13–15] have indicated that nephrotoxicity is more frequent in CYP3A5 non-expressers. Recently, a systematic review and meta-analysis investigating the relationships between CYP3A5 genetic polymorphisms and nephrotoxicity in kidney transplant recipients was published. In the paper, Rojas et al. concluded that compared with CYP3A5 non-expressers, CYP3A5 expressers probably have a higher risk of tacrolimus-related chronic nephrotoxicity, but without a statistical significance [16]. As far as we know, the matter of adverse effects and CYP3A5 genetic polymorphisms in UC patients has never been investigated. Hirai et al. reported on the influence of CYP3A5 polymorphisms on tacrolimus pharmacokinetics and therapeutic outcomes in patients with UC [17]. According to their study, at 2–5 days after therapy initiation CYP3A5 non-expressers had higher tacrolimus trough levels than CYP3A5 expressers and CYP3A5 non-expressers had a significantly higher clinical remission rate than CYP3A5 expressers. In this study, we investigated the correlation between CYP3A5 genetic polymorphisms and adverse events of tacrolimus in UC patients. We also investigated the relationships between CYP3A5 genetic polymorphisms and the pharmacokinetics of tacrolimus or clinical outcomes.
Mononuclear cells were isolated from heparinized blood using a Ficoll density gradient. The genomic DNA was isolated by a DNA extraction kit purchased from QIAGEN (Valencia, CA). Genotyping for CYP3A5 A6986G (rs776746) was performed using Custom TaqMan® SNP genotyping assays (ID: C 26201809 30; Applied Biosystems, Inc., Foster City, CA) in accordance with information on the Applied Biosystems website (http://www.appliedbiosystems. com).
2. Methods
2.6. Hardy–Weinberg equilibrium (HWE)
2.1. Study population and clinical datas
HWE analysis was performed for the research subjects by comparing the detected distribution of allele frequencies with the theoretical distribution estimated on the basis of the SNP allele frequencies. P > 0.05 (chi-squared test) was considered to indicate equilibrium.
This study was conducted with the approval of the Ethics Committee of the Shiga University of Medical Science. The subjects were a consecutive series of 29 patients with moderate to severe refractory UC who underwent remission induction therapy with tacrolimus on an inpatient basis between April 2010 and March 2015. All subjects were of Japanese ethnicity. Clinical background factors, type of UC, concomitant medication, blood biochemistry findings, and other clinical data were collected retrospectively. 2.2. Tacrolimus treatment and nephrotoxicity When tacrolimus was administered orally, the initial dose was 0.05 mg/kg twice per day, 1 h before meals, every 12 h. Blood tacrolimus levels were measured three times per week for the first 2 weeks of remission induction therapy. Doses were adjusted to achieve a high target trough level of 10–15 ng/ml for both oral and intravenous administration. After maintaining high trough levels for 2 weeks, the dose was decreased so as to achieve a low trough level target of 5–10 ng/ml. The concentration and dose ratio (C/D ratio) was calculated as an index of the drug metabolism of tacrolimus using the formula shown below. C/D ratio [(ng/ml)/(mg/kg)] =
[tacrolimus trough level (ng/ml) × body weight (kg)] [tacrolimus dose (mg)]
2.3. Safety The adverse effects of tacrolimus were investigated. In this study, adverse effects of ≥grade 2 according to the Common Terminology Criteria for Adverse Events (CTCAE) were included. Nephrotoxicity was defined as a ≥grade 2 of “Creatinine increased” (an increase of >1.5-fold over the baseline creatinine level or an
increase of >1.5-fold over the upper limit of normal). To prevent Pneumocystis jiroveci pneumonia, sulfamethoxazole-trimethoprim were used for all cases treated with tacrolimus as prophylactic administration. The dose of prophylaxis was sulfamethoxazoletrimethoprim 400–80 mg once daily. 2.4. Clinical disease activity Clinical disease activity was assessed using the partial Mayo score at 1, 2, and 4 weeks. “Responders” were defined as having a decrease of ≥2 points in the partial Mayo score, ≥30% decrease from the partial Mayo score measured prior to the start of treatment, and a decrease of ≥1 point in the rectal bleeding score or a rectal bleeding score of ≤1. “Non-responders” were defined as patients who did not meet the above definition or those whose therapeutic strategy was changed prior to achieving remission. 2.5. Genotyping of CYP3A5 A6986G (rs776746)
2.7. Statistical analyses All statistical analyses were performed using Prism version 6.05 (GraphPad, San Diego, CA). The chi-squared test and Mann–Whitney U test were used appropriately. A P value of <0.05 was regarded as statistically significant. 3. Results The allele frequency of the CYP3A5*1 in our subjects was 27.6% and the frequency of the CYP3A5*3 allele was 72.1%. This result agrees with previous reports on CYP3A5 polymorphism analysis in the Japanese population [18–20]. HWE exact test showed a significant deviation from equilibrium (P = 0.040), which could be a result of small sample size or might be a result of genotyping error. No differences were noted in our comparison of the background factors between CYP3A5 expressers and non-expressers (Table 1). The C/D ratios of CYP3A5 expressers and non-expressers who received tacrolimus orally indicated that CYP3A5 expressers had significantly lower C/D ratios at all measurement points (Fig. 1). Fig. 2(a) shows the period required for achieving the target trough level (≥10 ng/ml). The periods required for achieving the trough levels of 10 ng/ml tended to be shorter in CYP3A5 non-expressers than in expressers; however, without reaching statistical significance. With regard to the required tacrolimus dose, CYP3A5 non-expressers were able to achieve the target trough level (≥10 ng/ml) with a smaller dose than CYP3A5 expressers (Fig. 2(b)). As for concomitant medications, we found the prescription of loxoprofen which may affect the renal function in four patients. Loxoprofen was only used episodically and the total amount of
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Table 1 Clinical backgrounds before the administration of tacrolimus. CYP3A5 expressers (n = 16)
CYP3A5 non-expressers (n = 13)
P value
Male/female Body mass index (kg/m2 ) Food intake (yes/no) Hemoglobin (g/dl) Albumin (g/dl) Creatinine (mg/dl) C-reactive protein (mg/dl) Partial Mayo score before starting tacrolimus therapy, mean ± SD Disease duration before starting tacrolimus therapy (month)
12/4 21.2 ± 4.5 10/6 12.1 ± 2.0 3.3 ± 0.7 0.62 ± 0.14 2.8 ± 4.5 7.1 ± 1.5 56.3 ± 54.4
6/7 22.5 ± 5.4 11/2 12.5 ± 1.9 3.5 ± 0.5 0.59 ± 0.16 0.8 ± 0.8 7.8 ± 1.0 89.1 ± 55.6
0.11a 0.44b 0.19a 0.51b 0.49b 0.38b 0.28b 0.30b 0.17b
Disease location Left-sided colitis Pancolitis
7 9
4 9
0.47a
Response to steroid therapy Steroid-dependent Steroid-resistant
8 5
7 4
0.92a
Concomitant medication starting tacrolimus (%) 5-ASA Prednisolone (intravenous or oral) Cytapheresis Azathioprine/6-mercaptopurine
14 (87.2) 9 (56.3) 3 (18.8) 5 (31.3)
11 (84.6) 9 (69.3) 3 (23.1) 8 (50.0)
0.82a 0.47a 0.77a 0.10a
a b
Chi-squared test. Mann–Whitney U test.
(ng/ml)/(mg/kg)
**
C/D ratio
200
* n=15
**
*
** CYP3A5 expressers
n=14
n=15
n=14
150
n=13
CYP3A5 non-expressers
n=16 n=12
100
*
n=12 n=12
n=12
n=10
n=13
50 0
Fig. 1. Changes in C/D ratio: oral administration. Numbers of cases noted at each measurement point. * P < 0.05, **P < 0.01.
(a)
(b) P = 0.27
Days to high trough
6 4 2
n=16
P = 0.0074
(mg/kg)
8
n=13
0
Daily dose when reached high trough
(Days)
0.20 0.15 0.10 0.05
n=16
n=13
0.00
Fig. 2. (a) Days required to achieve target trough level (≥10 ng/ml). (b) Tacrolimus dose required to achieve target trough level (≥10 ng/ml). The Mann–Whitney U test was used to test for significant differences. Error bar represents standard error of the mean.
loxoprofen during the tacrolimus treatment was 60–180 mg. Therefore the relevance between loxoprofen and nephrotoxicity was not observed. In addition, there were total three patients prescribed medicine which can be metabolized by CYP3A5. One each
for amlodipine, clarithromycin and loratadine. These drugs are supposed to affect the C/D ratio. Even if excluding these three cases, the results of Fig. 1 were consistent.
Please cite this article in press as: Asada A, et al. The effect of CYP3A5 genetic polymorphisms on adverse events in patients with ulcerative colitis treated with tacrolimus. Dig Liver Dis (2016), http://dx.doi.org/10.1016/j.dld.2016.09.008
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Table 2 Comparison of CYP3A5 genetic polymorphisms and therapeutic effect.
Response rate at 1 week after the start of tacrolimus Response rate at 2 weeks after the start of tacrolimus Response rate at 4 weeks after the start of tacrolimus a
CYP3A5 expressers (n = 16)
CYP3A5 non-expressers (n = 13)
P value
25.0% (4/16) 56.3% (9/16) 81.3% (13/16)
53.8% (7/13) 76.9% (10/13) 92.3% (12/13)
0.11a 0.24a 0.39a
Chi-squared test.
Table 3 Adverse events in 37 patients treated with tacrolimus. Total period of administration
Number of patients with adverse events Nephrotoxicity Hyperkalemia Elevated alanine aminotransferase Headache Tremors Hyperglycemia Skin infection (candidiasis) Varicella Hypocalcemia Hypophosphatemia
CYP3A5 non-expressers (n = 13)
P value
10 5 2 2 1 1 1 1 0 0 0
3 0 0 0 1 0 0 0 1 1 1
0.034a 0.027a 0.19a 0.19a 0.88a 0.36a 0.36a 0.36a 0.26a 0.26a 0.26a
Chi-squared test.
Cumulative colectomy-free survival (%)
a
CYP3A5 expressers (n = 16)
100
P = 0.26 (Log-rank test)
50
CYP3A5 expressers CYP3A5 non-expressers
0 0
500
1000
1500
2000
Days Fig. 3. Cumulative colectomy-free survival rate.
As for the short-term outcome, we compared the therapeutic responses between CYP3A5 expressers and non-expressers at 1, 2, and 4 weeks (Table 2). The response rate in CYP3A5 non-expressers was relatively higher in the early phase of treatment compared to expressers, but not statistically significant. Long-term outcome was also evaluated based on the cumulative colectomy-free survival (Fig. 3). There was no significant difference in the response rate and colectomy-free survival between two groups. The adverse events experienced during the administration of tacrolimus were shown in Table 3. The incidence of overall adverse events was significantly higher in CYP3A5 expressers than in non-expressers. In particular, there was a significant increase of nephrotoxicity in CYP3A5 expressers compared to nonexpressers. The period from starting tacrolimus to nephrotoxicity were 6–52 days (18 days in average). The trough levels at the time of nephrotoxicity were 10.2–13.6 ng/ml (11.8 ng/ml in average). All of the nephrotoxicity were reversible and resolved by discontinuation or dose reduction of tacrolimus. 4. Discussion This study elucidated the fact that adverse events especially nephrotoxicity was frequently observed in CYP3A5 expressers as compared to non-expressers. In addition, the dose of tacrolimus is influenced by CYP3A5 genetic polymorphisms when administered orally in patients with UC.
It has been reported that in addition to CYP3A5 genetic polymorphisms, other factors that influence tacrolimus levels in the blood include age, sex, body mass index (BMI), steroid dose, and drugs that are metabolized by CYP3A5 (proton pump inhibitors, etc.) [21,22]. In the present study, when we compared patients with a BMI of ≥20 with those with a BMI of <20, we found that those with a BMI of ≥20 had a significantly higher C/D ratio during days 7–10 of treatment, but no significant differences for any other measurement period or factors (data not shown). Thus, we believe that CYP3A5 genetic polymorphism is the factor that has the greatest influence over tacrolimus levels in the blood. The C/D ratio is significantly low in CYP3A5 expressers, which means that they require a larger dose of tacrolimus to achieve effective blood levels. At our hospital, the initial dose of tacrolimus is set at 0.1 mg/kg/day. According to our results shown in Fig. 2(b), the dose requirement for reaching target trough of ≥10 ng/ml is 0.17 mg/kg/day for CYP3A5 expressers, whereas non-expressers required a dose of 0.11 mg/kg/day. Thus, the initial dose at our hospital is an optimal initial dose for CYP3A5 non-expressers. Because CYP3A5 expressers require a higher dose of tacrolimus, dosage adjustment is necessary. Therefore, CYP3A5 expressers tended to require longer to achieve a blood level of 10 ng/ml. We investigated if CYP3A5 genetic polymorphisms correlate with therapeutic response or colectomy rate as an indicator of longterm prognosis, but found no correlation between these factors. Hirai et al. [17] reported that CYP3A5 non-expressers experienced a higher rate of effectiveness. The higher rate of effectiveness is supposed to originate from a higher trough level during the early period of administration in CYP3A5 non-expressers. Therefore, rapid dose adjustment of CYP3A5 expressers should enable the achievement of the same efficacy for CYP3A5 expressers as non-expressers. The results of this study indicated that many CYP3A5 expressers experienced nephrotoxicity. In addition, the trough levels at the time of nephrotoxicity were within a high trough level of 10–15 ng/ml. The reason for this was the fact that the peak levels of tacrolimus concentration are thought to be higher in CYP3A5 expressers than non-expressers if you set equivalent trough levels for both CYP3A5 expressers and non-expressers. When a high trough level of 10–15 ng/ml is targeted in cases of oral administration, the blood level immediately after administration is likely to exceed 20 ng/ml [23]. In addition, it has been reported that
Please cite this article in press as: Asada A, et al. The effect of CYP3A5 genetic polymorphisms on adverse events in patients with ulcerative colitis treated with tacrolimus. Dig Liver Dis (2016), http://dx.doi.org/10.1016/j.dld.2016.09.008
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nephrotoxicity becomes more prevalent when blood levels exceed 20 ng/ml [24]. These data support our results. It should be noted that the all of the nephrotoxicity were reversible and resolved by discontinuation or dose reduction of tacrolimus. The limitations of this study were the fact that it was a retrospective single-center study and included a small number of subjects. It remains necessary to conduct further prospective studies whether CYP3A5 genotyping before starting tacrolimus enables the rapid and safe induction of tacrolimus in UC. In conclusion, we found that the adverse events especially nephrotoxicity were frequently observed in CYP3A5 expressers. In addition, tacrolimus dose requirements are influenced by CYP3A5 genetic polymorphisms. CYP3A5 expressers require that particular attention should be paid to the onset of nephrotoxicity. Prior genotyping for CYP3A5 genetic polymorphisms allows individualized care to be practiced. Specifically, it allows drug doses to be set in accordance with each patient’s individual metabolism, which we believe will allow tacrolimus blood levels to achieve the therapeutic range more quickly. Conflict of interest All authors, except Akira Andoh, have no conflicts of interest to declare. Akira Andoh reports speaker fees from AbbVie and Eisai Pharmaceutical. Acknowledgement This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (15K08967), a grant for the Intractable Diseases from the Ministry of Health, Labor and Welfare of Japan, a grant from the Practical Research Project for Rare/Intractable Diseases from Japan Agency for Medical Research and development, AMED, and a grant from Smoking Research Foundation. References [1] Engel MA, Neurath MF. New pathophysiological insights and modern treatment of IBD. Journal of Gastroenterology 2010;45:571–83. [2] Naganuma M, Fujii T, Watanabe M. The use of traditional and newer calcineurin inhibitors in inflammatory bowel disease. Journal of Gastroenterology 2011;46:129–37. [3] Ogata H, Matsui T, Nakamura M, et al. A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis. Gut 2006;55:1255–62. [4] Cervelli M, Russ G. Specialty practice series: intrapatient variability with tacrolimus. The Australian Journal of Pharmacy 2012;93:83–6. [5] Hesselink DA, Bouamar R, Elens L, et al. The role of pharmacogenetics in the disposition of and response to tacrolimus in solid organ transplantation. Clinical Pharmacokinetics 2014;53:123–39. [6] Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nature Genetics 2001;27:383–91.
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Please cite this article in press as: Asada A, et al. The effect of CYP3A5 genetic polymorphisms on adverse events in patients with ulcerative colitis treated with tacrolimus. Dig Liver Dis (2016), http://dx.doi.org/10.1016/j.dld.2016.09.008