Intest Res.  2019 Apr;17(2):218-226. 10.5217/ir.2018.00117.

Individualized treatment based on CYP3A5 single-nucleotide polymorphisms with tacrolimus in ulcerative colitis

Affiliations
  • 1Center for Advanced IBD Research and Treatment, Department of Research, Kitasato University Kitasato Institute Hospital, Tokyo, Japan. kobataku@insti.kitasato-u.ac.jp
  • 2Department of Gastroenterology and Hepatology, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.
  • 3Department of Rheumatology, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.
  • 4Department of Pharmacy, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.
  • 5Biomedical Laboratory, Department of Research, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.

Abstract

BACKGROUND/AIMS
The pharmacokinetics of tacrolimus (TAC) is known to be largely influenced by single-nucleotide polymorphisms (SNPs) in CYP3A5. Patients starting TAC require careful dose adjustment, owing to the wide range of optimal dosages, depending on their CYP3A5 expression status. Here, we evaluated whether individualization of TAC dosages based on CYP3A5 SNPs would improve its therapeutic efficacy in ulcerative colitis.
METHODS
Twenty-one patients were prospectively treated, with their initial dosage adjusted according to their CYP3A5 status (0.1, 0.15, and 0.2 mg/kg/day for CYP3A5*3/*3, CYP3A5*1/*3, and CYP3A5*1/*1, respectively). Their clinical outcomes were compared with those of patients treated with a fixed dose (0.1 mg/kg/day).
RESULTS
The first blood trough level of CYP3A5 expressors, CYP3A5*1/*3 or CYP3A5*1/*1, and the overall rate in achieving the target blood trough level within a week in the individualized-dose group were significantly higher than those in the fixed-dose group (5.15±2.33 ng/mL vs. 9.63±0.79 ng/mL, P=0.035 and 12.5% vs. 66.7%, P=0.01). The remission rate at 2 weeks in the expressors was as high as that in the nonexpressors, CYP3A5*3/*3, in the individualized-dose group.
CONCLUSIONS
Individualized TAC treatment is effective against ulcerative colitis regardless of the CYP3A5 genotype.

Keyword

Colitis, ulcerative; Tacrolimus; Individualized treatment; CYP3A5

MeSH Terms

Colitis, Ulcerative*
Cytochrome P-450 CYP3A*
Genotype
Humans
Pharmacokinetics
Polymorphism, Single Nucleotide
Prospective Studies
Tacrolimus*
Ulcer*
Cytochrome P-450 CYP3A
Tacrolimus

Figure

  • Fig. 1. The required tacrolimus (TAC) dosages in achieving the target blood trough level of 10 ng/mL in study 1 and 2. The required TAC dosages in achieving the target blood trough level were higher in patients with both CYP3A5*1/*1 and CYP3A5*1/*3 than CYP3A5*3/*3 by the Kruskal-Wallis test and the Dunn multiple comparisons test. (A) Study 1: CYP3A5*1/*1 vs. *CYP3A5*3/*3, P=0.027; CYP3A5*1/*3 vs. CYP3A5*3/*3, P=0.046. (B) Study 2: CYP3A5*1/*1 vs. CYP3A5*3/*3, P=0.039; CYP3A5*1/*3 vs. CYP3A5*3/*3, P=0.093. aP<0.05.

  • Fig. 2. The flowchart showing the initial enrollment cohort for the final analysis. TAC, tacrolimus.

  • Fig. 3. The comparison of clinical outcomes between the fixedand individualized-dose groups. (A) The first blood trough levels in patients with CYP3A5 expressors in the individualized-dose group were significantly higher than those in the fixed-dose group (5.15±2.33 ng/mL vs. 9.63±0.79 ng/mL, aP=0.035). (B) The overall rate in achieving the target blood trough level within a week was significantly higher in the individualized-dose group than in the fixed-dose group (12.5% vs. 66.7%, P=0.014). (C) The clinical remission rate at 2 weeks in the individualized-dose group was numerically higher than in the fixed-dose group (40.0% vs. 45.0%, P=1.00). The clinical remission rate at 2 weeks in CYP3A5 expressors was as high as nonexpressors in the individualizeddose group (44.4% vs. 45.4%, P=1.00).

  • Fig. 4. A Kaplan-Meier curve of relapse-free survival rate according to CYP3A5 genotype in patients who had clinical remission induced successfully at 4 weeks (n=14). There was no statistical difference between CYP3A5 expressors and nonexpressors (P=0.22).

  • Fig. 5. A Kaplan-Meier curve of renal dysfunction-free survival rate according to CYP3A5 genotype after performing dose adjustment (n=25). There was no statistical difference between CYP3A5 expressors and nonexpressors (P=0.87).


Reference

1. Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet. 2007; 369:1627–1640.
Article
2. Dinesen LC, Walsh AJ, Protic MN, et al. The pattern and outcome of acute severe colitis. J Crohns Colitis. 2010; 4:431–437.
Article
3. Turner D, Walsh CM, Steinhart AH, Griffiths AM. Response to corticosteroids in severe ulcerative colitis: a systematic review of the literature and a meta-regression. Clin Gastroenterol Hepatol. 2007; 5:103–110.
Article
4. Matsuoka K, Kobayashi T, Ueno F, et al. Evidence-based clinical practice guidelines for inflammatory bowel disease. J Gastroenterol. 2018; 53:305–353.
Article
5. Harbord M, Eliakim R, Bettenworth D, et al. Third European evidence-based consensus on diagnosis and management of ulcerative colitis. Part 2: current management. J Crohns Colitis. 2017; 11:769–784.
Article
6. Komaki Y, Komaki F, Ido A, Sakuraba A. Efficacy and safety of tacrolimus therapy for active ulcerative colitis; a systematic review and meta-analysis. J Crohns Colitis. 2016; 10:484–494.
Article
7. Schreiber SL, Crabtree GR. The mechanism of action of cyclosporin A and FK506. Immunol Today. 1992; 13:136–142.
Article
8. Kelly PA, Burckart GJ, Venkataramanan R. Tacrolimus: a new immunosuppressive agent. Am J Health Syst Pharm. 1995; 52:1521–1535.
Article
9. Ogata H, Kato J, Hirai F, et al. Double-blind, placebo-controlled trial of oral tacrolimus (FK506) in the management of hospitalized patients with steroid-refractory ulcerative colitis. Inflamm Bowel Dis. 2012; 18:803–808.
Article
10. Ogata H, Matsui T, Nakamura M, et al. A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis. Gut. 2006; 55:1255–1262.
Article
11. Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol. 2009; 4:481–508.
Article
12. Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet. 2001; 27:383–391.
Article
13. Schwab M, Eichelbaum M, Fromm MF. Genetic polymorphisms of the human MDR1 drug transporter. Annu Rev Pharmacol Toxicol. 2003; 43:285–307.
14. 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. J Gastroenterol Hepatol. 2014; 29:60–66.
Article
15. Herrlinger KR, Koc H, Winter S, et al. ABCB1 single-nucleotide polymorphisms determine tacrolimus response in patients with ulcerative colitis. Clin Pharmacol Ther. 2011; 89:422–428.
Article
16. Onodera M, Endo K, Kakuta Y, et al. ATP-binding cassette subfamily B member 1 1236C/T polymorphism significantly affects the therapeutic outcome of tacrolimus in patients with refractory ulcerative colitis. J Gastroenterol Hepatol. 2017; 32:1562–1569.
Article
17. Barbarino JM, Staatz CE, Venkataramanan R, Klein TE, Altman RB. PharmGKB summary: cyclosporine and tacrolimus pathways. Pharmacogenet Genomics. 2013; 23:563–585.
18. Provenzani A, Notarbartolo M, Labbozzetta M, et al. Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients. Int J Mol Med. 2011; 28:1093–1102.
Article
19. Satoh S, Saito M, Inoue T, et al. CYP3A5*1 allele associated with tacrolimus trough concentrations but not subclinical acute rejection or chronic allograft nephropathy in Japanese renal transplant recipients. Eur J Clin Pharmacol. 2009; 65:473–481.
Article
20. Suzuki Y, Homma M, Doki K, Itagaki F, Kohda Y. Impact of CYP3A5 genetic polymorphism on pharmacokinetics of tacrolimus in healthy Japanese subjects. Br J Clin Pharmacol. 2008; 66:154–155.
Article
21. Bannai M, Higuchi K, Akesaka T, et al. Single-nucleotide-polymorphism genotyping for whole-genome-amplified samples using automated fluorescence correlation spectroscopy. Anal Biochem. 2004; 327:215–221.
Article
22. Bekersky I, Dressler D, Mekki Q. Effect of time of meal consumption on bioavailability of a single oral 5 mg tacrolimus dose. J Clin Pharmacol. 2001; 41:289–297.
Article
23. Tada H, Tsuchiya N, Satoh S, et al. Impact of CYP3A5 and MDR1(ABCB1) C3435T polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplant Proc. 2005; 37:1730–1732.
Article
24. Ball SE, Scatina J, Kao J, et al. Population distribution and effects on drug metabolism of a genetic variant in the 5’ promoter region of CYP3A4. Clin Pharmacol Ther. 1999; 66:288–294.
Article
25. Sata F, Sapone A, Elizondo G, et al. CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12: evidence for an allelic variant with altered catalytic activity. Clin Pharmacol Ther. 2000; 67:48–56.
Article
26. Tsuchiya N, Satoh S, Tada H, et al. Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplantation. 2004; 78:1182–1187.
Article
27. Masuda S, Inui K. An up-date review on individualized dosage adjustment of calcineurin inhibitors in organ transplant patients. Pharmacol Ther. 2006; 112:184–198.
Article
Full Text Links
  • IR
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr