European Journal of Clinical Pharmacology

, Volume 76, Issue 1, pp 117–125 | Cite as

Drug interactions between tacrolimus and clotrimazole troche: a data mining approach followed by a pharmacokinetic study

  • Takaya Uno
  • Kyoichi Wada
  • Kouichi Hosomi
  • Sachi Matsuda
  • Megumi Morii Ikura
  • Hiromi Takenaka
  • Nobue Terakawa
  • Akira Oita
  • Satoshi Yokoyama
  • Atsushi Kawase
  • Mitsutaka TakadaEmail author
Pharmacoepidemiology and Prescription



This study investigated the effects of clotrimazole troche on the risk of transplant rejection and the pharmacokinetics of tacrolimus.


The data mining approach was used to investigate whether the use of clotrimazole increased the risk of transplant rejection in patients receiving tacrolimus therapy. Patient data were acquired from the US Food and Drug Administration’s Adverse Event Reporting System (FAERS) from the first quarter of 2004 to the end of 2017. Next, we retrospectively investigated the effect of clotrimazole troche on tacrolimus pharmacokinetics in seven patients who underwent heart transplantation between March and December 2017.


The FAERS subset data indicated a significant association between transplant rejection and tacrolimus with clotrimazole [reporting odds ratio 1.92, 95% two-sided confidence interval (95% CI) 1.43–2.58, information component 0.81, 95% CI 0.40–1.23]. The pharmacokinetic study demonstrated a significant correlation between trough concentration (C0) and area under the concentration-time curve of tacrolimus after discontinuation of clotrimazole (R2 = 0.60, P < 0.05) but not before its discontinuation. Furthermore, the median clearance/bioavailability of tacrolimus after discontinuation of clotrimazole was 2.2-fold greater than that before its discontinuation (0.27 vs. 0.59 L/h/kg, P < 0.05). The median C0 decreased from 10.7 ng/mL on the day after discontinuation of clotrimazole to 6.5 ng/mL at 1 day and 5.3 ng/mL at 2 days after its discontinuation.


Immediate dose adjustments of tacrolimus may be beneficial to avoid transplant rejection when clotrimazole troche is added or discontinued.


Tacrolimus Clotrimazole Drug interaction Transplant rejection Heart transplantation 



We would like to thank all the patients who participated in this study.

Author contributions

Participated in research design: Uno, Wada, Hosomi, Ikura, and Takada

Conducted experiments and clinical study: Uno, Wada, Hosomi, and Takada

Performed data analysis: Uno, Wada, Hosomi, Kawase, and Takada

Wrote or contributed to the writing of the manuscript: Uno, Wada, Hosomi, Matsuda, Ikura, Takenaka, Terakawa, Oita, Yokoyama, Kawase, and Takada

Funding information

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

This study was approved by the local ethics committee of the National Cerebral and Cardiovascular Center.

Informed consent

This study was a retrospective observational study, and informed consent to participate was obtained via the opt-out method.

Supplementary material

228_2019_2770_MOESM1_ESM.docx (33 kb)
ESM 1 (DOCX 33.1 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Takaya Uno
    • 1
    • 2
    • 3
  • Kyoichi Wada
    • 4
  • Kouichi Hosomi
    • 2
    • 3
  • Sachi Matsuda
    • 1
  • Megumi Morii Ikura
    • 1
  • Hiromi Takenaka
    • 1
  • Nobue Terakawa
    • 1
  • Akira Oita
    • 1
  • Satoshi Yokoyama
    • 2
    • 3
  • Atsushi Kawase
    • 5
  • Mitsutaka Takada
    • 2
    • 3
    Email author
  1. 1.Department of PharmacyNational Cerebral and Cardiovascular CenterSuitaJapan
  2. 2.Division of Clinical Drug Informatics, School of PharmacyKindai UniversityHigashi-osakaJapan
  3. 3.Division of Cardiovascular Drugs, TherapyKindai University Graduate School of PharmacyHigashi-osakaJapan
  4. 4.Education and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical SciencesTakatsukiJapan
  5. 5.Department of Pharmacy, Faculty of PharmacyKindai UniversityHigashi-osakaJapan

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