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Pharmaceutical and genetic determinants for interindividual differences of tacrolimus bioavailability in renal transplant recipients

  • Pharmacokinetics and Disposition
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European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The pharmacokinetics of orally administered immediate-release, twice-daily (BID) and modified-release, once-daily (QD) formulations of tacrolimus have high interindividual variability. We investigated factors affecting interindividual variability of tacrolimus bioavailability in renal transplant patients.

Methods

Ninety-seven Japanese renal transplant patients (47 patients on tacrolimus BID and 50 patients on tacrolimus QD) were enrolled in this study. The tacrolimus absolute bioavailability was calculated using the area under the concentration–time curve from 0 to 24 h (AUC0–24) after continuous intravenous infusion and oral formulations of tacrolimus in the same recipient.

Results

The median (quartile 1–quartile 3) tacrolimus relative bioavailability for recipients with the CYP3A5*1 or CYP3A5*3/*3 alleles was significantly lower for the tacrolimus QD group [9.1 % (6.3–10.7 %) and 15.4 % (11.5–18.7 %), respectively] than for the tacrolimus BID group [12.6 % (9.9–14.2 %) and 19.3 % (16.5–24.8 %), respectively] (P = 0.004 and 0.028, respectively). Consequently, tacrolimus absolute bioavailability was lowest for recipients with the CYP3A5*1 allele taking tacrolimus QD. The CYP3A5 polymorphism had no impact on the dose-adjusted AUC0–24 of tacrolimus in patients on continuous intravenous infusion (P = 0.906).

Conclusion

The larger interindividual variability of tacrolimus bioavailability for oral formulations appears to be due to the effects of the CYP3A5 polymorphism and the tacrolimus oral formulation. These factors should therefore be taken into account when determining individualized tacrolimus dosing.

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Acknowledgments

This work was supported by a grant (No. 23592378 and No. 24927005) from the Japan Society for the Promotion of Science, Tokyo, Japan.

Conflict of interest

None.

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Authors and Affiliations

  1. Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan

    Takenori Niioka, Hideaki Kagaya & Masatomo Miura

  2. Department of Urology, Akita University School of Medicine, Akita, Japan

    Kazuyuki Numakura, Mitsuru Saito, Takamitsu Inoue, Tomonori Habuchi & Shigeru Satoh

  3. Division of Renal Replacement Therapeutic Science, Akita University School of Medicine, Akita, Japan

    Shigeru Satoh

Authors
  1. Takenori Niioka
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  2. Hideaki Kagaya
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  3. Masatomo Miura
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  4. Kazuyuki Numakura
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  5. Mitsuru Saito
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  6. Takamitsu Inoue
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  7. Tomonori Habuchi
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  8. Shigeru Satoh
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Corresponding author

Correspondence to Masatomo Miura.

Additional information

Takenori Niioka and Hideaki Kagaya contributed equally to this work.

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Niioka, T., Kagaya, H., Miura, M. et al. Pharmaceutical and genetic determinants for interindividual differences of tacrolimus bioavailability in renal transplant recipients. Eur J Clin Pharmacol 69, 1659–1665 (2013). https://doi.org/10.1007/s00228-013-1514-8

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  • DOI: https://doi.org/10.1007/s00228-013-1514-8

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