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Impact of the CYP3A5*1 Allele on the Pharmacokinetics of Tacrolimus in Japanese Heart Transplant Patients

European Journal of Drug Metabolism and Pharmacokinetics volume 43, pages 665–673 (2018)Cite this article

Abstract

Background and Objective

Tacrolimus, a major immunosuppressant used after transplantation, is associated with large interindividual variation involving genetic polymorphisms in metabolic processes. A common variant of the cytochrome P450 (CYP) 3A5 gene, CYP3A5*3, affects blood concentrations of tacrolimus. However, tacrolimus pharmacokinetics at the early stage of transplantation have not been adequately studied in heart transplantation. We retrospectively examined the impact of the CYP3A5 genotype on tacrolimus pharmacokinetics at the early stage of heart transplantation.

Methods

The tacrolimus pharmacokinetic profile was obtained from 65 patients during the first 5 weeks after heart transplantation. Differences in the patients’ characteristics and tacrolimus pharmacokinetic parameters between the CYP3A5 expresser (*1/*1 or *1/*3 genotypes) and non-expresser (*3/*3 genotype) groups were assessed by the Chi-square test, Student’s t test, or Mann–Whitney U test.

Results

The CYP3A5 *1/*1, *1/*3, and *3/*3 genotypes were detected in 5, 22, and 38 patients, respectively. All patients started clotrimazole therapy approximately 1 week after starting tacrolimus. Apparent clearance and dose/weight to reach the target trough concentration (C0) were significantly higher in the expresser group than in the non-expresser group (0.32 vs. 0.19 L/h/kg, p = 0.0003; 0.052 vs. 0.034 mg/kg/day, p = 0.0002); there were no significant differences in the area under the concentration-time curve from 0 to 12 h (AUC0–12) and concentrations at any sampling time point between the two groups.

Conclusion

Similar concentration–time curves for tacrolimus were obtained in the expresser and non-expresser groups by dose adjustment based on therapeutic drug monitoring. These results demonstrate the importance of the CYP3A5 genotype in tacrolimus dose optimization based on therapeutic drug monitoring after heart transplantation.

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Author information

Affiliations

  1. Department of Pharmacy, National Cerebral and Cardiovascular Center, Suita, Japan

    Takaya Uno, Kyoichi Wada, Sachi Matsuda, Yuka Terada & Akira Oita

  2. Division of Clinical Drug Informatics, Faculty of Pharmacy, Kindai University, Higashi-osaka, Japan

    Takaya Uno & Mitsutaka Takada

  3. Department of Pharmacy, Faculty of Pharmacy, Kindai University, Higashi-osaka, Japan

    Atsushi Kawase

  4. Division of Cardiovascular Drugs, Therapy, Kindai University Graduate School of Pharmacy, Higashi-osaka, Japan

    Takaya Uno, Kyoichi Wada & Mitsutaka Takada

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  1. Takaya Uno
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  2. Kyoichi Wada
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  3. Sachi Matsuda
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  4. Yuka Terada
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  5. Akira Oita
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  6. Atsushi Kawase
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  7. Mitsutaka Takada
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Correspondence to Mitsutaka Takada.

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Funding

No source of funding was used to conduct this study.

Disclosure of potential conflicts of interest

Takaya Uno, Kyoichi Wada, Sachi Matsuda, Yuka Terada, Akira Oita, Atsushi Kawase, and Mitsutaka Takada declare that they have no conflicts of interest.

Ethical approval

The study protocol was approved by the National Cerebral and Cardiovascular Center Ethics Committee (reference number M27-067-5).

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Written informed consent regarding the disclosure of clinical data was obtained from all individual participants included in the study.

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Uno, T., Wada, K., Matsuda, S. et al. Impact of the CYP3A5*1 Allele on the Pharmacokinetics of Tacrolimus in Japanese Heart Transplant Patients. Eur J Drug Metab Pharmacokinet 43, 665–673 (2018). https://doi.org/10.1007/s13318-018-0478-6

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