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Case  Report

Effect of fluconazole on the pharmacokinetics of everolimus and tacrolimus in a heart transplant recipient: Case report

Kazuki Nakagita, Kyoichi Wada, Yuka Terada, Sachi Matsuda, Nobue Terakawa, Akira Oita, and Mitsutaka Takada

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Volume 56 (2018) p. 270 - 276

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 56 – No. 6/2018 (270-276)

Effect of fluconazole on the pharmacokinetics of everolimus and tacrolimus in a heart transplant recipient: Case report

Kazuki Nakagita¹#², Kyoichi Wada¹#², Yuka Terada¹, Sachi Matsuda¹, Nobue Terakawa¹, Akira Oita¹, and Mitsutaka Takada²

¹Department of Pharmacy, National Cerebral and Cardiovascular Center, Suita, and ²Division of Cardiovascular Drugs and Therapy, Kindai University Graduate School of Pharmacy, Higashi-Osaka, Osaka, Japan
Objective: Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR) and has been used in combination with calcineurin inhibitors (tacrolimus and cyclosporine) to prevent allograft rejection following organ transplantation. In heart transplant recipients, everolimus should be maintained at a target blood concentration of 3 – 8 ng/mL, in combination with reduced-dose calcineurin inhibitors and therefore, requires strict monitoring. Fluconazole, an azole antifungal agent, affects blood concentration of tacrolimus by inhibiting the cytochromes P450 (CYP) 3A4 and 3A5. Therefore, to avoid overexposure during everolimus-azole cotreatment, the dose of everolimus should be reduced. However, the mechanism of interaction between everolimus and fluconazole remains unclear. Case report: We report the case of a heart transplant recipient who experienced a 2.8-fold increase in everolimus clearance and a 3.5-fold increase in everolimus dosage, following withdrawal of fluconazole therapy. The clearance and dosage of tacrolimus increased 4.7- and 3.0-fold, respectively. Conclusion: The concentrations of everolimus and tacrolimus should be carefully monitored when administered concomitantly with fluconazole to heart transplant recipients. The patient in this case had a CYP3A5*1/*3 genotype, and CYP3A5 constituted the metabolic pathway. Therefore, concomitant use of fluconazole might have a relatively small impact on everolimus and tacrolimus pharmacokinetics in this case. Correspondence to:
Kyoichi Wada, PhD 
Department of  Pharmacy
National Cerebral and Cardiovascular Center
5-7-1 Fujishirodai,  Suita 565-8565, Japan 
Email: [email protected]

Original

Relationship between serum bepridil concentration and corrected QT interval 

Kazuki Matsui, Yutaro Mukai, Kota Sakakura, Kyoichi Wada, Tsutomu Nakamura, Atsufumi Kawabata, Nobue Terakawa, Naoki Hayakawa, Kengo Kusano, Kouichi Hosomi, Satoshi Yokoyama, and Mitsutaka Takada

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Volume 59 (2021) p. 63 - 70

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 59 – No. 1/2021 (63-70)

Relationship between serum bepridil concentration and corrected QT interval 

Kazuki Matsui¹#²#³, Yutaro Mukai³, Kota Sakakura³, Kyoichi Wada⁴, Tsutomu Nakamura⁴, Atsufumi Kawabata², Nobue Terakawa³, Naoki Hayakawa³, Kengo Kusano⁵, Kouichi Hosomi⁶#⁷, Satoshi Yokoyama⁶#⁷, and Mitsutaka Takada¹#⁶#⁷

¹Division of Cardiovascular Drugs, Therapy, Kindai University Graduate School of Pharmacy, ²Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, Higashi-Osaka, ³Department of Pharmacy, National Cerebral and Cardiovascular Center, Suita, ⁴Education and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical Sciences, Takatsuki, ⁵Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, ⁶Division of Clinical Drug Informatics, Kindai University Graduate School of Pharmacy, and ⁷Division of Clinical Drug Informatics, School of Pharmacy, Kindai University, Higashi-Osaka, Japan
Objective: Bepridil prolongs the QT interval and can induce torsade de pointes. Although increased bepridil concentration may be a primary cause of prolonged QT, the relationship between serum bepridil concentration and prolonged QT remains unclear. We investigated the relationship between serum bepridil concentration and the corrected QT (QTc) interval in patients treated with bepridil.
Materials and methods: A retrospective study was performed at the National Cerebral and Cardiovascular Center in Japan. Patients with atrial fibrillation who were treated with bepridil from January 2014 to December 2015 were enrolled in the study. Serum bepridil concentrations and electrocardiogram data collected more than 21 days after the initiation of bepridil were used for analysis.
Results: A total of 60 patients were included in this study. There was a significant difference in mean QTc interval before and after initiation of bepridil (p < 0.0001). A significant relationship was observed between bepridil dose (p = 0.014) or serum bepridil concentration (p < 0.001) and QTc interval. Additionally, a significant relationship was observed between serum bepridil concentration and ΔQTc (p = 0.034). In the study, 4 patients developed QTc prolongation ≥ 500 ms after the initiation of bepridil. Serum bepridil concentration in this group was significantly higher compared with the group that did not display prolonged QTc (973 ± 651 vs. 526 ± 310 ng/mL, p = 0.01).
Conclusion: This study revealed that the QTc interval was significantly associated with serum bepridil concentration. Serum bepridil concentration beyond a therapeutic range may be a critical risk factor for developing QTc prolongation.Correspondence to:
Mitsutaka Takada, PhD
Division of Clinical Drug Informatics
Kindai University Graduate School of Pharmacy
Higashi-Osaka, Osaka, 577-8502, Japan
Email:  takada@ phar.kindai.ac.jp

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