Drug-Drug Interaction between Tacrolimus and Vonoprazan in Kidney Transplant Recipients.

Takuya Yoshihashi,Kinji Furuya,Masato Homma,Kazuhiro Takahashi,Yoshiharu Suzuki,Tatsuya Oda,Nobuhiro Ohkohchi

doi:10.3390/jcm10173964

Takuya Yoshihashi, Kinji Furuya + Show 5 more

Open Access

https://doi.org/10.3390/jcm10173964

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Abstract

Kidney transplant recipients with tacrolimus-based immunosuppressive therapy are often treated with proton-pump inhibitors (PPIs) to prevent gastric ulcer complications. Vonoprazan, a potassium-competitive acid blocker, is a novel PPI possessing different metabolic pathways from conventional PPIs (e.g., omeprazole, lansoprazole and rabeprazole). However, no data are available on the change in blood concentration of tacrolimus after switching rabeprazole, a conventional PPI, to vonoprazan coadministration in the initial period of post-transplantation. This is a retrospective study of 18 kidney transplant recipients. The blood concentration and the concentration to dose (C/D) ratio of tacrolimus were compared before and after switching from rabeprazole to vonoprazan. Impacts of CYP2C19 and CYP3A5 genetic polymorphisms on the drug–drug interaction were also examined. The median (range) trough concentration of tacrolimus was significantly increased from 5.2 (3.6–7.4) to 8.1 (6.1–11.7) ng/mL (p < 0.0005) after switching from rabeprazole to vonoprazan. The C/D ratio of tacrolimus was also significantly increased from 38.1 (16.5–138.1) to 48.9 (26.2–207.2) (p < 0.0005). The percent changes of tacrolimus concentrations and C/D were 65.8% and 41.8%, respectively. CYP2C19 and CYP3A5 genetic polymorphisms did not affect the change in concentration and C/D ratio of tacrolimus. The present study indicates that vonoprazan coadministration increases the tacrolimus concentration regardless of CYP2C19 or CYP3A5 genetic polymorphisms. Thus, frequent monitoring of blood tacrolimus concentration is required when vonoprazan is introduced as an intensive gastric acid blocker in the early phase of post-transplantation.

Highlights

Tacrolimus, a calcineurin inhibitor, is used as an immunosuppressive agent for allograft transplantation in combination with mycophenolate mofetil and corticosteroids [1].Tacrolimus requires frequent measurements of the blood concentration due to the narrow therapeutic range of 5–15 ng/mL [2]
Conventional pump inhibitors (PPIs), omeprazole and lansoprazole, produce drug–drug interactions (DDIs) with tacrolimus, where blood tacrolimus concentration was increased by competitively inhibiting tacrolimus metabolism on hepatic CYP3A4
Current interests have been focused on a novel PPI, vonoprazan, which acts as a potassium-competitive acid blocker and provides rapid and strong suppression on gastric acid secretion [18,19]

Summary

Introduction

Tacrolimus, a calcineurin inhibitor, is used as an immunosuppressive agent for allograft transplantation in combination with mycophenolate mofetil and corticosteroids [1].Tacrolimus requires frequent measurements of the blood concentration due to the narrow therapeutic range of 5–15 ng/mL [2]. Conducting therapeutic drug monitoring of tacrolimus is important for optimizing the dose keeping the therapeutic range of the blood concentration in individual patients [5,6,7,8]. The conventional proton-pump inhibitors (PPIs), lansoprazole and omeprazole, which are substrates for CYP2C19 and 3A4, are often given with tacrolimus for preventing gastrointestinal complications in kidney transplant recipients [11]. Coadministration of these PPIs with tacrolimus has been known to produce DDIs where blood tacrolimus was increased, especially in patients carrying

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