Tacrolimus, a calcineurin inhibitor, is widely used as an immunosuppressive agent for allograft transplantation in combination with corticosteroids and mycophenolate mofetil (MMF). It is important to control the blood concentration of tacrolimus in organ transplant recipients to avoid acute cellular rejection (1).

Proton pump inhibitors (PPIs) are administered to prevent upper gastrointestinal complications in transplant recipients. Vonoprazan fumarate (vonoprazan) is a newly developed acid suppressant and potassium-competitive acid blocker that reversibly inhibits the gastric acid pump in a K⁺-competitive manner (2). Vonoprazan is used in transplant recipients because it seems to be superior to common PPIs for preventing upper gastrointestinal complications.

Tacrolimus is metabolized by cytochrome p450 3A4/5 (CYP3A4/5), so CYP metabolism affects the blood concentration of tacrolimus (3). The conventional PPI rabeprazole was reported to affect the blood concentration of tacrolimus regardless of the CYP2C19 gene polymorphism (4). However, although vonoprazan is metabolized by CYP3A4/5 (5), there have been no reports concerning the effect of vonoprazan on the tacrolimus blood concentration in liver transplant (LT) recipients.

The present study investigated the effect of vonoprazan on the liver and kidney functions and tacrolimus blood concentration in LT recipients.

Patient selection. A total of 331 patients underwent LT from August 1997 to 2022 at Nagasaki University Hospital. Among these patients, 18 adult recipients who had a follow-up period exceeding 3 months between 2016 and 2018 and changed from PPIs (rabeprazole or omeprazole, lansoprazole) to vonoprazan were retrospectively enrolled in this study after their informed consent was obtained.

These patients had indications for LT, as defined by the ethics committee of our hospital. The management of living donor liver transplantation (LDLT) recipients and the donor selection has been described previously (6,7). Immunosuppression after LDLT was managed by steroids and tacrolimus, the trough level of which was adjusted to be between 10-15 ng/ml within one month after surgery and between 5-10 ng/ml subsequently. In cases with acute kidney dysfunction after LT, MMF was administered to the recipient to prevent severe kidney dysfunction (8). The steroid dose was tapered within the first three to six months. We have performed ABO blood incompatible LT since 2004, and rituximab was used as treatment before LDLT in all cases, and local treatment was performed via the portal vein or hepatic artery until 2009.

The exclusion criteria were as follows: i) patients with an unstable liver function within 3 months before conversion; ii) those with liver function test values above the normal range before conversion [normal range: aspartate transaminase (AST) <30 IU/l and/or alanine transaminase (ALT) <42 IU/l in males and <23 IU/l in females, and total bilirubin (T.Bil) <1.5 mg/dl], and iii) those with an unstable blood trough level of tacrolimus within one month before conversion. The initial concentration (C₀) (ng/ml) of tacrolimus was monitored by a chemiluminescence immunoassay on the Architect-i1000 System (Abbott Japan, Tokyo, Japan). All recipients were administered tacrolimus once or twice daily. Analysis results are presented in Table I.

Ethics statement. This study was approved by the appropriate ethics committee (number 20012022) and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Statistical analyses. The preoperative and postoperative clinical data examined included the recipient age, model for end-stage liver disease (MELD) score, etiology (hepatitis B, hepatitis C, nonBnonC), hepatocellular carcinoma (HCC) status, the rate of ABO incompatible recipients, and liver function test results for AST, ALT, and T.Bil after LDLT. The clinical variables serum creatinine, creatinine-based estimated glomerular filtration rate (eGFR), which is the most commonly used method in clinical practice, were measured to assess kidney function. However, previous studies have shown that cystatin C-based eGFR or GFR calculated by inulin or 125-I-iothalamate would be more accurate in evaluating renal function in liver transplant patients (9). The data are presented as the median (range) values for continuous variables and as frequencies for categorical variables. The Friedman test was used to analyze differences in the median values for AST, ALT, T.Bil, eGFR, tacrolimus C₀, and tacrolimus C₀/Dosage (D) before and at three and six months after conversion. Differences were statistically significant at p<0.05. Statistical analyses were performed using the SPSS Version 24.0 software package (IBM, Tokyo, Japan).

Patient characteristics. The clinical background data of LT recipients are shown in Table I. Eighteen patients converted to vonoprazan from PPIs (rabeprazole 10, omeprazole 6, lansoprazole 2). The reasons for conversion to vonoprazan were epigastric pain in 5, a history of gastric or duodenal ulcer in 3, and unknown reasons in 10. Median age, height, weight, BMI, MELD score and Child Pugh score were 59.5 years, 1.61 m, 61.4 kg, 24.8 kg/m², 16.5 and 11, respectively. Six patients received ABO incompatible liver transplantation. Regarding immunosuppression therapy, the rates of MMF and steroid consumption were 83.3% and 11.1%, respectively. The dose of tacrolimus at conversion was 2 mg (range=0.5-8). The duration between conversion and transplantation was 25.5 months (range=8-62). The tacrolimus C₀/D ratio at conversion was 2.23 (range=0.67-7.30).

Comparison of the liver and kidney function and trough level (C₀) and C₀/D of tacrolimus before and after conversion. Table II shows that AST, ALT, T.Bil, and serum creatinine were not worse at 3 and 6 months after conversion; however, the eGFR showed gradual worsening at three and six months after conversion compared to before conversion. There was no significant difference in the tacrolimus trough level or C₀/D value after conversion (Figure 1).

In this study, the median tacrolimus trough level and C₀/D were stably maintained. However, two studies have shown that the tacrolimus C₀/D value after conversion from rabeprazole to vonoprazan was significantly elevated, the liver and kidney functions were not worse after conversion (10,11).

The reason for the elevation of the tacrolimus trough level and C₀/D value is thought to involve the metabolism of CTP3A4 (10,11). Tacrolimus is mainly metabolized by CYP3A4/5 (3); the concomitant use of drugs metabolized by CTP3A4/5 may provide changes in the blood levels of tacrolimus. Conventional PPIs (omeprazole, lansoprazole) interact with tacrolimus, which can lead to an increased blood tacrolimus concentration by the inhibition of tacrolimus metabolism through a competition for CYP3A4. Interactions of tacrolimus with other drugs are often observed in CYP2C19 intermediate metabolizer (IM)/poor metabolizer (PM) patients, whose blood concentrations of PPIs are higher than those of CYP2C19 extensive metabolizer (EM) patients (12,13). The conventional PPI rabeprazole, the main metabolic pathway of which is nonenzymatic, does not interact with tacrolimus (12,13).

Suzuki et al. investigated the relationship between the CYP family and tacrolimus trough level in kidney transplant recipients. They found no significant differences in the tacrolimus blood concentration or tacrolimus C₀/D ratio after conversion from rabeprazole to vonoprazan among patients with CYP2C19 and CYP3A5 genotype statuses (11). CYP3A5 gene polymorphisms were correlated with the blood concentrations of tacrolimus in kidney transplant recipients (14). Vonoprazan was also reported to inhibit CYP3A5 activity as well as CYP3A4 (5). Furthermore, vonoprazan coadministration showed a slightly higher increase in the tacrolimus C₀/D ratio in CYP3A5*1-carriers than in noncarriers (15). Watari et al. investigated the relationship between the CYP3A5 genotype and tacrolimus blood concentration in kidney transplant recipients and found that the median tacrolimus trough level among all recipients after conversion from rabeprazole to vonoprazan increased slightly but not significantly (15). These investigations suggested that the conversion from PPIs to vonoprazan might be considered safe for concomitant use in kidney transplant recipients.

In the LT field, Hosohata et al. reported that tacrolimus and lansoprazole interact in patients with genetic polymorphisms of CYP2C19 and CYP3A5 (16). As lansoprazole and omeprazole are metabolized by CYP2C19 as well as CYP3A4/5 (13,17), tacrolimus and PPI interactions are more likely to be observed in patients with CYP2C19 polymorphisms. Our study showed that the tacrolimus trough concentration and C₀/D ratio were not elevated in LT recipients after conversion to vonoprazan, possibly due to CYP2C19, 3A4/5 polymorphism, although further investigation is needed.

Several limitations associated with the present study warrant mention. First, this study was a small retrospective investigation at a single center. Second, the mechanism underlying the expression of CYP3A4/5 was not investigated. Interactions between tacrolimus and vonoprazan might have been important factors influencing the blood tacrolimus concentration. The CYP3A4/5 genotype of LT recipients will be investigated in future studies.

In conclusion, elevation of the tacrolimus trough level and C₀/D value was not observed in LT recipients after conversion from PPI to vonoprazan. The concomitant administration of vonoprazan did not affect the liver function or trough level in stable LDLT recipients after conversion from a PPI to vonoprazan. Thus, vonoprazan can be safely administered to LT recipients receiving tacrolimus during the stable period.

The Authors who have taken part in this study declare that they do not have anything to disclose regarding funding or conflicts of interest with respect to this manuscript.

MH, AS, JH, KO and SE designed and drafted the manuscript. TH, NM, HM, TT, TH, HI, TA and KK collected data and assisted in preparing the manuscript. All Authors have read and approved the final manuscript.

The Authors wish to thank their colleagues in the Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan for their kind cooperation and support.