Research ArticleClinical Studies

Switching from Intravenous to Oral Tacrolimus Reduces its Blood Concentration in Paediatric Cancer Patients

HARUKI UJIIE, SATORU NIHEI, NAOYUKI NISHIYA, SHINPEI GOTO, YOSHIKO ASAKURA, SHOKO MIURA, DAISHI HIRAI, MIKIYA ENDO, TATSUO OYAKE, SHIGEKI ITO, TAKESHI CHIBA and KENZO KUDO
Anticancer Research May 2021, 41 (5) 2591-2596; DOI: https://doi.org/10.21873/anticanres.15038

Abstract

Background/Aim: Tacrolimus is an essential immunosuppressant for successful allogeneic haematopoietic stem cell transplantation (Allo-HSCT). This study aimed to examine the change in the blood concentration of tacrolimus during switching from intravenous to oral administration in allo-HSCT for paediatric cancer to predict the optimal dosage. Patients and Methods: We retrospectively examined the medical records of 63 patients who received allo-HSCT and were administered tacrolimus. To compare bioavailability among different dose ranges, the blood concentration was divided by the dose (C/D). Results: Thirty-nine patients (age range=children 1-15 years, adults 17-67 years) were switched to oral administration of tacrolimus. The C/D after switching was significantly lower in children than in adults (p=0.039). There was a strong positive correlation between age and C/D in children, whereas no correlation was observed in adults. Conclusion: In paediatric cancer patients, switching tacrolimus administration route may result in reduced blood concentrations. This tendency is more prominent in younger children.

Key Words:

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is the ultimate treatment for haematological malignancies. However, graft-versus-host disease (GVHD) may lead to serious complications. GVHD is an immune response reaction that occurs when donor-derived lymphocytes recognise the recipient organ as a foreign body (1, 2), and a major cause of decreased quality of life (QOL) and treatment-related death due to skin disorders and watery diarrhoea. Therefore, GVHD management with immunosuppressants is extremely important for patients undergoing allo-HSCT. Particularly, the calcineurin inhibitor tacrolimus is widely used as a standard preventive agent for GVHD.

In patients who received tacrolimus, high blood concentration increases the risk of developing serious side effects, such as renal failure, infection, and generalised convulsions, whereas low blood concentration results in severe GVHD. Therefore, it is necessary to measure the blood concentration frequently for optimisation of tacrolimus dosage. Blood trough concentrations of tacrolimus are often 7-12 ng/ml in children who have received allo-HSCT (3). Usually, tacrolimus is started by continuous intravenous administration by injection, and when possible, it is switched to oral medication and continued to be administered for a long time thereafter. The optimum dosage for switching from a continuous intravenous injection to oral administration is 3–4 times that of the intravenous dosage in adults (4). However, optimal dosage for switching to oral administration in Japanese children has not yet been established. This study compared the tacrolimus dosage and blood concentration in children after allo-HSCT with those in adults and examined the optimal switching ratio for Japanese children.

Patients and Methods

Study design and participants. This study involved patients who received allo-HSCT and were treated with tacrolimus to prevent GVHD in Iwate Medical University Hospital from April 2011 to March 2017. Patients who did not switch from intravenous to oral administration of tacrolimus and patients who discontinued within 2 weeks after switching to oral administration were excluded. Patients were defined as children under 15 years of age and adults over 16 years of age. This is a retrospective study, which was approved by the ethics committee of the Iwate Medical University School of Medicine (Approval number: H29-158) in accordance with the ‘ethical guidelines for human-based medical research’.

Clinical data collection and assessment. The study data were collected retrospectively from electronic medical records. The data collected were: age, gender, body surface area, body mass index, clinical test values, disease name, transplant type, tacrolimus dosage and blood concentration, irradiation dose, total body irradiation, and concomitant medication.

Evaluation of tacrolimus dosage and blood concentration. The time for evaluating the dose and blood concentration of tacrolimus in intravenous administration was immediately before switching to oral administration. The evaluation time of doses and blood concentrations of tacrolimus in oral administration were 1 and 2 weeks after switching to oral administration. The blood concentration of tacrolimus after oral administration was evaluated just before the next medication, after achievement of a steady state. Also, the blood concentration of tacrolimus divided by the dose was defined as the blood concentration/dose ratio (C/D).

Statistical analysis. The subjects were divided into children and adults, and the tacrolimus dose, blood concentration, and C/D were compared using Mann–Whitney’s U-test. The correlation between age and C/D after switching to oral administration was analysed using Spearman’s rank correlation coefficient test. In the box plot, the line in the box indicates the median. The border between the top and bottom of the box is the 75th and 25th percentiles. The upper and lower limits of the whisker length were 1.5 times the quartile range, and those beyond the whisker range are outliers. BellCurve for Excel (Social Survey Research Information Co., Ltd., Tokyo, Japan) was used for the statistical analyses of this study. All analyses excluded outliers, and a significance level of less than 5% was considered statistically significant.

Results

Patient background. A total 39 cases were included in this study; 12 were children aged <15 years and 27 were adults aged >16 years. The background of the subjects is shown in Table I. The mean age of children was 10.0±5.5 years and that of adults was 48.1±14.1 years. There were no significant differences between the background of children and adult patients, such as concomitant medications and total body irradiation. Also, regarding the administration status of tacrolimus, no significant difference was observed between the two groups in terms of the dose at the time of intravenous administration, blood concentration, and C/D.

View this table:
Table I.

Patient baseline characteristics.

After switching to oral administration of tacrolimus, dosages in children and adults were in the same range. Figure 1 shows the tacrolimus dosage after switching between oral administration in children and adults. Analysis excluded outliers. One week after switching to oral administration, analysis of dosage was performed on 10 children and 26 adults. The dosage in children was 0.151±0.024 mg/kg, which was not significantly different from that in adults at 0.135±0.053 mg/kg (p=0.216). After two weeks, the analysis of dosage was performed on 11 children and 27 adults. The oral dosage for children was 0.163±0.065 mg/kg, which tended to be higher than that for adults at 0.130±0.057 mg/kg (p=0.135).

Figure 1.
Figure 1.

Oral dosages of tacrolimus were in the same range between children and adults. We compared the tacrolimus dosage after switching to oral administration between children and adults. The line inside the box indicates the median. The boundaries at the top and bottom of the box are 75th and 25th percentiles, respectively. The upper and lower limits of whisker length were 1.5 times the quartile range. × indicates an outlier. Statistical analyses were performed using the Mann–Whitney U-test. The results of statistical analyses excluded abnormal values.

Blood concentration of tacrolimus after switching to oral administration was decreased in children. Figure 2 shows the blood concentration of tacrolimus after switching to oral administration in children and adults. No outliers were found in the analysis of blood concentrations. One week after switching to oral administration, the blood concentration in children was 6.4±3.5 ng/ml, which was significantly lower than that in adults 8.7±2.9 ng/ml (p=0.046). However, no significant difference was observed between the two groups 2 weeks after switching to oral administration (p=0.761).

Figure 2.
Figure 2.

The blood concentration of tacrolimus in children was significantly lower than that in adults one week after switching to oral administration. We compared the blood concentration of tacrolimus after switching to oral administration between children and adults. The line inside the box indicates the median. The boundaries at the top and bottom of the box are 75th and 25th percentiles, respectively. The upper and lower limits of whisker length were 1.5 times the quartile range. Statistical analyses were performed using the Mann–Whitney U-test. *indicates p<0.05.

C/D after oral administration was significantly reduced in children. Figure 3 shows the C/D after switching to oral administration in children and adults. One week after switching to oral administration, analysis of C/D was performed on 12 children and 26 adults, excluding outliers. The C/D in children was 40.1±26.5, which was significantly lower than that in adults 65.0±28.1 (p=0.026). Similarly, two weeks after switching to oral administration, analysis of C/D was performed on 12 children and 24 adults, excluding outliers. The C/D in children was 50.7±33.9, which tended to be lower than that in adults 64.8±25.2. (p=0.107).

Figure 3.
Figure 3.

The concentration/dose ratio (C/D) in children was significantly lower than that in adults. This figure compares C/D two weeks after switching to oral administration of tacrolimus between children and adults. The line inside the box indicates the median. The boundaries at the top and bottom of the box are 75th and 25th percentiles, respectively. The upper and lower limits of whisker length were 1.5 times the quartile range. The results of statistical analyses excluded abnormal values. Statistical analyses were performed using the Mann–Whitney U-test. *indicates p<0.05.

Correlation of C/D with age or weight in children. Age or body weight were plotted in scatter diagrams against C/D to evaluate their correlation (Figure 4). Age and weight are presented on the horizontal axis and C/D on the vertical axis. Data from children showed a strong positive correlation between age and C/D (rs=0.791, p<0.001). Similar results were also obtained for body weight (rs=0.752, p<0.001). In contrast, no significant correlations were found either between C/D and age (rs=0.014, p=0.881) or between C/D and body weight (rs=0.104, p=0.332) in adults.

Figure 4.
Figure 4.

Positive correlation was observed between the C/D and the age or weight in children. This figure is a scatter plot with age or weight on the horizontal axis and C/D one week after switching to oral administration on the vertical axis. The solid line represents the regression line. (A) Correlation between C/D and age in children and adults. (B) Correlation between C/D and weight in children and adults.

Discussion

In allo-HSCT, immunosuppressants are administered for the prevention and treatment of GVHD. Particularly, when using tacrolimus, it is important to monitor the blood concentration in terms of effectiveness and safety, and to control the appropriate blood concentration by optimising the dosage. This study revealed that switching from intravenous to oral administration decreased the blood concentration of tacrolimus in Japanese children during allo-HSCT, and the switching effect was larger in children than in adults.

Switching from intravenous to oral administration decreases the blood concentration of tacrolimus after paediatric allo-HSCT. During intravenous administration, the dosage and blood concentration of tacrolimus were equivalent between children and adults. However, oral administration decreased blood concentration in children 1 week after switching from intravenous administration, even though oral dosage was increased up to approximately 6.4 times that of the intravenous dosage (Figure 1). Wallin et al. analysed the population pharmacokinetics of tacrolimus in 22 patients who underwent paediatric allo-HSCT, and concluded that the optimal dosage of enteric therapy with tacrolimus was six times higher than the intravenous dosage, indicating that the pharmacokinetics of tacrolimus differed between children and adults (5). Oral administration could be affected to a higher extent than enteric therapy because of difficulties in giving children medicines, which might result in improper administration. This study, therefore, revealed that the decrease in tacrolimus blood concentration in children necessitates detailed investigation of different administration methods in the future. Also, tacrolimus has many drug interactions, including voriconazole, an antifungal azole, which inhibits CYP3A4 and increases the C/D of tacrolimus by 1.4 times (6). In this study, the combination of tacrolimus with voriconazole was recorded in only one child and one adult. Proton pump inhibitors such as lansoprazole and omeprazole also interact with tacrolimus (7), and this study included four cases in children and five in adults. Therefore, we considered that the drug interactions had little effect on the results of this study. Consequently, a higher dose of tacrolimus is required in paediatric allo-HSCT than in adults after switching to oral administration.

In this study, the C/D correlated with age or weight during childhood. The C/D of children was significantly lower than that of adults two weeks after switching to oral administration (Figure 3). Przepiorka et al. reported that children under 6 years old have higher tacrolimus clearance after allo-HSCT than children over 6 years old (8). Increased tacrolimus clearance decreases blood concentration and C/D, supporting our findings. In addition to the decrease in C/D in the younger age, our analysis of the association between C/D and age revealed a positive correlation during childhood (Figure 4). Indeed, our paediatric approximate equation for age and C/D (data not shown) fitted well with data reported by Przepiorka et al. (8), indicating that our prediction formula can be generalised. However, tacrolimus is a typical fat-soluble drug, which has its maximum blood concentration reduced by approximately 30% when administered after meals (9). Meal ingestion could have affected C/D because in our study, tacrolimus was not consistently administered either before or after meals. In the future, it is necessary to standardize administration either before or after meals. Also, GVHD and pretreatment with chemotherapy cause severe diarrhoea in allo-HSCT (4). Tacrolimus blood concentration is elevated after onset of gastroenteritis in organ-transplant patients (10, 11). However, our study was a retrospective study, and thus, we were unable to evaluate the severity of diarrhoea in children and adults. Therefore, further studies are needed to reveal whether diarrhoea in allo-HSCT affects the blood concentration of tacrolimus.

Based on the above results, when switching from intravenous administration to oral administration of tacrolimus after allo-HSCT in Japanese children, it may be difficult to obtain blood concentrations at the same switching ratio as in adults. Therefore, it is desirable to frequently monitor the blood concentration for one week after switching to oral administration and adjust the dose based on the results.

Acknowledgements

The Authors would like to thank Dr. Junya Sato (International University of Health and Welfare, Department of Pharmaceutical Sciences) for his constructive comments.

Footnotes

  • Authors’ Contributions

    HU, SN contributed to the conception of the work, data acquisition, data analysis, manuscript drafting, revision, approval of final manuscript. NN contributed to manuscript drafting, revision, approval of final manuscript. SG, YA, SM, DH, ME, TO and SI each contributed to data acquisition, manuscript drafting, revision, approval of final manuscript. TC and KK contributed to the conception of the work and the approval of the final manuscript.

  • Conflicts of Interest

    The Authors declare no conflicts of interest in relation to this study.

  • Received April 1, 2021.
  • Revision received April 15, 2021.
  • Accepted April 16, 2021.

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Switching from Intravenous to Oral Tacrolimus Reduces its Blood Concentration in Paediatric Cancer Patients
HARUKI UJIIE, SATORU NIHEI, NAOYUKI NISHIYA, SHINPEI GOTO, YOSHIKO ASAKURA, SHOKO MIURA, DAISHI HIRAI, MIKIYA ENDO, TATSUO OYAKE, SHIGEKI ITO, TAKESHI CHIBA, KENZO KUDO
Anticancer Research May 2021, 41 (5) 2591-2596; DOI: 10.21873/anticanres.15038
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