Elevation of tacrolimus concentration after administration of methotrexate for treatment of graft-versus-host disease in pediatric patients received allogeneic hematopoietic stem cell transplantation
Abstract Background Methotrexate (MTX) is used to treat graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recently, a case was encountered in which the blood concentration of tacrolimus (TCR) at steady state increased after intravenous MTX adm...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-12-01
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| Series: | Journal of Pharmaceutical Health Care and Sciences |
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| Online Access: | https://doi.org/10.1186/s40780-023-00306-w |
| _version_ | 1827590399764463616 |
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| author | Chiaki Inoue Takehito Yamamoto Hiroshi Miyata Hiroshi Suzuki Tappei Takada |
| author_facet | Chiaki Inoue Takehito Yamamoto Hiroshi Miyata Hiroshi Suzuki Tappei Takada |
| author_sort | Chiaki Inoue |
| collection | DOAJ |
| description | Abstract Background Methotrexate (MTX) is used to treat graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recently, a case was encountered in which the blood concentration of tacrolimus (TCR) at steady state increased after intravenous MTX administration for GVHD treatment (therapeutic IV-MTX administration). Therefore, this study aimed to investigate the effect of therapeutic IV-MTX administration on the pharmacokinetics of TCR. Methods This single-center, retrospective, observational study included patients who underwent allo-HSCT and received therapeutic IV-MTX administration during immunosuppressive therapy with continuous intravenous infusion (CIV) of TCR from April 2004 to December 2021. Here, each therapeutic IV-MTX administration was defined as a case and independently subjected to subsequent analyses. The blood concentration of TCR at steady state (Css), ratio of Css to daily TCR dose (C/D), and clinical laboratory data were compared before and after therapeutic IV-MTX administration. In addition, dose changes in the TCR after therapeutic IV-MTX administration were evaluated. Results Ten patients (23 cases) were included in this study. The C/D value significantly increased after therapeutic IV-MTX administration (median: 697 vs. 771 (ng/mL)/(mg/kg), 1.16-fold increase, P < 0.05), indicating a reduction in the apparent clearance of TCR. Along with the increase in C/D, significant increases were observed in aspartate transaminase level (median: 51.0 vs. 92.9 U/L, P < 0.01) and alanine aminotransferase level (median: 74.5 vs. 99.4 U/L, P < 0.01) indicating that liver injury after therapeutic IV-MTX administration contributes to the observed C/D increase. In addition, the daily dose of TCR was reduced in 11 cases (47.8%) after therapeutic IV-MTX administration, and the relative frequency of dose reduction tended to be higher than that of dose increase (median: 37.5% vs. 0.0%, P = 0.0519, permuted Brunner-Munzel test). The magnitude of dose reduction was 18.8% (7.4–50.0%) in the 11 cases with dose reduction. Conclusions Therapeutic IV-MTX administration cause a significant increase in C/D, which requires TCR dose reduction. Careful therapeutic drug monitoring of TCR is needed after therapeutic IV-MTX administration in patients receiving immunosuppressive therapy with TCR after allo-HSCT. |
| first_indexed | 2024-03-09T01:16:19Z |
| format | Article |
| id | doaj.art-20babbe05c3e437f812eb2c811fca49e |
| institution | Directory Open Access Journal |
| issn | 2055-0294 |
| language | English |
| last_indexed | 2024-03-09T01:16:19Z |
| publishDate | 2023-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Pharmaceutical Health Care and Sciences |
| spelling | doaj.art-20babbe05c3e437f812eb2c811fca49e2023-12-10T12:26:39ZengBMCJournal of Pharmaceutical Health Care and Sciences2055-02942023-12-01911910.1186/s40780-023-00306-wElevation of tacrolimus concentration after administration of methotrexate for treatment of graft-versus-host disease in pediatric patients received allogeneic hematopoietic stem cell transplantationChiaki Inoue0Takehito Yamamoto1Hiroshi Miyata2Hiroshi Suzuki3Tappei Takada4Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of TokyoDepartment of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of TokyoDepartment of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of TokyoDepartment of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of TokyoDepartment of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of TokyoAbstract Background Methotrexate (MTX) is used to treat graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recently, a case was encountered in which the blood concentration of tacrolimus (TCR) at steady state increased after intravenous MTX administration for GVHD treatment (therapeutic IV-MTX administration). Therefore, this study aimed to investigate the effect of therapeutic IV-MTX administration on the pharmacokinetics of TCR. Methods This single-center, retrospective, observational study included patients who underwent allo-HSCT and received therapeutic IV-MTX administration during immunosuppressive therapy with continuous intravenous infusion (CIV) of TCR from April 2004 to December 2021. Here, each therapeutic IV-MTX administration was defined as a case and independently subjected to subsequent analyses. The blood concentration of TCR at steady state (Css), ratio of Css to daily TCR dose (C/D), and clinical laboratory data were compared before and after therapeutic IV-MTX administration. In addition, dose changes in the TCR after therapeutic IV-MTX administration were evaluated. Results Ten patients (23 cases) were included in this study. The C/D value significantly increased after therapeutic IV-MTX administration (median: 697 vs. 771 (ng/mL)/(mg/kg), 1.16-fold increase, P < 0.05), indicating a reduction in the apparent clearance of TCR. Along with the increase in C/D, significant increases were observed in aspartate transaminase level (median: 51.0 vs. 92.9 U/L, P < 0.01) and alanine aminotransferase level (median: 74.5 vs. 99.4 U/L, P < 0.01) indicating that liver injury after therapeutic IV-MTX administration contributes to the observed C/D increase. In addition, the daily dose of TCR was reduced in 11 cases (47.8%) after therapeutic IV-MTX administration, and the relative frequency of dose reduction tended to be higher than that of dose increase (median: 37.5% vs. 0.0%, P = 0.0519, permuted Brunner-Munzel test). The magnitude of dose reduction was 18.8% (7.4–50.0%) in the 11 cases with dose reduction. Conclusions Therapeutic IV-MTX administration cause a significant increase in C/D, which requires TCR dose reduction. Careful therapeutic drug monitoring of TCR is needed after therapeutic IV-MTX administration in patients receiving immunosuppressive therapy with TCR after allo-HSCT.https://doi.org/10.1186/s40780-023-00306-wTacrolimusMethotrexateHematopoietic stem cell transplantationTherapeutic drug monitoring |
| spellingShingle | Chiaki Inoue Takehito Yamamoto Hiroshi Miyata Hiroshi Suzuki Tappei Takada Elevation of tacrolimus concentration after administration of methotrexate for treatment of graft-versus-host disease in pediatric patients received allogeneic hematopoietic stem cell transplantation Journal of Pharmaceutical Health Care and Sciences Tacrolimus Methotrexate Hematopoietic stem cell transplantation Therapeutic drug monitoring |
| title | Elevation of tacrolimus concentration after administration of methotrexate for treatment of graft-versus-host disease in pediatric patients received allogeneic hematopoietic stem cell transplantation |
| title_full | Elevation of tacrolimus concentration after administration of methotrexate for treatment of graft-versus-host disease in pediatric patients received allogeneic hematopoietic stem cell transplantation |
| title_fullStr | Elevation of tacrolimus concentration after administration of methotrexate for treatment of graft-versus-host disease in pediatric patients received allogeneic hematopoietic stem cell transplantation |
| title_full_unstemmed | Elevation of tacrolimus concentration after administration of methotrexate for treatment of graft-versus-host disease in pediatric patients received allogeneic hematopoietic stem cell transplantation |
| title_short | Elevation of tacrolimus concentration after administration of methotrexate for treatment of graft-versus-host disease in pediatric patients received allogeneic hematopoietic stem cell transplantation |
| title_sort | elevation of tacrolimus concentration after administration of methotrexate for treatment of graft versus host disease in pediatric patients received allogeneic hematopoietic stem cell transplantation |
| topic | Tacrolimus Methotrexate Hematopoietic stem cell transplantation Therapeutic drug monitoring |
| url | https://doi.org/10.1186/s40780-023-00306-w |
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