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Limited Sampling Strategy for Estimation of Mycophenolic Acid Exposure in Adult Chinese Heart Transplant Recipients

Background: With the increasing use of mycophenolic acid (MPA) formulations in organ transplantation, the need for personalized immunosuppressive therapy has become well recognized based on therapeutic drug monitoring (TDM) for avoidance of drug-related toxicity while maintaining efficacy. Few studi...

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Autores principales: Xiang, Hongping, Zhou, Hong, Zhang, Jing, Sun, Yongfeng, Wang, Yirong, Han, Yong, Cai, Jie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072337/
https://www.ncbi.nlm.nih.gov/pubmed/33912061
http://dx.doi.org/10.3389/fphar.2021.652333
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author Xiang, Hongping
Zhou, Hong
Zhang, Jing
Sun, Yongfeng
Wang, Yirong
Han, Yong
Cai, Jie
author_facet Xiang, Hongping
Zhou, Hong
Zhang, Jing
Sun, Yongfeng
Wang, Yirong
Han, Yong
Cai, Jie
author_sort Xiang, Hongping
collection PubMed
description Background: With the increasing use of mycophenolic acid (MPA) formulations in organ transplantation, the need for personalized immunosuppressive therapy has become well recognized based on therapeutic drug monitoring (TDM) for avoidance of drug-related toxicity while maintaining efficacy. Few studies have assessed area under the 12 h concentration-time curve of MPA (MPA-AUC(0–12h)) in heart transplant recipients who received mycophenolate mofetil (MMF) dispersible tablets (MMFdt). The aim of the study was to investigate the pharmacokinetics (PK) of MMFdt combined with tacrolimus and further to develop a practical method for estimation of MPA-AUC(0–12h) using a limited sampling strategy (LSS). Methods: A prospective study in a single center was performed in patients who continuously administrated with MMFdt or MMF capsule (MMFc) for at least 7 days after cardiac transplantation from 2018 to 2020. A total of 48 Chinese adult heart transplant recipients were enrolled. Blood samples were collected before and 0.5, 1, 1.5, 2, 4, 6, 8, 10 and 12 h after MMF administration. The validated high-performance liquid chromatography combined with tandem mass spectrometry method was used to measure MPA concentrations. Non-compartmental pharmacokinetic (PK) analysis was applied to calculate the data obtained from individual recipients by WinNonlin. LSS models were developed for MPA-AUC(0–12h) prediction with multivariate stepwise regression analysis. Results: A large inter-individual variability was observed in AUC(0–12h), T(max), C(max), MRT(0–12h), t(1/2) and CL/F after multiple dosing of MMFdt. However, no significant differences were observed between main PK parameters of MMFdt and MMFc. The best estimation of MPA-AUC(0–12h) was achieved with four points: MPA-AUC(0–12h) = 8.424 + 0.781 × C(0.5) + 1.263 × C(2) + 1.660 × C(4) + 3.022 × C(6) (R (2) = 0.844). The mean prediction error (MPE) and mean absolute prediction error (MAPE) of MPA-AUC(0–12h) were 2.09 ± 14.05% and 11.17 ± 8.52%, respectively. Both internal and external validations showed good applicability for four-point LSS equation. Conclusion: The results provide strong evidence for the use of LSS model other than a single time-point concentration of MPA when performing TDM. A four-point LSS equation using the concentrations at 0.5, 2, 4, 6 h is recommended to estimate MPA-AUC(0–12h) during early period after transplantation in Chinese adult heart transplant recipients receiving MMFdt or MMFc. However, proper internal and external validations with more patients should be conducted in the future.
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spelling pubmed-80723372021-04-27 Limited Sampling Strategy for Estimation of Mycophenolic Acid Exposure in Adult Chinese Heart Transplant Recipients Xiang, Hongping Zhou, Hong Zhang, Jing Sun, Yongfeng Wang, Yirong Han, Yong Cai, Jie Front Pharmacol Pharmacology Background: With the increasing use of mycophenolic acid (MPA) formulations in organ transplantation, the need for personalized immunosuppressive therapy has become well recognized based on therapeutic drug monitoring (TDM) for avoidance of drug-related toxicity while maintaining efficacy. Few studies have assessed area under the 12 h concentration-time curve of MPA (MPA-AUC(0–12h)) in heart transplant recipients who received mycophenolate mofetil (MMF) dispersible tablets (MMFdt). The aim of the study was to investigate the pharmacokinetics (PK) of MMFdt combined with tacrolimus and further to develop a practical method for estimation of MPA-AUC(0–12h) using a limited sampling strategy (LSS). Methods: A prospective study in a single center was performed in patients who continuously administrated with MMFdt or MMF capsule (MMFc) for at least 7 days after cardiac transplantation from 2018 to 2020. A total of 48 Chinese adult heart transplant recipients were enrolled. Blood samples were collected before and 0.5, 1, 1.5, 2, 4, 6, 8, 10 and 12 h after MMF administration. The validated high-performance liquid chromatography combined with tandem mass spectrometry method was used to measure MPA concentrations. Non-compartmental pharmacokinetic (PK) analysis was applied to calculate the data obtained from individual recipients by WinNonlin. LSS models were developed for MPA-AUC(0–12h) prediction with multivariate stepwise regression analysis. Results: A large inter-individual variability was observed in AUC(0–12h), T(max), C(max), MRT(0–12h), t(1/2) and CL/F after multiple dosing of MMFdt. However, no significant differences were observed between main PK parameters of MMFdt and MMFc. The best estimation of MPA-AUC(0–12h) was achieved with four points: MPA-AUC(0–12h) = 8.424 + 0.781 × C(0.5) + 1.263 × C(2) + 1.660 × C(4) + 3.022 × C(6) (R (2) = 0.844). The mean prediction error (MPE) and mean absolute prediction error (MAPE) of MPA-AUC(0–12h) were 2.09 ± 14.05% and 11.17 ± 8.52%, respectively. Both internal and external validations showed good applicability for four-point LSS equation. Conclusion: The results provide strong evidence for the use of LSS model other than a single time-point concentration of MPA when performing TDM. A four-point LSS equation using the concentrations at 0.5, 2, 4, 6 h is recommended to estimate MPA-AUC(0–12h) during early period after transplantation in Chinese adult heart transplant recipients receiving MMFdt or MMFc. However, proper internal and external validations with more patients should be conducted in the future. Frontiers Media S.A. 2021-04-12 /pmc/articles/PMC8072337/ /pubmed/33912061 http://dx.doi.org/10.3389/fphar.2021.652333 Text en Copyright © 2021 Xiang, Zhou, Zhang, Sun, Wang, Han and Cai. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Xiang, Hongping
Zhou, Hong
Zhang, Jing
Sun, Yongfeng
Wang, Yirong
Han, Yong
Cai, Jie
Limited Sampling Strategy for Estimation of Mycophenolic Acid Exposure in Adult Chinese Heart Transplant Recipients
title Limited Sampling Strategy for Estimation of Mycophenolic Acid Exposure in Adult Chinese Heart Transplant Recipients
title_full Limited Sampling Strategy for Estimation of Mycophenolic Acid Exposure in Adult Chinese Heart Transplant Recipients
title_fullStr Limited Sampling Strategy for Estimation of Mycophenolic Acid Exposure in Adult Chinese Heart Transplant Recipients
title_full_unstemmed Limited Sampling Strategy for Estimation of Mycophenolic Acid Exposure in Adult Chinese Heart Transplant Recipients
title_short Limited Sampling Strategy for Estimation of Mycophenolic Acid Exposure in Adult Chinese Heart Transplant Recipients
title_sort limited sampling strategy for estimation of mycophenolic acid exposure in adult chinese heart transplant recipients
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072337/
https://www.ncbi.nlm.nih.gov/pubmed/33912061
http://dx.doi.org/10.3389/fphar.2021.652333
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