Estimation of Mycophenolic Acid Exposure in Heart Transplant Recipients by Population Pharmacokinetic and Limited Sampling Strategies

Purpose: The aim of this study is i) to establish a strategy to estimate the area under the curve of the dosing interval (AUC0–12h) of mycophenolic acid (MPA) in the heart transplant recipients and ii) to find the covariates that significantly affect the pharmacokinetics of MPA exposure.Methods: Thi...

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Autores principales:	Xipei Wang, Yijin Wu, Jinsong Huang, Songgui Shan, Mingjie Mai, Jiade Zhu, Min Yang, Dewei Shang, Zheng Wu, Jinhua Lan, Shilong Zhong, Min Wu
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	heart transplantation enzyme multiplied immunoassay technique maximum a posteriori Bayesian estimation limited sampling strategy multilinear regression analysis population pharmacokinetics Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/0dc0b4ec8c2c4af6b69ac97df6a4e9d4
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spelling	oai:doaj.org-article:0dc0b4ec8c2c4af6b69ac97df6a4e9d42021-11-19T07:55:17ZEstimation of Mycophenolic Acid Exposure in Heart Transplant Recipients by Population Pharmacokinetic and Limited Sampling Strategies1663-981210.3389/fphar.2021.748609https://doaj.org/article/0dc0b4ec8c2c4af6b69ac97df6a4e9d42021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.748609/fullhttps://doaj.org/toc/1663-9812Purpose: The aim of this study is i) to establish a strategy to estimate the area under the curve of the dosing interval (AUC0–12h) of mycophenolic acid (MPA) in the heart transplant recipients and ii) to find the covariates that significantly affect the pharmacokinetics of MPA exposure.Methods: This single-center, prospective, open-label, observational study was conducted in 91 adult heart transplant recipients orally taking mycophenolate mofetil dispersible tablets. Samples collected intensively and sparsely were analyzed by the enzyme-multiplied immunoassay technique, and all the data were used in PPK modeling. Potential covariates were tested stepwise. The goodness-of-fit plots, the normalized prediction distribution error, and prediction-corrected visual predictive check were used for model evaluation. Optimal sampling times by ED-optimal strategy and multilinear regression (MLR) were analyzed based on the simulated data by the final PPK model. Moreover, using intensive data from 14 patients, the accuracy of AUC0–12h estimation was evaluated by Passing–Bablok regression analysis and Bland–Alman plots for both the PPK model and MLR equation.Results: A two-compartment model with first-order absorption and elimination with a lag time was chosen as the structure model. Co-medication of proton pump inhibitors (PPIs), estimated glomerular filtration rate (eGFR), and albumin (ALB) were found to significantly affect bioavailability (F), clearance of central compartment (CL/F), and the distribution volume of the central compartment (V2/F), respectively. Co-medication of PPIs decreased F by 27.6%. When eGFR decreased by 30 ml/min/1.73 m2, CL/F decreased by 23.7%. However, the impact of ALB on V2/F was limited to MPA exposure. The final model showed an adequate fitness of the data. The optimal sampling design was pre-dose and 1 and 4 h post-dose for pharmacokinetic estimation. The best-fit linear equation was finally established as follows: AUC0–12h = 3.539 × C0 + 0.288 × C0.5 + 1.349 × C1 + 6.773 × C4.5.Conclusion: A PPK model was established with three covariates in heart transplant patients. Co-medication of PPIs and eGFR had a remarkable impact on AUC0–12h of MPA. A linear equation was also concluded with four time points as an alternative way to estimate AUC0–12h for MPA.Xipei WangXipei WangYijin WuJinsong HuangSonggui ShanMingjie MaiJiade ZhuMin YangDewei ShangZheng WuJinhua LanShilong ZhongShilong ZhongMin WuFrontiers Media S.A.articleheart transplantationenzyme multiplied immunoassay techniquemaximum a posteriori Bayesian estimationlimited sampling strategymultilinear regression analysispopulation pharmacokineticsTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	heart transplantation enzyme multiplied immunoassay technique maximum a posteriori Bayesian estimation limited sampling strategy multilinear regression analysis population pharmacokinetics Therapeutics. Pharmacology RM1-950
spellingShingle	heart transplantation enzyme multiplied immunoassay technique maximum a posteriori Bayesian estimation limited sampling strategy multilinear regression analysis population pharmacokinetics Therapeutics. Pharmacology RM1-950 Xipei Wang Xipei Wang Yijin Wu Jinsong Huang Songgui Shan Mingjie Mai Jiade Zhu Min Yang Dewei Shang Zheng Wu Jinhua Lan Shilong Zhong Shilong Zhong Min Wu Estimation of Mycophenolic Acid Exposure in Heart Transplant Recipients by Population Pharmacokinetic and Limited Sampling Strategies
description	Purpose: The aim of this study is i) to establish a strategy to estimate the area under the curve of the dosing interval (AUC0–12h) of mycophenolic acid (MPA) in the heart transplant recipients and ii) to find the covariates that significantly affect the pharmacokinetics of MPA exposure.Methods: This single-center, prospective, open-label, observational study was conducted in 91 adult heart transplant recipients orally taking mycophenolate mofetil dispersible tablets. Samples collected intensively and sparsely were analyzed by the enzyme-multiplied immunoassay technique, and all the data were used in PPK modeling. Potential covariates were tested stepwise. The goodness-of-fit plots, the normalized prediction distribution error, and prediction-corrected visual predictive check were used for model evaluation. Optimal sampling times by ED-optimal strategy and multilinear regression (MLR) were analyzed based on the simulated data by the final PPK model. Moreover, using intensive data from 14 patients, the accuracy of AUC0–12h estimation was evaluated by Passing–Bablok regression analysis and Bland–Alman plots for both the PPK model and MLR equation.Results: A two-compartment model with first-order absorption and elimination with a lag time was chosen as the structure model. Co-medication of proton pump inhibitors (PPIs), estimated glomerular filtration rate (eGFR), and albumin (ALB) were found to significantly affect bioavailability (F), clearance of central compartment (CL/F), and the distribution volume of the central compartment (V2/F), respectively. Co-medication of PPIs decreased F by 27.6%. When eGFR decreased by 30 ml/min/1.73 m2, CL/F decreased by 23.7%. However, the impact of ALB on V2/F was limited to MPA exposure. The final model showed an adequate fitness of the data. The optimal sampling design was pre-dose and 1 and 4 h post-dose for pharmacokinetic estimation. The best-fit linear equation was finally established as follows: AUC0–12h = 3.539 × C0 + 0.288 × C0.5 + 1.349 × C1 + 6.773 × C4.5.Conclusion: A PPK model was established with three covariates in heart transplant patients. Co-medication of PPIs and eGFR had a remarkable impact on AUC0–12h of MPA. A linear equation was also concluded with four time points as an alternative way to estimate AUC0–12h for MPA.
format	article
author	Xipei Wang Xipei Wang Yijin Wu Jinsong Huang Songgui Shan Mingjie Mai Jiade Zhu Min Yang Dewei Shang Zheng Wu Jinhua Lan Shilong Zhong Shilong Zhong Min Wu
author_facet	Xipei Wang Xipei Wang Yijin Wu Jinsong Huang Songgui Shan Mingjie Mai Jiade Zhu Min Yang Dewei Shang Zheng Wu Jinhua Lan Shilong Zhong Shilong Zhong Min Wu
author_sort	Xipei Wang
title	Estimation of Mycophenolic Acid Exposure in Heart Transplant Recipients by Population Pharmacokinetic and Limited Sampling Strategies
title_short	Estimation of Mycophenolic Acid Exposure in Heart Transplant Recipients by Population Pharmacokinetic and Limited Sampling Strategies
title_full	Estimation of Mycophenolic Acid Exposure in Heart Transplant Recipients by Population Pharmacokinetic and Limited Sampling Strategies
title_fullStr	Estimation of Mycophenolic Acid Exposure in Heart Transplant Recipients by Population Pharmacokinetic and Limited Sampling Strategies
title_full_unstemmed	Estimation of Mycophenolic Acid Exposure in Heart Transplant Recipients by Population Pharmacokinetic and Limited Sampling Strategies
title_sort	estimation of mycophenolic acid exposure in heart transplant recipients by population pharmacokinetic and limited sampling strategies
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/0dc0b4ec8c2c4af6b69ac97df6a4e9d4
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Estimation of Mycophenolic Acid Exposure in Heart Transplant Recipients by Population Pharmacokinetic and Limited Sampling Strategies

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