Increased Exposure of Tacrolimus by Co-administered Mycophenolate Mofetil: Population Pharmacokinetic Analysis in Healthy Volunteers

Abstract The objective of the study was to investigate the pharmacokinetic drug-drug interactions between tacrolimus (TAC) and mycophenolate mofetil (MMF) in healthy Korean male volunteers. Seventeen volunteers participated in a three-period, single-dose, and fixed sequence study. They sequentially...

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Autores principales:	Jae Hyun Kim, Nayoung Han, Myeong Gyu Kim, Hwi-Yeol Yun, Sunhwa Lee, Eunjin Bae, Yon Su Kim, In-Wha Kim, Jung Mi Oh
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/095381bc52c44e56b97e82c0b8187741
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spelling	oai:doaj.org-article:095381bc52c44e56b97e82c0b81877412021-12-02T15:07:56ZIncreased Exposure of Tacrolimus by Co-administered Mycophenolate Mofetil: Population Pharmacokinetic Analysis in Healthy Volunteers10.1038/s41598-018-20071-32045-2322https://doaj.org/article/095381bc52c44e56b97e82c0b81877412018-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-20071-3https://doaj.org/toc/2045-2322Abstract The objective of the study was to investigate the pharmacokinetic drug-drug interactions between tacrolimus (TAC) and mycophenolate mofetil (MMF) in healthy Korean male volunteers. Seventeen volunteers participated in a three-period, single-dose, and fixed sequence study. They sequentially received MMF, TAC, and the combination. Concentrations of TAC, mycophenolic acid (MPA), and its metabolites MPA 7-O-glucuronide and MPA acyl glucuronide were measured. The variants of CYP3A4, CYP3A5, SLCO1B1, SLCO1B3, ABCC2, UGT1A9, and UGT2B7 were genotyped. Drug interaction was evaluated with a non-compartmental analysis and population pharmacokinetic modelling to quantify the interaction effect. A total of 1,082 concentrations of those analytes were analysed. AUC0-inf of TAC increased by 22.1% (322.4 ± 174.1 to 393.6 ± 121.7 ng·h/mL; P < 0.05) when co-administered with MMF, whereas the pharmacokinetic parameters of MPA and its metabolites were not changed by TAC. Apparent clearance (CL/F) of TAC was 17.8 L/h [relative standard error (RSE) 11%] or 13.8 L/h (RSE 11%) without or with MMF, respectively. Interaction was explained by the exponential model. The CYP3A5 genotype was the only significant covariate. The population estimate of CL/F of TAC was 1.48-fold (RSE 16%) in CYP3A5 expressers when compared to nonexpressers. CL/F of TAC was decreased when co-administered with MMF in these subjects.Jae Hyun KimNayoung HanMyeong Gyu KimHwi-Yeol YunSunhwa LeeEunjin BaeYon Su KimIn-Wha KimJung Mi OhNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-9 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jae Hyun Kim Nayoung Han Myeong Gyu Kim Hwi-Yeol Yun Sunhwa Lee Eunjin Bae Yon Su Kim In-Wha Kim Jung Mi Oh Increased Exposure of Tacrolimus by Co-administered Mycophenolate Mofetil: Population Pharmacokinetic Analysis in Healthy Volunteers
description	Abstract The objective of the study was to investigate the pharmacokinetic drug-drug interactions between tacrolimus (TAC) and mycophenolate mofetil (MMF) in healthy Korean male volunteers. Seventeen volunteers participated in a three-period, single-dose, and fixed sequence study. They sequentially received MMF, TAC, and the combination. Concentrations of TAC, mycophenolic acid (MPA), and its metabolites MPA 7-O-glucuronide and MPA acyl glucuronide were measured. The variants of CYP3A4, CYP3A5, SLCO1B1, SLCO1B3, ABCC2, UGT1A9, and UGT2B7 were genotyped. Drug interaction was evaluated with a non-compartmental analysis and population pharmacokinetic modelling to quantify the interaction effect. A total of 1,082 concentrations of those analytes were analysed. AUC0-inf of TAC increased by 22.1% (322.4 ± 174.1 to 393.6 ± 121.7 ng·h/mL; P < 0.05) when co-administered with MMF, whereas the pharmacokinetic parameters of MPA and its metabolites were not changed by TAC. Apparent clearance (CL/F) of TAC was 17.8 L/h [relative standard error (RSE) 11%] or 13.8 L/h (RSE 11%) without or with MMF, respectively. Interaction was explained by the exponential model. The CYP3A5 genotype was the only significant covariate. The population estimate of CL/F of TAC was 1.48-fold (RSE 16%) in CYP3A5 expressers when compared to nonexpressers. CL/F of TAC was decreased when co-administered with MMF in these subjects.
format	article
author	Jae Hyun Kim Nayoung Han Myeong Gyu Kim Hwi-Yeol Yun Sunhwa Lee Eunjin Bae Yon Su Kim In-Wha Kim Jung Mi Oh
author_facet	Jae Hyun Kim Nayoung Han Myeong Gyu Kim Hwi-Yeol Yun Sunhwa Lee Eunjin Bae Yon Su Kim In-Wha Kim Jung Mi Oh
author_sort	Jae Hyun Kim
title	Increased Exposure of Tacrolimus by Co-administered Mycophenolate Mofetil: Population Pharmacokinetic Analysis in Healthy Volunteers
title_short	Increased Exposure of Tacrolimus by Co-administered Mycophenolate Mofetil: Population Pharmacokinetic Analysis in Healthy Volunteers
title_full	Increased Exposure of Tacrolimus by Co-administered Mycophenolate Mofetil: Population Pharmacokinetic Analysis in Healthy Volunteers
title_fullStr	Increased Exposure of Tacrolimus by Co-administered Mycophenolate Mofetil: Population Pharmacokinetic Analysis in Healthy Volunteers
title_full_unstemmed	Increased Exposure of Tacrolimus by Co-administered Mycophenolate Mofetil: Population Pharmacokinetic Analysis in Healthy Volunteers
title_sort	increased exposure of tacrolimus by co-administered mycophenolate mofetil: population pharmacokinetic analysis in healthy volunteers
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/095381bc52c44e56b97e82c0b8187741
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Increased Exposure of Tacrolimus by Co-administered Mycophenolate Mofetil: Population Pharmacokinetic Analysis in Healthy Volunteers

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