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

Jae Hyun Kim, Nayoung Han, Myeong Gyu Kim, Hwi Yeol Yun, Sunhwa Lee, Eunjin Bae, Yon Su Kim, In Wha Kim, Jung Mi Oh

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27 Scopus citations


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.

Original languageEnglish
Article number1687
JournalScientific Reports
Issue number1
StatePublished - 1 Dec 2018

Bibliographical note

Funding Information:
This research was supported by a grant (15182MFDS504) from Ministry of Food and Drug Safety in 2015, National Research Foundation of Korea (NRF-2014M3C1B3064644) and the 2017 Brain Korea (BK) 21 Plus. The authors would like to thank to H.A.J. for her contribution with regard to conduct of clinical trial.

Publisher Copyright:
© 2018 The Author(s).


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