TY - JOUR
T1 - Increased Exposure of Tacrolimus by Co-administered Mycophenolate Mofetil
T2 - Population Pharmacokinetic Analysis in Healthy Volunteers
AU - Kim, Jae Hyun
AU - Han, Nayoung
AU - Kim, Myeong Gyu
AU - Yun, Hwi Yeol
AU - Lee, Sunhwa
AU - Bae, Eunjin
AU - Kim, Yon Su
AU - Kim, In Wha
AU - Oh, Jung Mi
N1 - 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).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85041127904&partnerID=8YFLogxK
U2 - 10.1038/s41598-018-20071-3
DO - 10.1038/s41598-018-20071-3
M3 - Article
C2 - 29374217
AN - SCOPUS:85041127904
SN - 2045-2322
VL - 8
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 1687
ER -