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Sci Rep. 2018 Jan 26;8(1):1687. doi: 10.1038/s41598-018-20071-3.

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

Author information

1
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
2
College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
3
Department of Biomedical Sciences, Seoul National University, Seoul, Republic of Korea.
4
Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea.
5
Kidney Research Institute, Seoul National University, Seoul, Republic of Korea.
6
Department of Medical Science, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, Republic of Korea.
7
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea. jmoh@snu.ac.kr.

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.

PMID:
29374217
PMCID:
PMC5786104
DOI:
10.1038/s41598-018-20071-3
[Indexed for MEDLINE]
Free PMC Article

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