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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Nature Portfolio
2018-01-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-018-20071-3 |
| _version_ | 1818344053725462528 |
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| 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 |
| collection | DOAJ |
| 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. |
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| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-13T16:40:22Z |
| publishDate | 2018-01-01 |
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| series | Scientific Reports |
| spelling | doaj.art-095381bc52c44e56b97e82c0b81877412022-12-21T23:38:18ZengNature PortfolioScientific Reports2045-23222018-01-01811910.1038/s41598-018-20071-3Increased Exposure of Tacrolimus by Co-administered Mycophenolate Mofetil: Population Pharmacokinetic Analysis in Healthy VolunteersJae Hyun Kim0Nayoung Han1Myeong Gyu Kim2Hwi-Yeol Yun3Sunhwa Lee4Eunjin Bae5Yon Su Kim6In-Wha Kim7Jung Mi Oh8College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National UniversityCollege of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National UniversityCollege of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National UniversityCollege of Pharmacy, Chungnam National UniversityDepartment of Biomedical Sciences, Seoul National UniversityDepartment of Internal Medicine, Gyeongsang National University Changwon HospitalKidney Research Institute, Seoul National UniversityCollege of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National UniversityCollege of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National UniversityAbstract 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.https://doi.org/10.1038/s41598-018-20071-3 |
| spellingShingle | 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 Scientific Reports |
| title | 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_short | 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 |
| url | https://doi.org/10.1038/s41598-018-20071-3 |
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