Tong Lu1,2, Xu Zhu1, Shansen Xu1, Mingming Zhao1, Xueshi Huang3, Zhanyou Wang4, Limei Zhao5,6. 1. Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, 110004, China. 2. School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China. 3. College of Life and Health Sciences, Northeastern University, Shenyang, 110169, China. 4. Institute of Health Sciences, Key Laboratory of Medical Cell Biology of Ministry of education, China Medical University, Shenyang, 110122, China. 5. Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, 110004, China. zhaolm@sj-hospital.org. 6. School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China. zhaolm@sj-hospital.org.
Abstract
PURPOSE: The objective of this study was to merge genetic and non-genetic factors of tacrolimus pharmacokinetics to establish a more stable population pharmacokinetic model for individualized dosage regimen in Chinese nephrotic syndrome patients. METHODS: Nephrotic syndrome patients (>16 years old) treated with tacrolimus were included in the study. The population pharmacokinetic approach was analyzed using NONMEM version 7.3.0 software. Monte Carlo simulations were performed to optimize the dosage according to the population pharmacokinetic parameters of tacrolimus. RESULTS: The mean apparent clearance (CL/F) of tacrolimus was 13.4 L/h, with an inter-individual variability of 22.4%. The CL/F of tacrolimus in Wuzhi tablets co-administration and CYP3A5 non-expresser groups were 19.3% and 19.1% lower than that of the non-Wuzhi tablets and CYP3A5 expresser groups, respectively. The NR1I2 rs2276707 TT variant carriers had 1.17-fold CL/F compared to the CC/CT variant carriers. Monte Carlo simulation showed that the nephrotic syndrome patients that were CYP3A5 non-expressers or co-administered Wuzhi tablets received 50% or 33.3% lower dose of tacrolimus to reach the target concentration. In contrast, the NR1I2 rs227707 TT genotype carriers were administered a 33.3% higher dose of tacrolimus than the NR1I2 rs227707 CC/CT genotype carriers. CONCLUSIONS: A new population pharmacokinetic model was established to describe the pharmacokinetics of tacrolimus in nephrotic syndrome patients, which can be used to select rational dosage regimens to achieve a desirable whole-blood concentration.
PURPOSE: The objective of this study was to merge genetic and non-genetic factors of tacrolimus pharmacokinetics to establish a more stable population pharmacokinetic model for individualized dosage regimen in Chinese nephrotic syndromepatients. METHODS:Nephrotic syndromepatients (>16 years old) treated with tacrolimus were included in the study. The population pharmacokinetic approach was analyzed using NONMEM version 7.3.0 software. Monte Carlo simulations were performed to optimize the dosage according to the population pharmacokinetic parameters of tacrolimus. RESULTS: The mean apparent clearance (CL/F) of tacrolimus was 13.4 L/h, with an inter-individual variability of 22.4%. The CL/F of tacrolimus in Wuzhi tablets co-administration and CYP3A5 non-expresser groups were 19.3% and 19.1% lower than that of the non-Wuzhi tablets and CYP3A5 expresser groups, respectively. The NR1I2rs2276707 TT variant carriers had 1.17-fold CL/F compared to the CC/CT variant carriers. Monte Carlo simulation showed that the nephrotic syndromepatients that were CYP3A5 non-expressers or co-administered Wuzhi tablets received 50% or 33.3% lower dose of tacrolimus to reach the target concentration. In contrast, the NR1I2rs227707 TT genotype carriers were administered a 33.3% higher dose of tacrolimus than the NR1I2rs227707 CC/CT genotype carriers. CONCLUSIONS: A new population pharmacokinetic model was established to describe the pharmacokinetics of tacrolimus in nephrotic syndromepatients, which can be used to select rational dosage regimens to achieve a desirable whole-blood concentration.
Entities:
Keywords:
dosage optimization; genetic polymorphisms; nephrotic syndrome; population pharmacokinetics; tacrolimus
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