Effects of Postoperative Day and NR1I2 on Tacrolimus Clearance in Chinese Liver Transplant Recipients—A Population Model Approach

Abstract

We aimed to explore the new biomarkers influencing tacrolimus in vivo behavior in Chinese liver transplant recipients. A total of 418 drug concentration samples of 41 liver transplant patients were collected for modeling. A population pharmacokinetic model was developed using the nonlinear mixed-effects modeling approach. The potential covariates, such as postoperative day (POD), age, body weight, hepatic and renal function, and recipient genetic polymorphisms (ABCB1, CYP3A4, CYP3A5, NR1I2) were evaluated using forward-inclusion and backward-elimination methods. A 1-compartment model was used describing the in vivo behavior of tacrolimus in liver transplant patients. The estimates of CL/F and V/F were 8.88 L/h and 495.82 L, respectively. Two covariates, POD and NR1I2 rs2276707 genotypes, were incorporated into the final population pharmacokinetic model, and they could significantly impact the CL/F: CL/F (L/h) = 8.88 × (POD/16) 0.18 × e 0.91 × NR1I2 × e ηCL . The model evaluation and validation indicated a stable and precise performance of the final model. The functional annotation using ENCODE data indicated that rs2276707 was located on the higher peak of the H3K4Me1 and H3K4Me3 histone marker. To our knowledge, this is the first report indicating NR1I2 rs2276707 genotypes is another biomarker impacting tacrolimus clearance in liver transplant recipients. The NR1I2 gene polymorphism may affect the in vivo behavior of tacrolimus by regulating gene expression.

Tacrolimus pharmacokinetics are influenced by CYP3A5, age, and concomitant fluconazole in pediatric kidney transplant patients

“…Another polymorphism is POR*28 , which was significantly associated with lower tacrolimus dose requirements and higher C 0 / D ratio in the first month post‐transplant 30,31,33 . Moreover, the gene NR1I2 has been shown to impact tacrolimus pharmacokinetics 32 . Variants in transporter genes ABCB1 and ABCC2 were associated with changes in tacrolimus pharmacokinetics in other studies 34,35,38 .…”

“…Many studies have identified genetic variants other than those in CYP3A5 that could affect the tacrolimus pharmacokinetics 30–36 . CYP3A4 is increasingly being recognized as having an influence on tacrolimus pharmacokinetics.…”

Performance assessment of medical service for organ transplant department based on diagnosis-related groups: A programme incorporating ischemia-free liver transplantation in China

“…For example, the median postoperative LOS after LT at Mayo Clinic Hospital Arizona was 6 days, while median postoperative LOS after LT at UF Health Shands Hospital was 14 days. Compared with that in the United States, For example, a retrospective study from Beijing suggested that the median postoperative LOS after LT was 16 days (41). In addition, a retrospective study from Shanghai suggested that the median postoperative LOS after pediatric living donor LT was 24 days (42).…”

“…Compared with that in the United States, the median postoperative LOS after LT in China was relatively longer. For example, a retrospective study from Beijing suggested that the median postoperative LOS after LT was 16 days ( 41 ). In addition, a retrospective study from Shanghai suggested that the median postoperative LOS after pediatric living donor LT was 24 days ( 42 ).…”

Early essential newborn care for cesarean section newborns in China: study protocol for a multi-centered randomized controlled trial

“…Deaths before 5 years of age have been estimated to 5.3 million globally in 2018, 47% of which occurred in the neonatal period (the first 28 days of life) [1]. In China, the neonatal mortality rate has been estimated at 4.5‰, accounting for nearly half of the under-five deaths [2]. To reduce preventable neonatal morbidity and mortality and improve women's and newborns' health, World Health Organization (WHO) and the United Nations Children's Fund (UNICEF) jointly developed the Action Plan for Healthy Newborn Infants in the Western Pacific Region (2014-2020) which focused on delivery of early essential newborn care (EENC) [3].…”