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

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 × e0.91 × NR1I2 × eηCL . 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.