Aim: The aim of this study was to establish a population pharmacokinetic (PPK) model for rivaroxaban in Chinese elderly patients with NVAF to evaluate precision dosing regimens and analyze hemorrhagic risk after rivaroxaban treatment. Method: A population pharmacokinetic model was developed using the nonlinear mixed-effects model (NONMEM). The plasma concentration of rivaroxaban was detected by UPLC-MS/MS method and the gene polymorphisms were detected by Sanger dideoxy DNA sequencing method. A Monte Carlo simulation was performed to evaluate various dosing schemes and different levels of covariates for the target range of therapeutic drug monitoring concentrations (Cmax,ss, Cmin,ss). Exposure of rivaroxaban was simulated and assessed in hemorrhagic risk evaluation. Results: Model-building dataset including 360 plasma concentrations from 180 Chinese elderly patients (median age 81year). A one-compartment population PK model with estimated glomerular filtration rate (eGFR), total bilirubin (TBIL) and ABCB1 rs1045642 as major covariates for apparent clearance were developed. The average probability of target attainment (PTA) of optimal dosing regimens with different covariates levels for targeted Cmax,ss and Cmin,ss were 29.35%-31.30% and 64.91%-65.80%, respectively. 10 mg of rivaroxaban in Chinese elderly patients with normal renal and liver function was appropriate. AUC24,ss was statistically significant associated with the increased risk of the bleeding events (OR 1.0006; 95%CL 1.0003-1.001; p<0.0001). Conclusion: Lower dose is recommended for older patients with renal impairment to avoid overexposure and bleeding events. The population pharmacokinetic model could inform individualized dosing for Chinese older NVAF patients with rivaroxaban anticoagulation therapy.

Aims: Imipenem is a widely used antibiotic for the treatment of critically ill patients with severe infections. Here, we present a translational pharmacokinetic/pharmacodynamic mathematical model to assess fT>MIC and evaluate the clinical outcomes of imipenem treatment in critically ill patients. Methods: Critically ill patients with severe infections were included in our study. Blood samples at different time points were collected after imipenem plasma concentration reached a steady state in vivo. A one-compartment model was used for pharmacokinetic profiles. PK/PD parameters were calculated separately with or without a mathematical model. Clinical results were mainly defined as the microbiological results. The resolution of fever and the decrease in PCT and WBC levels were also considered. Results: A total of 54 patients were enrolled in our study. The fT>MIC calculated by the mathematical model was 67.26±39.96%, and the fT>MIC was 73.75±23.11% without the model. The PK/PD parameters calculated between the two groups were not significantly different. Regarding clinical outcomes, 35 (64.3%) patients were defined as having clinical success. The fT>MIC was 83.33±12.90% in the clinical success group and 59.42±19.11% in the clinical failure group. The fT>MIC was significantly different between the two groups (p=0.022). Based on the regimens, the PCT level decreased to at least 20% of the peak level and the WBC level decreased during the first 3 days when patients’ fT>MIC was greater than 70%. Conclusion: The pharmacokinetic mathematical model may be used for PK/PD parameter evaluation. To treat critically ill patients, achieving fT>MIC greater than 70% may be necessary.