LAUSR

AIMS To assess the appropriateness of the bodyweight or fixed dosing regimen, population pharmacokinetic (PopPK) model of kukoamine B has been built in sepsis patients. METHODS Plasma Concentrations of kukoamine B and the covariates information were from 30 sepsis patients assigned into 0.06 mg/kg, 0.12 mg/kg and 0.24 mg/kg groups in Phase IIa clinical trial. PopPK model was built using nonlinear mixed-effect (NLME) modelling approach. Based on the final model, PK profiles were respectively simulated for 500 times applying the bodyweight and renal function information of 12 sepsis patients from 0.24 mg/kg group on the bodyweight or the fixed dosing regimen. For each dosing regimen, PK profiles of 6000 virtual patients were obtained. Statistical analyses for Cmax and Cmin were performed. If the biases of Cmax and Cmin can all meet the criteria of ±15%, the fixed dosing regimen can substitute the bodyweight dosing regimen. RESULTS PopPK model was successfully developed by NLME approach. Bi-compartmental model was selected as the basic model. Renal function was identified as a statistically significant covariate about systemic clearance with OFV decreasing 8.6, resulting in a 5.2% decrease inter-individual variability (IIV) of systemic clearance. Body weight was not identified as a statistically significant covariate. Simulation results demonstrated two methods had a bias of 8.1% for Cmax , and 8.6% for Cmin . Furthermore, PK variability was lower on the fixed dosing regimen than the body weight regimen. CONCLUSIONS Based on simulation results, fixed dosing regimen was recommended in the following clinical trials.