Proteomics-Informed Prediction Of Rosuvastatin Plasma Profiles In Patients With A Wide Range Of Body Weight

Rosuvastatin is a frequently used probe to study transporter-mediated hepatic uptake. Pharmacokinetic models have therefore been developed to predict transporter impact on rosuvastatin dispositionin vivo. However, the interindividual differences in transporter concentrations were not considered in these models, and the predicted transporter impact was compared with historicalin vivodata. In this study, we investigated the influence of interindividual transporter concentrations on the hepatic uptake clearance of rosuvastatin in 54 patients covering a wide range of body weight. The 54 patients were given an oral dose of rosuvastatin the day before undergoing gastric bypass or cholecystectomy, and pharmacokinetic (PK) parameters were established from each patient's individual time-concentration profiles. Liver biopsies were sampled from each patient and their individual hepatic transporter concentrations were quantified. We combined the transporter concentrations within vitrouptake kinetics determined in HEK293-transfected cells, and developed a semimechanistic model with a bottom-up approach to predict the plasma concentration profiles of the single dose of rosuvastatin in each patient. The predicted PK parameters were evaluated against the measuredin vivoplasma PKs from the same 54 patients. The developed model predicted the rosuvastatin PKs within two-fold error for rosuvastatin area under the plasma concentration versus time curve (AUC; 78% of the patients; average fold error (AFE): 0.96), peak plasma concentration (C-max; 76%; AFE: 1.05), and terminal half-life (t(1/2); 98%; AFE: 0.89), and captured differences in the rosuvastatin PKs in patients with theOATP1B1521T更多