1. Proteomics-Informed Prediction of Rosuvastatin Plasma Profiles in Patients With a Wide Range of Body Weight.
- Author
-
Wegler C, Prieto Garcia L, Klinting S, Robertsen I, Wiśniewski JR, Hjelmesaeth J, Åsberg A, Jansson-Löfmark R, Andersson TB, and Artursson P
- Subjects
- Administration, Oral, Adult, Female, HEK293 Cells, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacokinetics, Liver-Specific Organic Anion Transporter 1 genetics, Male, Middle Aged, Models, Biological, Pharmacogenomic Variants, Polymorphism, Single Nucleotide, Rosuvastatin Calcium administration & dosage, Rosuvastatin Calcium pharmacokinetics, Young Adult, Body Weight, Hydroxymethylglutaryl-CoA Reductase Inhibitors blood, Liver metabolism, Liver-Specific Organic Anion Transporter 1 metabolism, Proteomics, Rosuvastatin Calcium blood
- Abstract
Rosuvastatin is a frequently used probe to study transporter-mediated hepatic uptake. Pharmacokinetic models have therefore been developed to predict transporter impact on rosuvastatin disposition in vivo. However, the interindividual differences in transporter concentrations were not considered in these models, and the predicted transporter impact was compared with historical in vivo data. 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 with in vitro uptake 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 measured in vivo plasma 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 (t1/2 ; 98%; AFE: 0.89), and captured differences in the rosuvastatin PKs in patients with the OATP1B1 521T- Published
- 2021
- Full Text
- View/download PDF