Proteomics‐Informed Prediction of Rosuvastatin Plasma Profiles in Patients With a Wide Range of Body Weight

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 twofold 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 the OATP1B1 521T<C polymorphism. This demonstrates that hepatic uptake clearance determined in transfected cell lines, together with proteomics scaling, provides a useful tool for prediction models, without the need for empirical scaling factors.

Short‐ and long‐term effects of body weight loss following calorie restriction and gastric bypass on CYP3A‐activity – a non‐randomized three‐armed controlled trial

“…Proteins were extracted from small intestinal and liver biopsies in an SDS‐containing (2% w/v) lysis buffer and quantified, as previously described. 30 , 31 Details are presented in the Supplement, in short, samples were processed with the multi‐enzyme digestion filter‐aided sample preparation (MED‐FASP) protocol, using LysC and trypsin. 32 Proteomics analysis was performed with Q Exactive HF or Q Exactive HF‐X mass spectrometer in data dependent mode.…”

Conditions for maintenance of hepatocyte differentiation and function in 3D cultures

“…However, the correlation between expression and function varies from one ADME protein to another. Differences in transcriptional regulation, access to co-factors such as NADPH, and expression and half-life of drug-metabolizing enzymes influence CYP metabolic activity, resulting in varying degrees of correlation ( Neve et al., 2013 ; Wegler et al., 2021 ).…”

A Tribute to Professor Per Artursson - Scientist, Explorer, Mentor, Innovator, and Giant in Pharmaceutical Research

“…65 Using transporter concentrations measured in tissues from each subject, the plasma concentration profiles of rosuvastatin were predicted without any arbitrary scaling factors. 66 This is an important step forward in the field of predictive pharmacokinetics, demonstrating that proteomic data can provide transparent models without the need for "black box fudge factors".…”