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Journal Article

Proteomics-informed prediction of rosuvastatin plasma profiles in patients with a wide range of body weight.

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Wiśniewski,  Jacek R.
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Fulltext (public)

cpt.2056.pdf
(Publisher version), 917KB

Supplementary Material (public)

cpt2056-sup-0001-supinfos1.xlsx
(Supplementary material), 13KB

cpt2056-sup-0002-supinfos2.pdf
(Supplementary material), 3MB

Citation

Wegler, C., Prieto Garcia, L., Klinting, S., Robertsen, I., Wiśniewski, J. R., Hjelmesaeth, J., et al. (2021). Proteomics-informed prediction of rosuvastatin plasma profiles in patients with a wide range of body weight. Clinical pharmacology and therapeutics. doi:10.1002/cpt.2056.


Cite as: http://hdl.handle.net/21.11116/0000-0007-DF8E-F
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 inter-individual 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 inter-individual 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 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 semi-mechanistic model with a bottom-up approach to predict the plasma concentration profiles of the single dose of rosuvastatin in each patient. The predicted pharmacokinetic parameters were evaluated against the measured in vivo plasma pharmacokinetics from the same 54 patients. The developed model predicted the rosuvastatin pharmacokinetics within two-fold error for rosuvastatin AUC (78% of the patients; AFE: 0.96), Cmax (76%; AFE: 1.05), and t1/2 (98%; AFE: 0.89), and captured differences in the rosuvastatin pharmacokinetics 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. This article is protected by copyright. All rights reserved.