Population modeling integrating pharmacokinetics, pharmacodynamics, pharmacogenetics, and clinical outcome in patients with sunitinib‐treated cancer

  • The tyrosine kinase inhibitor sunitinib is used as first‐line therapy in patients with metastasized renal cell carcinoma (mRCC), given in fixed‐dose regimens despite its high variability in pharmacokinetics (PKs). Interindividual variability of drug exposure may be responsible for differences in response. Therefore, dosing strategies based on pharmacokinetic/pharmacodynamic (PK/PD) models may be useful to optimize treatment. Plasma concentrations of sunitinib, its active metabolite SU12662, and the soluble vascular endothelial growth factor receptors sVEGFR‐2 and sVEGFR‐3, were measured in 26 patients with mRCC within the EuroTARGET project and 21 patients with metastasized colorectal cancer (mCRC) from the C‐II‐005 study. Based on these observations, PK/PD models with potential influence of genetic predictors were developed and linked to time‐to‐event (TTE) models. Baseline sVEGFR‐2 levels were associated with clinical outcome in patients with mRCC, whereas active drug PKs seemed to be more predictive in patients with mCRC. The models provide the basis of PK/PD‐guided strategies for the individualization of anti‐angiogenic therapies.
Author:Meta H. Diekstra, Achim Fritsch, Friederike Kanefendt, Jesse Joachim Swen, Dirk Jan A. R. Moes, Fritz Sörgel, Martina Kinzig, Christoph Stelzer, Daniel Schindele, Thomas Gauler, Stefan Hauser, Danny Houtsma, Max Roessler, Berta Moritz, Klaus Mross, Lothar Bergmann, Egbert Oosterwijk, Lambertus Adrianus Kiemeney, Henk-Jan Guchelaar, Ulrich Jaehde
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/28571114
Parent Title (English):CPT: pharmacometrics & systems pharmacology
Publisher:Nature Publ. Group
Place of publication:London
Document Type:Article
Year of Completion:2017
Date of first Publication:2017/06/01
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/05/29
Page Number:10
First Page:604
Last Page:613
© 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0