Population Modeling Integrating Pharmacokinetics, Pharmacodynamics, Pharmacogenetics, and Clinical Outcome in Patients With Sunitinib-Treated Cancer

M. H. Diekstra, A. Fritsch, F. Kanefendt, J. J. Swen, D. J. A. R. Moes, F. Soergel, M. Kinzig, C. Stelzer, D. Schindele, T. Gauler, S. Hauser, D. Houtsma, M. Roessler, B. Moritz, K. Mross, L. Bergmann, E. Oosterwijk, L. A. Kiemeney, H. J. Guchelaar, U. Jaehde*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

14 Citations (Web of Science)

Abstract

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.

Original languageEnglish
Pages (from-to)604-613
Number of pages10
JournalCPT: Pharmacometrics and Systems Pharmacology
Volume6
Issue number9
DOIs
Publication statusPublished - Sep 2017

Keywords

  • RENAL-CELL CARCINOMA
  • ENDOTHELIAL GROWTH-FACTOR
  • SINGLE-NUCLEOTIDE POLYMORPHISMS
  • 1ST-LINE SUNITINIB
  • METABOLITE SU12662
  • HEALTHY-VOLUNTEERS
  • ACTIVE METABOLITE
  • INTERFERON-ALPHA
  • SU11248
  • BIOMARKER

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