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Population Modeling Integrating Pharmacokinetics, Pharmacodynamics, Pharmacogenetics, and Clinical Outcome in

M H Diekstra1, A Fritsch2, F Kanefendt2

  • 1Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.

CPT: Pharmacometrics & Systems Pharmacology
|June 2, 2017
PubMed

Insights

Sunitinib dosing for metastatic renal cell carcinoma (mRCC) has high variability. Pharmacokinetic/pharmacodynamic (PK/PD) models and genetic predictors may personalize anti-angiogenic therapy for better patient outcomes.

Area of Science:

  • Oncology
  • Pharmacology
  • Translational Medicine

Background:

  • Sunitinib is a first-line tyrosine kinase inhibitor for metastatic renal cell carcinoma (mRCC).
  • Current fixed-dose regimens do not account for high interindividual variability in pharmacokinetics (PKs), potentially affecting treatment response.
  • Pharmacokinetic/pharmacodynamic (PK/PD) modeling offers a strategy to optimize sunitinib dosing.

Purpose of the Study:

  • To develop PK/PD models to guide sunitinib dosing for individualizing anti-angiogenic therapy.
  • To investigate the influence of genetic predictors on sunitinib's PK/PD profile and clinical outcomes.
  • To link PK/PD models with time-to-event (TTE) models for improved treatment strategies.

Main Methods:

  • Plasma concentrations of sunitinib, its active metabolite SU12662, and soluble vascular endothelial growth factor receptors (sVEGFR-2, sVEGFR-3) were measured.
  • PK/PD models were developed using data from mRCC and metastatic colorectal cancer (mCRC) patients.
  • Models were integrated with TTE analysis, considering potential genetic predictors.

Main Results:

  • Baseline sVEGFR-2 levels correlated with clinical outcomes in mRCC patients.
  • Active drug PKs appeared more predictive of outcomes in mCRC patients.
  • Developed PK/PD models provide a foundation for personalized anti-angiogenic therapy.

Conclusions:

  • PK/PD modeling and consideration of biomarkers like sVEGFR-2 can help optimize sunitinib therapy.
  • Individualized dosing strategies based on PK/PD models may improve treatment efficacy in mRCC and mCRC.
  • This approach supports the personalization of anti-angiogenic treatments in cancer therapy.

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