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; Djar Moes; F Sörgel; 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

doi:10.1002/psp4.12210

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

CPT Pharmacometrics Syst Pharmacol. 2017 Sep;6(9):604-613. doi: 10.1002/psp4.12210. Epub 2017 Jul 13.

Authors

M H Diekstra¹, A Fritsch², F Kanefendt², J J Swen¹, Djar Moes¹, F Sörgel³, M Kinzig³, C Stelzer³, D Schindele⁴, T Gauler⁵, S Hauser⁶, D Houtsma⁷, M Roessler⁸, B Moritz⁸, K Mross⁹, L Bergmann¹⁰, E Oosterwijk¹¹, L A Kiemeney¹², H J Guchelaar¹, U Jaehde²

Affiliations

¹ Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
² Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Bonn, Germany.
³ IBMP - Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany.
⁴ Department for Urology and Paediatric Urology, University of Magdeburg, Magdeburg, Germany.
⁵ West German Cancer Center, University Hospital Essen, Essen, Germany.
⁶ Department of Urology, University Hospital Bonn, Bonn, Germany.
⁷ Haga Hospital, Den Haag, The Netherlands.
⁸ CESAR Central Office, Vienna, Austria.
⁹ Department of Medical Oncology, Tumor Biology Center Freiburg, Freiburg, Germany.
¹⁰ Cancer-Center Rhein-Main, University Hospital Frankfurt, Frankfurt, Germany.
¹¹ Department of Urology, Radboud University Nijmegen, Nijmegen, The Netherlands.
¹² Department of Epidemiology and Biostatistics, Radboud University Nijmegen, Nijmegen, The Netherlands.

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.

Publication types

Clinical Trial, Phase IV
Multicenter Study

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / genetics
Adult
Aged
Aged, 80 and over
Antineoplastic Agents / blood
Antineoplastic Agents / pharmacokinetics*
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Carcinoma, Renal Cell / blood
Carcinoma, Renal Cell / drug therapy
Carcinoma, Renal Cell / genetics
Colorectal Neoplasms / blood
Colorectal Neoplasms / drug therapy
Colorectal Neoplasms / genetics
Cytochrome P-450 CYP3A / genetics
Female
Genotype
Humans
Indoles / blood
Indoles / pharmacokinetics*
Indoles / pharmacology*
Indoles / therapeutic use
Interleukin-8 / genetics
Kidney Neoplasms / blood
Kidney Neoplasms / drug therapy
Kidney Neoplasms / genetics
Male
Middle Aged
Models, Biological*
Polymorphism, Single Nucleotide
Protein Kinase Inhibitors / blood
Protein Kinase Inhibitors / pharmacokinetics*
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / therapeutic use
Pyrroles / blood
Pyrroles / pharmacokinetics*
Pyrroles / pharmacology*
Pyrroles / therapeutic use
Sunitinib
Treatment Outcome
Vascular Endothelial Growth Factor A / genetics
Vascular Endothelial Growth Factor Receptor-2 / blood
Vascular Endothelial Growth Factor Receptor-2 / genetics
Vascular Endothelial Growth Factor Receptor-3 / blood
Vascular Endothelial Growth Factor Receptor-3 / genetics

Substances

ABCB1 protein, human
ATP Binding Cassette Transporter, Subfamily B
Antineoplastic Agents
CXCL8 protein, human
Indoles
Interleukin-8
Protein Kinase Inhibitors
Pyrroles
SU 12662
VEGFA protein, human
Vascular Endothelial Growth Factor A
CYP3A5 protein, human
Cytochrome P-450 CYP3A
FLT4 protein, human
KDR protein, human
Vascular Endothelial Growth Factor Receptor-2
Vascular Endothelial Growth Factor Receptor-3
Sunitinib