Abstract
The tyrosine kinase inhibitor sunitinib is used as first-line therapy in patients with metastasized renal cell carcinoma (mRC given in fixed-dose regimens despite its high variability in pharmacokinetics (PKs). Interindividual variability of drug expos may be responsible for differences in response. Therefore, dosing strategies based on pharmacokinetic/pharmacodyna (PK/PD) models may be useful to optimize treatment. Plasma concentrations of sunitinib, its active metabolite SU12662, a the soluble vascular endothelial growth factor receptors sVEGFR-2 and sVEGFR-3, were measured in 26 patients with mR within the EuroTARGET project and 21 patients with metastasized colorectal cancer (mCRC) from the C-II-005 study. Based these observations, PK/PD models with potential influence of genetic predictors were developed and linked to time-to-ev (TTE) models. Baseline sVEGFR-2 levels were associated with clinical outcome in patients with mRCC, whereas active d PKs seemed to be more predictive in patients with mCRC. The models provide the basis of PK/PD-guided strategies for individualization of anti-angiogenic therapies.
Original language | English |
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Pages (from-to) | 604-613 |
Number of pages | 10 |
Journal | CPT: Pharmacometrics and Systems Pharmacology |
Volume | 6 |
Issue number | 9 |
DOIs | |
Publication status | Published - Sept 2017 |
Externally published | Yes |
Keywords
- ATP Binding Cassette Transporter, Subfamily B/genetics
- Adult
- Aged
- Aged, 80 and over
- Antineoplastic Agents/blood
- Carcinoma, Renal Cell/blood
- Colorectal Neoplasms/blood
- Cytochrome P-450 CYP3A/genetics
- Female
- Genotype
- Humans
- Indoles/blood
- Interleukin-8/genetics
- Kidney Neoplasms/blood
- Male
- Middle Aged
- Models, Biological
- Polymorphism, Single Nucleotide
- Protein Kinase Inhibitors/blood
- Pyrroles/blood
- Sunitinib
- Treatment Outcome
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor Receptor-2/blood
- Vascular Endothelial Growth Factor Receptor-3/blood