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.
Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Agents/pharmacokinetics , Indoles/pharmacology , Indoles/pharmacokinetics , Models, Biological , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/pharmacokinetics , Pyrroles/pharmacology , Pyrroles/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B/genetics , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/blood , 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/therapeutic use , Interleukin-8/genetics , Kidney Neoplasms/blood , Kidney Neoplasms/drug therapy , Kidney Neoplasms/genetics , Male , Middle Aged , Polymorphism, Single Nucleotide , Protein Kinase Inhibitors/blood , Protein Kinase Inhibitors/therapeutic use , Pyrroles/blood , 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/geneticsSubject(s)
Biomarkers, Tumor/blood , Colorectal Neoplasms/drug therapy , Indoles/therapeutic use , Pyrroles/therapeutic use , Adult , Aged , Colorectal Neoplasms/pathology , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Sunitinib , Vascular Endothelial Growth Factor A/blood , Vascular Endothelial Growth Factor Receptor-2/analysis , Vascular Endothelial Growth Factor Receptor-3/analysisSubject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Indoles/therapeutic use , Liver Neoplasms/secondary , Pyrroles/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers, Tumor/analysis , Camptothecin/adverse effects , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Colorectal Neoplasms/pathology , Fluorouracil/adverse effects , Fluorouracil/therapeutic use , Humans , Indoles/administration & dosage , Indoles/pharmacokinetics , Leucovorin/adverse effects , Leucovorin/therapeutic use , Magnetic Resonance Imaging , Pyrroles/administration & dosage , Pyrroles/pharmacokinetics , SunitinibABSTRACT
A pharmacokinetic/pharmacodynamic (PK/PD) study of the tyrosine kinase inhibitor sunitinib was conducted in 12 healthy volunteers using blood pressure and circulating biomarker levels as PD markers. Blood pressure was measured, and plasma concentration-time courses of sunitinib, its major metabolite SU12662, vascular endothelial growth factors VEGF-A and VEGF-C, and soluble VEGF receptor-2 (sVEGFR-2) were studied in healthy subjects receiving 50 mg of sunitinib orally for 3-5 consecutive days. Using NONMEM, PK/PD models were established that predicted changes (expressed as multiples relative to baseline values) in systolic blood pressure, diastolic blood pressure, VEGF-A level, and sVEGFR-2 level, of 1.10, 1.18, 2.24, and 0.76, respectively, for a typical subject after 4 weeks of treatment with 50 mg/day. Simulated blood pressure-time courses compare excellently with published data in patients, whereas changes in circulating biomarkers were greater in patients than simulations suggest for healthy subjects. In conclusion, the tumor-independent pharmacological response to sunitinib could be described by PK/PD models, thereby facilitating model-based investigations with antiangiogenic drugs, using blood pressure and circulating proteins as biomarkers.
