RESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Indoles/farmacología , Indoles/farmacocinética , Modelos Biológicos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/farmacocinética , Pirroles/farmacología , Pirroles/farmacocinética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/sangre , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/sangre , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Citocromo P-450 CYP3A/genética , Femenino , Genotipo , Humanos , Indoles/sangre , Indoles/uso terapéutico , Interleucina-8/genética , Neoplasias Renales/sangre , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirroles/sangre , Pirroles/uso terapéutico , Sunitinib , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangre , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 3 de Factores de Crecimiento Endotelial Vascular/sangre , Receptor 3 de Factores de Crecimiento Endotelial Vascular/genéticaAsunto(s)
Biomarcadores de Tumor/sangre , Neoplasias Colorrectales/tratamiento farmacológico , Indoles/uso terapéutico , Pirroles/uso terapéutico , Adulto , Anciano , Neoplasias Colorrectales/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Sunitinib , Factor A de Crecimiento Endotelial Vascular/sangre , Receptor 2 de Factores de Crecimiento Endotelial Vascular/análisis , Receptor 3 de Factores de Crecimiento Endotelial Vascular/análisisAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Indoles/uso terapéutico , Neoplasias Hepáticas/secundario , Pirroles/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/análisis , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Neoplasias Colorrectales/patología , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Humanos , Indoles/administración & dosificación , Indoles/farmacocinética , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Imagen por Resonancia Magnética , Pirroles/administración & dosificación , Pirroles/farmacocinética , SunitinibRESUMEN
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.