RESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Indóis/farmacologia , Indóis/farmacocinética , Modelos Biológicos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Pirróis/farmacologia , Pirróis/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Neoplasias Colorretais/sangue , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Citocromo P-450 CYP3A/genética , Feminino , Genótipo , Humanos , Indóis/sangue , Indóis/uso terapêutico , Interleucina-8/genética , Neoplasias Renais/sangue , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/uso terapêutico , Pirróis/sangue , Pirróis/uso terapêutico , Sunitinibe , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/sangue , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genéticaAssuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais/tratamento farmacológico , Indóis/uso terapêutico , Pirróis/uso terapêutico , Adulto , Idoso , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Sunitinibe , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/análise , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/análiseAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Indóis/uso terapêutico , Neoplasias Hepáticas/secundário , Pirróis/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/análise , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Neoplasias Colorretais/patologia , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Indóis/administração & dosagem , Indóis/farmacocinética , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Imageamento por Ressonância Magnética , Pirróis/administração & dosagem , Pirróis/farmacocinética , SunitinibeRESUMO
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.
