RESUMEN
Sunitinib is an oral multi-targeted tyrosine kinase inhibitor approved for treating metastatic renal cell carcinoma. This study reports a specific and sensitive competitive enzyme-linked immunosorbent assay (ELISA) for the pharmacokinetic evaluation of sunitinib. Anti-sunitinib serum was obtained from mice by using N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (DFPC) as a hapten, which has the same substructure as sunitinib, in order to avoid the effects of structural changes in the geometrical isomers of sunitinib. Enzyme labeling of sunitinib with horseradish peroxidase was similarly performed using DFPC. Serum sunitinib concentrations below the limit of quantification of 0.52 ng/mL were reproducibly measurable. This ELISA was speciï¬c for sunitinib (Z- and E-isomers) and showed very low cross-reactivity (0.094%) with its major metabolite, N-desethyl sunitinib. Its analytical applicability was demonstrated by a kinetic study with human liver microsomes. In addition, the levels of sunitinib measured by ELISA in a kinetic study with human liver microsomes were comparable with those measured by HPLC, and there was a strong correlation between the values determined by both methods (y = 1.065x - 51.2, R2 = 0.9804). The developed ELISA provides for the specific and sensitive quantification of sunitinib without the influence of its major metabolite or light-induced geometric isomers. This ELISA will be a valuable tool in pharmacokinetic studies of sunitinib.
Asunto(s)
Monitoreo de Drogas/métodos , Sunitinib/análisis , Animales , Reacciones Cruzadas , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Isomerismo , Luz/efectos adversos , Límite de Detección , Ratones , Microsomas Hepáticos , Modelos Animales , Sunitinib/química , Sunitinib/farmacocinética , Sunitinib/efectos de la radiaciónRESUMEN
WHAT IS KNOWN AND OBJECTIVE: Sunitinib pharmacokinetics can be influenced by the physio-pathological conditions of individual patients. Therapeutic drug monitoring (TDM) helps to optimize efficacy and reduce the risk of adverse effects. We report on the use of Bayesian analysis to optimize sunitinib blood levels. CASE SUMMARY: We describe two patients with risk of sunitinib pharmacokinetic variability due to gastrectomy and ongoing haemodialysis, respectively. TDM and Bayesian estimation allowed maintaining their sunitinib pharmacokinetic profiles within the usual limits. WHAT IS NEW AND CONCLUSION: Our analysis showed that Bayesian analysis can be successfully applied for real-time TDM to optimize sunitinib blood levels in patients with major comorbidities.
Asunto(s)
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Monitoreo de Drogas/métodos , Neoplasias Renales/tratamiento farmacológico , Sunitinib/farmacocinética , Sunitinib/uso terapéutico , Factores de Edad , Anciano , Teorema de Bayes , Comorbilidad , Femenino , Gastrectomía , Humanos , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Diálisis RenalRESUMEN
BACKGROUND: Multi-targeted tyrosine kinase inhibitors (TKIs) are the standard of care for patients with advanced clear cell renal cell carcinoma (ccRCC). However, a significant number of ccRCC patients are primarily refractory to targeted therapeutics, showing neither disease stabilisation nor clinical benefits. METHODS: We used CRISPR/Cas9-based high-throughput loss of function (LOF) screening to identify cellular factors involved in the resistance to sunitinib. Next, we validated druggable molecular factors that are synthetically lethal with sunitinib treatment using cell and animal models of ccRCC. RESULTS: Our screening identified farnesyltransferase among the top hits contributing to sunitinib resistance in ccRCC. Combined treatment with farnesyltransferase inhibitor lonafarnib potently augmented the anti-tumour efficacy of sunitinib both in vitro and in vivo. CONCLUSION: CRISPR/Cas9 LOF screening presents a promising approach to identify and target cellular factors involved in the resistance to anti-cancer therapeutics.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Células Renales/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Farnesiltransferasa/antagonistas & inhibidores , Neoplasias Renales/tratamiento farmacológico , Piperidinas/farmacología , Piridinas/farmacología , Sunitinib/farmacología , Animales , Antineoplásicos/farmacocinética , Apoptosis , Sistemas CRISPR-Cas , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Fragmentación del ADN , Interacciones Farmacológicas , Quimioterapia Combinada , Inhibidores Enzimáticos/farmacología , Ensayos Analíticos de Alto Rendimiento , Humanos , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Lisosomas , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Terapia Molecular Dirigida , Trasplante de Neoplasias , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/farmacología , ARN Interferente Pequeño , Distribución Aleatoria , Sunitinib/farmacocinéticaRESUMEN
Tyrosine kinase inhibitors (TKI) are targeted anticancer drugs that have been successfully developed over the past 2 decades. To date, many of them (around 70%) require warnings for liver injury and five of them, including pazopanib and sunitinib, have Black Box Warning (BBW) labels. Although TKI-induced hepatotoxicity is the first cause of drug failures in clinical trials, BBW labels, and market withdrawals, the underlying mechanisms remain unclear. However, the recent discovery of new reactive metabolites (RM) with aldehyde structures during pazopanib and sunitinib metabolism offers new perspectives for investigating their involvement in the toxicity of these two TKI. These hard electrophiles have a high reactivity potential toward proteins and are thought to be responsible for cytochrome P450 inactivation, drug-drug interactions (DDI), and liver toxicity. We report here, for the first time, the presence of these aldehyde RM in human plasma samples obtained during drug monitoring. Docking experiments in the CYP3A4 active site were performed and showed that pazopanib and sunitinib fitting in the catalytic site are in accordance with their regioselective oxidation to aldehydes. They also suggested that aldehyde RM may react with lysine and arginine residues. Based on these results, we studied the reactivity of the aldehyde RM toward lysine and arginine residues as potential targets on the protein framework to better understand how these RM could be involved in liver toxicity and drug-drug interactions. Adduct formation with different hepatic and plasma proteins was investigated by LC-MS/MS, and adducts between pazopanib or sunitinib aldehyde derivatives and lysine residues on both CYP3A4 and plasma proteins were indeed shown for the first time.
Asunto(s)
Aldehídos/metabolismo , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/farmacocinética , Sulfonamidas/farmacocinética , Sunitinib/farmacocinética , Aldehídos/sangre , Inhibidores de la Angiogénesis/efectos adversos , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Interacciones Farmacológicas , Humanos , Indazoles , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/efectos adversos , Proteínas Recombinantes/metabolismo , Albúmina Sérica Humana/metabolismo , Sulfonamidas/efectos adversos , Sunitinib/efectos adversosRESUMEN
BACKGROUND: Sunitinib is an inhibitor of multiple receptor tyrosine kinases and is a standard-of-care treatment for advanced and metastatic renal cell carcinoma and a second-line treatment in locally advanced inoperable and metastatic gastrointestinal stromal tumors. A fixed dose of the drug, however, does not produce a uniform therapeutic outcome in all patients, and many face adverse effects and/or toxicity. One of the possible causes of the interindividual variability in the efficacy and toxicity response is the highly variable systemic exposure to sunitinib and its active metabolite. This review aims to summarize all available clinical evidence of the treatment of adult patients using sunitinib in approved indications, addressing the necessity to introduce proper and robust therapeutic drug monitoring (TDM) of sunitinib and its major metabolite, N-desethylsunitinib. METHODS: The authors performed a systematic search of the available scientific literature using the PubMed online database. The search terms were "sunitinib" AND "therapeutic drug monitoring" OR "TDM" OR "plasma levels" OR "concentration" OR "exposure." The search yielded 520 journal articles. In total, 447 publications were excluded because they lacked sufficient relevance to the reviewed topic. The remaining 73 articles were, together with currently valid guidelines, thoroughly reviewed. RESULTS: There is sufficient evidence confirming the concentration-efficacy and concentration-toxicity relationship in the indications of gastrointestinal stromal tumors and metastatic renal clear-cell carcinoma. For optimal therapeutic response, total (sunitinib + N-desethylsunitinib) trough levels of 50-100 ng/mL serve as a reasonable target therapeutic range. To avoid toxicity, the total trough levels should not exceed 100 ng/mL. CONCLUSIONS: According to the current evidence presented in this review, a TDM-guided dose modification of sunitinib in selected groups of patients could provide a better treatment outcome while simultaneously preventing sunitinib toxicity.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Gastrointestinales/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Sunitinib/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Carcinoma de Células Renales/patología , Esquema de Medicación , Cálculo de Dosificación de Drogas , Interacciones Farmacológicas , Monitoreo de Drogas , Neoplasias Gastrointestinales/patología , Tumores del Estroma Gastrointestinal/patología , Humanos , Neoplasias Renales/patología , Metástasis de la Neoplasia , Sunitinib/administración & dosificación , Sunitinib/efectos adversos , Sunitinib/farmacocinéticaRESUMEN
PURPOSE: Sunitinib and pazopanib, two tyrosine kinase inhibitors (TKI), may be targets of potential pharmacokinetic drug-drug interactions (P-PK-DDIs). While strong cytochrome P4503A (CYP3A4) inhibitors or inducers should cause a clinically relevant modification in plasma TKI concentrations, the effect of weak inhibitors is unknown. The objective of this study was to evaluate the association between weak P-PK-DDI and clinically relevant toxicity in real life. PATIENTS AND METHODS: This was a single-center retrospective study including patients treated with sunitinib or pazopanib for any malignancies, for whom a PK-DDI analysis was performed before starting TKI. The primary endpoint was the correlation between P-PK-DDIs and a dose decrease after 1 month of treatment. The secondary endpoint was the correlation between PK-DDIs and drug withdrawal due to toxicity. RESULTS: Seventy-six patients were assessed. A P-PK-DDI with weak CYP3A4 or P-gp inhibition was found in 14 patients. In patients with P-PK-DDI or without, the dose was reduced during the first month in 57.1% and 17.7% (p = 0.003) and the drug withdrawn in 42.8% and 11.3% (p = 0.011), respectively. In multivariate analysis, a significant correlation was found between P-PK-DDI (CYP3A4 and P-gp inhibitors) and dose reduction, and between drug withdrawal and PK-DDI (CYP3A4 inhibitors). CONCLUSION: P-PK-DDI was correlated with dose reduction and drug withdrawal due to toxicity. The causality of this relationship warrants to be assessed; therefore, therapeutic drug monitoring is necessary in patients treated with TKI.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Inhibidores del Citocromo P-450 CYP3A/toxicidad , Pirimidinas/toxicidad , Sulfonamidas/toxicidad , Sunitinib/toxicidad , Anciano , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Humanos , Indazoles , Masculino , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Estudios Retrospectivos , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinética , Sunitinib/administración & dosificación , Sunitinib/farmacocinéticaRESUMEN
AIM: Lenvatinib plus everolimus is approved for the treatment of advanced renal cell carcinoma (RCC) after one prior vascular endothelial growth factor-targeted therapy. Lenvatinib plus pembrolizumab demonstrated promising antitumor activity in a Phase I/II trial of RCC. METHODS: We describe the rationale and design of the CLEAR study, a three-arm Phase III trial comparing lenvatinib plus everolimus and lenvatinib plus pembrolizumab versus sunitinib monotherapy for first-line treatment of RCC. Eligible patients must have advanced clear cell RCC and must not have received any prior systemic anticancer therapy. The primary end point is progression-free survival; secondary end points include objective response rate, overall survival, safety, health-related quality of life and pharmacokinetics. Biomarker evaluations are included as exploratory end points.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/análisis , Carcinoma de Células Renales/tratamiento farmacológico , Ensayos Clínicos Fase III como Asunto , Neoplasias Renales/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Everolimus/farmacocinética , Everolimus/uso terapéutico , Femenino , Humanos , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Estudios Multicéntricos como Asunto , Compuestos de Fenilurea/farmacocinética , Compuestos de Fenilurea/uso terapéutico , Supervivencia sin Progresión , Calidad de Vida , Quinolinas/farmacocinética , Quinolinas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Sunitinib/farmacocinética , Sunitinib/uso terapéutico , Análisis de Supervivencia , Adulto JovenRESUMEN
BACKGROUND/AIMS: Angiogenesis is extensively developed in well-differentiated pancreatic neuroendocrine tumours (PanNET) where sunitinib was shown to prolong progression-free survival, leading to nationwide approval. However, clinical experience in patients with grade 3 gastroenteropancreatic neuroendocrine neoplasms (GEPNEN-G3) remains limited. This prospective phase II trial evaluated potential predictive biomarkers of sunitinib activity in patients with advanced GEPNEN-G3. METHODS: Sunitinib was given at a dose of 37.5 mg/day as a continuous daily dosing until progression or unacceptable toxicity. Evaluation of activity was based on RECIST1.1. Safety was evaluated according to NCI-CTCAE v4. Pharmacokinetics of sunitinib and its main active metabolite SU12662 were evaluated. All tumour samples were reviewed histologically for tumour differentiation. PDGFRß, carbonic anhydrase 9, Ki-67, VEGFR2, and p-AKT were quantified using immunohistochemistry and their expression correlated with response by RECIST1.1. RESULTS: Thirty-one patients were included and 26 had available histological tissue. Six and 20 patients presented well-differentiated tumours (NET-G3) and neuroendocrine carcinoma (NEC), respectively. Eighteen patients responded to sunitinib (4 experienced partial responses and 14 tumour stabilization). A high p-AKT expression correlated with lower response to sunitinib (OR 0.94, 95% CI 0.89-0.99, p = 0.04). Safety and PK exposure to sunitinib and SU12662 in these patients were consistent with that reported in PanNET. CONCLUSION: Sunitinib showed evidence of activity in patients with GEPNEN-G3 with expected toxicity profile. In the NET-G3 and NEC groups, 4/6 and 11/20 patients were responders, respectively. High p-AKT expression predicted a lower response to sunitinib. Our study allowed the identification of a potential biomarker of resistance/sensitivity to sunitinib in aggressive GEPNEN-G3.
Asunto(s)
Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/análisis , Neoplasias Intestinales/tratamiento farmacológico , Tumores Neuroendocrinos/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Sunitinib/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacocinética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteínas Proto-Oncogénicas c-akt/análisis , Sunitinib/farmacocinéticaRESUMEN
PURPOSE: During treatment with tyrosine kinase inhibitors, such as sunitinib, patients experience treatment and/or disease-related symptoms. Although application of patient-reported outcome measures (PROMs) enhances early recognition of symptoms, early clinical trials are focused on symptom severity objectified by the Common Terminology Criteria for Adverse Events (CTCAE) in order to evaluate drug safety and to determine a personalized and/or safe dosage range. To gain insight into patient-reported symptoms in addition to healthcare professional-reported adverse events (AEs), a substudy was conducted in an ongoing pharmacokinetic-guided sunitinib dosing study. METHODS: In patients for whom sunitinib was considered standard therapy or patients with advanced/metastatic tumors for whom no standard therapy was available, patient-reported symptoms and well-being besides healthcare professional-reported AEs were assessed. RESULTS: Twenty-nine patients were included for analysis. Over 50% of them experienced a decreased well-being, caused by symptoms of mild and moderate intensity. Compared to healthcare professionals, all measured symptoms, with the exception of fatigue and vomiting, were reported statistically significantly more often by patients. CONCLUSIONS: Application of PROMs in early clinical trials on personalized or individualized oral targeted anticancer agents is feasible and enhances early recognition of symptom burden due to multiple CTCAE grade 1-2 AEs, just as pro-active symptom management and effect evaluation of interventions performed. Application of PROMs in these trials might be clinically relevant in obtaining dose-limiting toxicities.
Asunto(s)
Medición de Resultados Informados por el Paciente , Medicina de Precisión/métodos , Sunitinib/uso terapéutico , Adulto , Anciano , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sunitinib/farmacocinéticaRESUMEN
INTRODUCTION: Hand foot skin reaction (HFSR) is a common dose-limiting adverse effect of multi kinase inhibitors (MKI) whose mechanism is not fully understood, and the prophylaxis is inadequate. OBJECTIVE: In this pilot study, a double-blind, randomized placebo-controlled trial was conducted to evaluate the effect of topical urea in secondary prevention of sunitinib-induced HFSR in renal cell cancer patients. METHODS: Out of 55 screened patients, 14 were randomized to receive topical urea or placebo for four weeks. The association of HFSR with drug levels of sunitinib and its metabolite (n-desethyl sunitinib), genetic polymorphism of VEGFR2 gene, quality of life (QOL) and biochemical markers was also assessed. RESULTS: The results showed that urea-based cream was not superior to placebo (P = .075). There was no change in the QOL in both the groups. Single nucleotide polymorphism was checked for two nucleotides rs1870377 and rs2305948 located in VEGFR2 gene on chromosome 4. SNP (variant T > A) at rs1870377 was associated with appearance of new HFSR as compared to the wild type, although the association was not statistically significant (OR 0.714). There was no statistically significant difference between mean plasma levels of sunitinib and N-desethyl sunitinib in urea arm as compared to placebo arm as compared to placebo. The best fit population pharmacokinetic model for sunitinib was one compartment model with first order absorption and linear elimination. The median (IQR) of population parameters calculated from the population pharmacokinetics model for Ka, V and Cl was 0.22 (0.21-0.24) h-1, 4.4 (4.09-4.47) L, 0.049 (0.042-0.12) L/hr, respectively. CONCLUSION: The study suggested that the urea-based cream was not superior to placebo in decreasing the appearance of new HFSR in renal cancer patients receiving 4:2 regimen of sunitinib.
Asunto(s)
Carcinoma de Células Renales , Síndrome Mano-Pie , Neoplasias Renales , Sunitinib , Urea , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Humanos , Sunitinib/administración & dosificación , Sunitinib/farmacocinética , Sunitinib/efectos adversos , Método Doble Ciego , Carcinoma de Células Renales/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Urea/análogos & derivados , Urea/farmacocinética , Urea/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Síndrome Mano-Pie/etiología , Síndrome Mano-Pie/prevención & control , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Proyectos Piloto , Anciano , Polimorfismo de Nucleótido Simple , Antineoplásicos/efectos adversos , Antineoplásicos/administración & dosificación , Calidad de Vida , Resultado del Tratamiento , Administración Tópica , Adulto , Indoles/administración & dosificación , Indoles/farmacocinética , Indoles/efectos adversosRESUMEN
Inter-individual variability in drug response pose significant challenges to treatment with tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC). TKIs meet traditional criteria for using therapeutic drug monitoring (TDM), but research is still limited. Understanding the role of TDM in individualizing treatment strategies could help optimize treatment. Here we review the state of knowledge of TDM for TKIs in mRCC treatment. A comprehensive literature review of original research studies focusing on TDM of TKIs in mRCC treatment, clinical in vivo studies reporting on pharmacokinetics-pharmacodynamics, therapeutic ranges, drug concentrations, dose adjustments, clinical outcomes, or other relevant aspects related to TDM. We reviewed studies involving human subjects published in peer-reviewed journals. A narrative synthesis approach was employed to summarize the findings. Key themes and trends related to TDM of TKIs in mRCC treatment were identified and synthesized to provide a comprehensive overview of the current state of knowledge. Our search yielded 25 articles. Most were observational. The most consistently reported association between plasma concentration and effect was pazopanib Ctrough >20 µg/mL, but this concentration was not significant across all studies. We found inconsistent evidence for sunitinib and cabozantinib. For axitinib, we found a clear exposure-response relationship, but research was too diverse to conclude on a therapeutic window to use for TDM. We found much heterogeneity between recommended time of measurement (minimum plasma concentration [Cmin], maximal plasma concentration [Cmax], area under the curve [AUC]) and large variation in plasma concentration associated with clinical outcomes, which makes it difficult to recommend specific concentration intervals based on 1 or more of these measurements. Results were more consistent with TKIs continuously administered. Further research is needed to elucidate the long-term impact of TDM to possibly establish standardized therapeutic intervals. Prospective studies are suggested. The application of TDM in TKI-combination therapy is warranted in future research.
Asunto(s)
Carcinoma de Células Renales , Monitoreo de Drogas , Neoplasias Renales , Inhibidores de Proteínas Quinasas , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/secundario , Monitoreo de Drogas/métodos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Indazoles/uso terapéutico , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinética , Pirimidinas/uso terapéutico , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacocinética , Antineoplásicos/administración & dosificación , Axitinib/uso terapéutico , Axitinib/administración & dosificación , Axitinib/farmacocinética , Sunitinib/uso terapéutico , Sunitinib/farmacocinética , Sunitinib/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: Pazopanib and sunitinib are oral tyrosine kinase inhibitors (TKI) approved for the treatment of renal cell carcinoma. For both oncolytics, a clear target trough concentration level in plasma has been defined above which improved clinical efficacy can be expected. However, many factors can alter TKI exposure, including disease characteristics. CASE: A 79-year old male with metastatic papillary renal cell carcinoma and malignant ascites was treated with pazopanib. Initially, treatment with pazopanib at adequate trough concentrations resulted in regression of ascites. After a 6-month puncture-free interval, paracenteses were again required and the plasma trough concentration of pazopanib had decreased to 5 mg/L without any dose adjustments. Despite a dose increase, pazopanib levels remained subtherapeutic and could not prevent new paracenteses. Pazopanib concentrations in the drained ascites fluid were comparable to plasma concentrations and remained high also after treatment discontinuation. This observation suggests that the ascites compartment may act as a third space in which pazopanib accumulates. During subsequent treatment with sunitinib, a similar distribution over ascites fluid was observed. CONCLUSION: Presence of ascites or pleural effusion in patients treated with TKIs may lead to subtherapeutic plasma exposure, which may hamper treatment efficacy. Measuring TKIs plasma concentrations regularly during treatment is essential to identify patients with subtherapeutic exposure.
Asunto(s)
Ascitis/tratamiento farmacológico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacocinética , Anciano , Carcinoma de Células Renales/patología , Relación Dosis-Respuesta a Droga , Humanos , Indazoles/administración & dosificación , Indazoles/farmacocinética , Neoplasias Renales/patología , Masculino , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinética , Sunitinib/administración & dosificación , Sunitinib/farmacocinética , Resultado del TratamientoRESUMEN
BACKGROUND: Imatinib, sunitinib, and gefitinib are the three most common tyrosine kinase inhibitors (TKIs). However, their quantitative drug-drug interaction potentials In vivo and the relationship between their structure and inhibitory activity remain unknown. OBJECTIVE: This study aimed to investigate the potential drug-drug interaction risk of three TKIs based on CYP3A. METHODS: 6ß-Hydroxylated testosterone formation was selected to probe the CYP3A activity in human liver microsomes. A molecular docking simulation was performed to explore the potential structural alerts. RESULTS: Imatinib exhibited the strongest inhibitory effect towards CYP3A, while the inhibitory potential of gefitinib and sunitinib were comparable to each other but weaker than imatinib. IC50 shift assays demonstrated that the inhibitory potential of all three TKIs was significantly increased after a 30-min preincubation with NADPH. The KI and Kinact values of imatinib, sunitinib, and gefitinib were 3.75 µM and 0.055 min-1, 1.96 µM and 0.037 min-1, and 9.94 µM and 0.031 min-1, respectively. IVIVE results showed that there was a 1.3- to 43.1-fold increase in the AUC of CYP3A-metabolizing drugs in the presence of the TKIs. CONCLUSION: All three TKIs exhibited a typical irreversible inhibitory effect towards CYP3A. The presence of more N-heterocycles and the resulting better binding confirmation of imatinib may have been responsible for its stronger inhibitory effect than sunitinib and gefitinib. Therefore, caution should be taken when CYP3A-metabolizing drugs are co-administrated with imatinib, sunitinib, or gefitinib.
Asunto(s)
Citocromo P-450 CYP3A/metabolismo , Gefitinib/farmacocinética , Hidroxitestosteronas/farmacocinética , Mesilato de Imatinib/farmacocinética , Microsomas Hepáticos/metabolismo , Sunitinib/farmacocinética , Interacciones Farmacológicas , Humanos , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/farmacocinética , Relación Estructura-ActividadRESUMEN
PURPOSE: The starting dose of sunitinib in children with gastrointestinal stromal tumors (GIST) was extrapolated based on data in adults with GIST or solid tumors and children with solid tumors. METHODS: Integrated population pharmacokinetics (PK), PK/pharmacodynamics (PD), and exposure-response analyses using nonlinear mixed-effects modeling approaches were performed to extrapolate PK and PD of sunitinib in children with GIST at projected dose(s) with plasma drug exposures comparable to 50-mg/day in adults with GIST. The analysis datasets included PK/PD data in adults with GIST and adults and children with solid tumors. The effect of covariates on PK and safety/efficacy endpoints were explored. RESULTS: Two-compartment models with lag time were successfully used to describe the PK of sunitinib and its active metabolite SU012662. PK/PD models were successfully built to describe key continuous safety and efficacy endpoints. The effect of age on sunitinib apparent clearance (CL/F) and body surface area on SU012662 CL/F was statistically significant (P ≤ 0.001): children who were younger or of smaller body size had lower CL/F; however, age and body size did not appear to negatively affect safety or efficacy response to plasma drug exposure. CONCLUSION: Based on PK, safety, and efficacy trial simulations, a sunitinib starting dose of ~ 25 mg/m2/day was predicted to provide comparable plasma drug exposures in children with GIST as in adults with GIST treated with 50 mg/day. However, in the absence of a tumor type effect of sunitinib on CL/F in children, the projected equivalent dose for this population would be ~ 20 mg/m2/day.
Asunto(s)
Neoplasias Gastrointestinales/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Sunitinib/farmacocinética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Humanos , Persona de Mediana Edad , Modelos Biológicos , Sunitinib/efectos adversos , Sunitinib/farmacología , Adulto JovenRESUMEN
Sunitinib is a small molecule inhibitor of multiple receptor tyrosine kinases such as platelet derived growth factor receptor, vascular endothelial growth factor receptor, kit receptor and other receptors. The US Food and Drug Administration (FDA) has approved sunitinib for the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumors. It has been reported that sunitinib was mainly metabolized by CYP3A but its pharmacokinetic interactions have not been revealed. In this study, we investigated whether CYP3A inhibitors (ketoconazole, voriconazole, and itraconazole) could influence the pharmacokinetics of sunitinib and its equipotent metabolite N-desethyl sunitinib in a drug-drug interaction study in Sprague Dawley (SD) rats. The results showed that ketoconazole and voriconazole significantly increased the exposure of sunitinib, decreased the exposure of N-desethyl sunitinib, and inhibited the metabolism of sunitinib in rats. However, itraconazole showed only a weak effect on pharmacokinetics and metabolism. Coadministration of sunitinib with ketoconazole and voriconazole should be avoided if possible or if not, there should be therapeutic drug monitoring of the levels of sunitinib and N-desethyl sunitinib. Therefore, drug-drug interaction should be considered when sunitinib is administered in conjunction with CYP3A inhibitors, which might lead to toxicity.
Asunto(s)
Inhibidores del Citocromo P-450 CYP3A/farmacología , Itraconazol/farmacología , Cetoconazol/farmacología , Sunitinib/farmacocinética , Voriconazol/farmacología , Administración Oral , Animales , Masculino , Ratas Sprague-Dawley , Sunitinib/administración & dosificaciónRESUMEN
BACKGROUND AND OBJECTIVE: Population pharmacokinetic analysis explored the pharmacokinetics of sunitinib and its primary active metabolite, SU012662, in children and evaluated the sunitinib dose(s) that produce comparable plasma exposures to adults receiving the approved daily dose. METHODS: Data were from 65 children with gastrointestinal stromal tumors (GIST) or solid tumors. Pharmacokinetic models of sunitinib and SU012662 were developed using a systematic multi-step approach employing nonlinear mixed-effects modeling. The effect of predefined covariates on pharmacokinetic parameters was assessed. Final models were validated using visual predictive check and statistical techniques. RESULTS: The final dataset comprised 439 sunitinib and 417 SU012662 post-baseline plasma observations. Base models were characterized by two-compartment models with first-order absorption and lag time. Body surface area (BSA) was the only covariate that affected (P < 0.001) pharmacokinetic parameters for sunitinib and SU012662 and was incorporated into the final models. Bootstrap results indicated that the final models represented the final dataset adequately. Based on the final models, a sunitinib dose of ~ 20mg/m2/day in children with GIST aged 6-17 years would be expected to lead to similar total plasma exposures of sunitinib and SU012661 as a dose of 50 mg/day in an adult with GIST on schedule 4/2. CONCLUSIONS: In children with GIST or solid tumors receiving sunitinib, population pharmacokinetic analysis identified BSA as the only covariate that affected pharmacokinetic parameters and predicted a dose of ~ 20 mg/m2/day as achieving equivalent exposure to 50 mg/day in adults with GIST on schedule 4/2. TRIAL REGISTRATION: ClinicalTrials.gov identifiers (date registered): NCT01396148 (July 2011); NCT01462695 (October 2011); NCT00387920 (October 2006).
Asunto(s)
Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Modelos Biológicos , Neoplasias/tratamiento farmacológico , Sunitinib/farmacocinética , Adolescente , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/patología , Tumores del Estroma Gastrointestinal/patología , Humanos , Indoles/farmacocinética , Lactante , Masculino , Pirroles/farmacocinética , Sunitinib/administración & dosificación , Adulto JovenRESUMEN
The previous clinical trials found that the co-administration of irinotecan with sunitinib exhibited a synergistic antitumor effect. In the current study, we aimed to investigate whether the synergistic effect is related to a potential pharmacokinetic interaction between sunitinib and irinotecan. The inhibitory effects of sunitinib on SN-38 glucuronidation were determined by measuring the formation rates for SN38 glucuronide using recombinant human UGT isoforms and human liver microsomes (HLMs) in the absence or presence of sunitinib. Our data indicated that sunitinib exhibited competitive inhibition against SN-38 glucuronidation by UGT1A1, but inhibitory effects of sunitinib were weak in pooled human liver microsomes (HLMs) (Ki = 119.00 µM) and recombinant UGT1A1 (Ki = 42.71 µM). Our further prediction study partly explains the possible mechanism of synergistic antitumor activity of sunitinib and irinotecan in the combined treatment and provides a basis for design of clinical studies for the development and optimization of this combination.
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Irinotecán/farmacocinética , Sunitinib/farmacocinética , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Glucuronosiltransferasa/metabolismo , Humanos , Cinética , Microsomas Hepáticos/metabolismoRESUMEN
PURPOSE: Various biomarkers have been proposed for sunitinib therapy in gastrointestinal stromal tumor (GIST). However, the lack of "real-life" comparative studies hampers the selection of the most appropriate one. We, therefore, set up a pharmacometric simulation framework to compare each proposed biomarker. EXPERIMENTAL DESIGN: Models describing relations between sunitinib exposure, adverse events (hand-foot syndrome, fatigue, hypertension, and neutropenia), soluble VEGFR (sVEGFR)-3, and overall survival (OS) were connected to evaluate the differences in survival and adverse events under different dosing algorithms. Various fixed dosing regimens [4/2 (weeks on/weeks off) or 2/1 (50 mg), and continuous daily dosing (37.5 mg)] and individualization approaches [concentration-adjusted dosing (CAD), toxicity-adjusted dosing (TAD), and sVEGFR-3-adjusted dosing (VAD)] were explored following earlier suggested blood sampling schedules and dose-reduction criteria. Model-based forecasts of biomarker changes were evaluated for predictive accuracy and the advantage of a model-based dosing algorithm was evaluated for clinical implementation. RESULTS: The continuous daily dosing regimen was predicted to result in the longest survival. TAD (24.5 months) and VAD (25.5 months) increased median OS as compared with a fixed dose schedule (19.9 and 21.5 months, respectively) and CAD (19.7 and 21.3 months, respectively), without markedly raising the risk of intolerable toxicities. Changes in neutrophil count and sVEGFR-3 were accurately forecasted in the majority of subjects (>65%), based on biweekly blood sampling. CONCLUSIONS: Dose adjustments based on the pharmacodynamic biomarkers neutrophil count and sVEGFR-3 can increase OS while retaining drug safety. Future efforts could explore the possibility of incorporating a model-based dose approach in clinical practice to increase dosing accuracy for these biomarkers.
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Biomarcadores de Tumor/sangre , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Modelos Biológicos , Inhibidores de Proteínas Quinasas/administración & dosificación , Sunitinib/administración & dosificación , Ensayos Clínicos como Asunto , Conjuntos de Datos como Asunto , Esquema de Medicación , Cálculo de Dosificación de Drogas , Tumores del Estroma Gastrointestinal/sangre , Tumores del Estroma Gastrointestinal/mortalidad , Humanos , Recuento de Leucocitos , Neutrófilos , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Sunitinib/efectos adversos , Sunitinib/farmacocinética , Análisis de Supervivencia , Resultado del Tratamiento , Receptor 3 de Factores de Crecimiento Endotelial Vascular/sangreRESUMEN
PURPOSE: The safety profile of sunitinib in children, including the impact of sunitinib exposure on safety endpoints, was assessed using population pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD) models. METHODS: Data were from two clinical studies in 59 children with solid tumors (age range 2-21 years, 28 male/31 female, body weight range 16.2-100 kg, body surface are [BSA] range 0.7-2.1 m2). Analysis of covariates that affected PK and PD parameters was conducted using a nonlinear mixed-effects model. Safety and tolerability endpoints were absolute neutrophil count, hepatic transaminases, diastolic blood pressure, hemoglobin, lymphocyte count, platelet count, white blood cell count, hand-foot syndrome, fatigue, nausea, intracranial hemorrhage, and vomiting. RESULTS: The models well described the time courses of concentrations of sunitinib and its primary active metabolite SU012662, as well as safety and tolerability endpoints. In PK models for sunitinib and SU012662, BSA was the only covariate that statistically significantly affected apparent clearance (CL/F) and apparent central volume of distribution (Vc/F). Higher BSA was associated with greater CL/F and Vc/F. No statistically significant covariates were identified in the PK-PD models. For safety endpoints that had a sufficient number of adverse events, a higher probability of adverse events was associated with higher average plasma sunitinib concentrations. CONCLUSION: In PK models, BSA was the only covariate that affected major PK parameters of sunitinib and SU012662. Based on analysis of safety and tolerability endpoints, the PK-PD relationships were mainly driven by sunitinib plasma exposures and were not affected by age, sex, respective baseline safety endpoint values, baseline Eastern Cooperative Oncology Group performance status, or body size. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00387920 (registered October 13, 2006), NCT01462695 (registered October 31, 2011).
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Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Modelos Estadísticos , Neoplasias/tratamiento farmacológico , Sunitinib/farmacocinética , Sunitinib/uso terapéutico , Adolescente , Adulto , Niño , Preescolar , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Femenino , Estudios de Seguimiento , Humanos , Masculino , Neoplasias/patología , Pronóstico , Distribución Tisular , Adulto JovenRESUMEN
Neovascular age-related macular degeneration and diabetic retinopathy are prevalent causes of vision loss requiring frequent intravitreous injections of VEGF-neutralizing proteins, and under-treatment is common and problematic. Here we report incorporation of sunitinib, a tyrosine kinase inhibitor that blocks VEGF receptors, into a non-inflammatory biodegradable polymer to generate sunitinib microparticles specially formulated to self-aggregate into a depot. A single intravitreous injection of sunitinib microparticles potently suppresses choroidal neovascularization in mice for six months and in another model, blocks VEGF-induced leukostasis and retinal nonperfusion, which are associated with diabetic retinopathy progression. After intravitreous injection in rabbits, sunitinib microparticles self-aggregate into a depot that remains localized and maintains therapeutic levels of sunitinib in retinal pigmented epithelium/choroid and retina for more than six months. There is no intraocular inflammation or retinal toxicity. Intravitreous injection of sunitinib microparticles provides a promising approach to achieve sustained suppression of VEGF signaling and improve outcomes in patients with retinal vascular diseases.