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Over the past two decades, targeted therapies have become cornerstone treatments for numerous cancers with oncogene addiction. Unfortunately, their effectiveness reduces over time and most patients who receive targeted therapies relapse within 12 months. The emergence of drug-resistance mechanisms in tumours paved the way for next-generation inhibitors. However, insufficient concentration of targeted therapy is a frequent but poorly explored mechanism of treatment failure. Additionally, the maximum tolerated dose (MTD) is not always reached in phase studies, and the recommended phase 2 dose is mostly based on benefit-risk ratio and pharmacokinetic considerations, which could result in a suboptimal dose. This scenario has led us to propose a new concept in clinical drug development: the late phase 1 study. The primary goal of this type of trial is to define an alternative MTD of a drug in patients who are chronically exposed and had an initial benefit from targeted therapy but subsequently progressed without an identified resistance alteration. Intrapatient dose escalation might increase drug concentration and restore drug activity or efficacy.
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Antineoplásicos/farmacocinética , Ensayos Clínicos Fase I como Asunto , Desarrollo de Medicamentos , Neoplasias/tratamiento farmacológico , Proyectos de Investigación , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Biomarcadores de Tumor/genética , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Humanos , Dosis Máxima Tolerada , Terapia Molecular Dirigida , Neoplasias/genética , Neoplasias/patología , Insuficiencia del TratamientoRESUMEN
INTRODUCTION: Cabozantinib is an oral tyrosine kinase inhibitor that is approved for the treatment of metastatic renal cell carcinoma (mRCC). Cabozantinib is a weak base that exhibits a pH-dependent solubility profile in vitro which raises concerns about its bioavailability in patients treated with proton pump inhibitors (PPIs). The purpose of this study was to investigate whether PPI use has an impact on the efficacy, safety, and residual concentration (Ctrough) of cabozantinib in patients with mRCC. MATERIALS AND METHODS: This is a retrospective review of a prospectively collected electronic database of patients with mRCC who received cabozantinib at Gustave Roussy between February 2014 and December 2018. The Kaplan-Meier method was used for survival analysis and the Cox proportional-hazard model for uni- and multivariate analysis. In parallel, we conducted a pharmacokinetic study of cabozantinib in a distinct cohort of 50 mRCC patients, in which cabozantinib Ctrough was assayed using a validated tandem mass spectrometry-liquid chromatography method. RESULTS: We identified 99 patients treated with cabozantinib, including 43 patients being PPI users. With a median follow-up of 30.3 months, PPI users showed similar progression-free survival and overall survival outcomes compared with PPI nonusers. Similarly, the incidence of adverse events was not significantly different between the PPI users and nonusers, although PPI users required dose reductions more often. In the independent pharmacokinetic cohort, of whom 21 received PPI concomitantly, Ctrough was similar between the two groups. CONCLUSION: In line with the pharmacologic data, the concomitant use of PPI does not significantly impact the efficacy or safety of cabozantinib in patients with mRCC. IMPLICATIONS FOR PRACTICE: Drug interactions, especially between targeted therapies and proton pump inhibitors (PPI), were shown to potentially impact the outcomes of cancer patients. Cabozantinib, a current therapeutic standard in metastatic renal cell carcinoma (mRCC), exhibits a pH-dependent solubility profile, which raises concerns about its bioavailability in patients treated with proton pump inhibitors (PPI). At the present time, there is no evidence regarding the effect of PPIs on cabozantinib's efficacy and safety in patients with mRCC. This study found that the concomitant use of PPI during cabozantinib treatment in mRCC patients does not appear to impact the residual concentration, efficacy, and safety of cabozantinib in a real-life context.
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Carcinoma de Células Renales , Neoplasias Renales , Anilidas , Carcinoma de Células Renales/tratamiento farmacológico , Humanos , Neoplasias Renales/tratamiento farmacológico , Inhibidores de la Bomba de Protones/uso terapéutico , Piridinas , Estudios RetrospectivosRESUMEN
BACKGROUND: Busulfan (Bu) is the cornerstone of conditioning regimens prior to hematopoietic stem cell transplantation, widely used in both adults and children for the treatment of malignant and nonmalignant diseases. Despite an intravenous formulation, interindividual variability (IIV) remains high and optimal exposure difficult to achieve, especially in neonates and infants. PROCEDURE: To ensure both efficacy and safety, we set up in 2005 an observational study designed for children not fully assessed during the drug registration procedure. From a large cohort of 540 patients, we developed a Bu population pharmacokinetic model based on body weight (BW) and maturation concepts to reduce IIV and optimize exposure. A new dosing nomogram was evaluated to better fit the population pharmacokinetic model. RESULTS: Bu clearance IIV was significantly decreased from 61.3% (covariate-free model) to 28.6% when combining BW and maturation function. Median Bu area under the curve (AUC) was 1179 µmol/L × min compared to 1025 with the EMA dosing nomogram for children <9 kg. The target AUC was reached for each BW strata, significantly increasing the percentages of patients achieving reaching the targeted AUC as compared to FDA schedule. CONCLUSION: This new model made it possible to propose a novel dosing nomogram that better considered children below 16 kg of BW and allowed better initial exposure as compared to existing dosing schedules. This nomogram, which would be easy to use to determine an optimal dosing schedule in daily practice, will need to be validated in clinical routine. Therapeutic drug monitoring remains strongly advisable for small children and those with specific diseases.
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Busulfano/farmacocinética , Busulfano/uso terapéutico , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Modelos Estadísticos , Nomogramas , Acondicionamiento Pretrasplante , Terapia Combinada , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas , Femenino , Estudios de Seguimiento , Neoplasias Hematológicas/patología , Humanos , Lactante , Masculino , Agonistas Mieloablativos/farmacocinética , Agonistas Mieloablativos/uso terapéutico , Pronóstico , Distribución TisularRESUMEN
Busulfan therapeutic drug monitoring (TDM) is often used to achieve target plasma exposures. Variability in busulfan plasma exposure units (BPEU) is a potential source for misinterpretation of publications and protocols and is a barrier to data capture by hematopoietic cell transplantation (HCT) registry databases. We sought to harmonize to a single BPEU for international use. Using Delphi consensus methodology, iterative surveys were sent to an increasing number of relevant clinical stakeholders. In survey 1, 14 stakeholders were asked to identify ideal properties of a BPEU. In survey 2, 52 stakeholders were asked (1) to evaluate BPEU candidates according to ideal BPEU properties established by survey 1 and local position statements for TDM and (2) to identify potential facilitators and barriers to adoption of the harmonized BPEU. The most frequently used BPEU identified, in descending order, were area under the curve (AUC) in µMâ¯×â¯min, AUC in mgâ¯×â¯h/L, concentration at steady state (Css) in ng/mL, AUC in µMâ¯×â¯h, and AUC in µgâ¯×â¯h/L. All respondents conceptually agreed on the ideal properties of a BPEU and to adopt a harmonized BPEU. Respondents were equally divided between selecting AUC in µMâ¯×â¯min versus mgâ¯×â¯h/L for harmonization. AUC in mgâ¯×â¯h/L was finally selected as the harmonized BPEU, because it satisfied most of the survey-determined ideal properties for the harmonized BPEU and is read easily understood in the clinical practice environment. Furthermore, 10 major professional societies have endorsed AUC in mgâ¯×â¯h/L as the harmonized unit for reporting to HCT registry databases and for use in future protocols and publications.
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Busulfano , Consenso , Bases de Datos Factuales , Monitoreo de Drogas , Trasplante de Células Madre Hematopoyéticas , Sistema de Registros , Aloinjertos , Busulfano/administración & dosificación , Busulfano/farmacocinética , Femenino , Humanos , MasculinoRESUMEN
Oncogenic isocitrate dehydrogenase (IDH)1 and IDH2 mutations at three hotspot arginine residues cause an enzymatic gain of function that leads to the production and accumulation of the metabolite 2-hydroxyglutarate (2HG), which contributes to the development of a number of malignancies. In the hematopoietic system, mutations in IDH1 at arginine (R) 132 and in IDH2 at R140 and R172 are commonly observed in acute myeloid leukemia, and elevated 2HG is observed in cells and serum. However, in angioimmunoblastic T-cell lymphoma (AITL), mutations are almost exclusively restricted to IDH2 R172, and levels of 2HG have not been comprehensively measured. In this study, we investigate the expression pattern of mutant IDH2 in the AITL tumor microenvironment and measure levels of 2HG in tissue and serum of AITL patients. We find that mutant IDH2 expression is restricted to the malignant T-cell component of AITL, and that 2HG is elevated in tumor tissue and serum of patients. We also investigate the differences between the three hotspot mutation sites in IDH1 and IDH2 using conditional knock-in mouse models. These studies show that in the lymphoid system, mutations in IDH2 at R172 produce high levels of 2HG compared with mutations at the other two sites and that lymphoid development is impaired in these animals. These data provide evidence that IDH2 R172 mutations may be the only variants present in AITL because of their capacity to produce significant amounts of the oncometabolite 2HG in the cell of origin of this disease.
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Glutaratos/metabolismo , Isocitrato Deshidrogenasa/genética , Linfoma de Células T/inmunología , Animales , Biomarcadores de Tumor , Citometría de Flujo , Regulación Neoplásica de la Expresión Génica , Genotipo , Humanos , Isocitrato Deshidrogenasa/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Linfocitos/metabolismo , Linfoma de Células T/metabolismo , Ratones , Ratones Noqueados , MutaciónRESUMEN
Background The risk of pharmacokinetic interaction is important in HIV-infected cancer patients receiving concomitantly highly active antiretroviral therapy (HAART) and anti-cancer systemic treatments. We aimed to evaluate the safety profile of raltegravir-based HAART in cancer patients receiving multi-kinase inhibitors (MKIs). Patients and Methods We conducted a retrospective medical record review of adult, HIV-infected cancer patients treated in our institutions from January 2010 to December 2015. Patients eligible for the present analysis were those receiving a raltegravir-based HAART at the time of the initiation of a MKI for the treatment of advanced solid tumors. Treatment-related toxicity, virological outcomes and pharmacokinetic profile of MKIs were examined. Results Twelve patients (7 males, median age 55 years) were identified. Seven had sarcoma/GIST, 3 had hepatocellular carcinoma, one had pancreatic neuroendocrine tumor, and one had NSCLC. Patients received the following MKIs: imatinib (n = 3), sorafenib (n = 3), pazopanib (n = 3), sunitinib (n = 2) and erlotinib (n = 1). The mean CD4+ count at baseline was 929 cells/mm3, and 860 cells/mm3 after completion of MKI treatment. In all patients, HIV viral loads remained below the limit of detection (40 copies/ mm3) during the whole MKI treatment. No virological failure occurred. No unexpected or serious adverse event related either to raltegravir-based HAART or to MKIs was observed. The trough plasma concentrations of MKIs were assessed in 8 patients, and were found normal in all but one case (not related to raltegravir-based HAART). Conclusions The present data represent the first documentation of the concomitant use of raltegravir-containing HAART and MKIs in HIV-infected adult patients with advanced non-AIDS defining malignancies, with a reassuring safety profile.
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Fármacos Anti-VIH/uso terapéutico , Antineoplásicos/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Raltegravir Potásico/uso terapéutico , Adulto , Anciano , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/farmacología , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Terapia Antirretroviral Altamente Activa/efectos adversos , Interacciones Farmacológicas , Femenino , Infecciones por VIH/metabolismo , Infecciones por VIH/virología , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/metabolismo , Neoplasias/virología , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Raltegravir Potásico/efectos adversos , Raltegravir Potásico/farmacología , Carga Viral/efectos de los fármacosRESUMEN
The Practice Guidelines Committee of the American Society of Blood or Marrow Transplantation (ASBMT) sought to develop an evidence-based review about personalizing busulfan-based conditioning. The Committee sought to grade the relevant published studies (June 1, 2008 through March 31, 2016) according to criteria set forth by the Steering Committee for Evidence Based Reviews from ASBMT. Unfortunately, the published literature was too heterogeneous and lacked adequately powered and sufficiently controlled studies for this to be feasible. Despite this observation, the continued interest in this topic led the Practice Guidelines Committee to develop a list of most frequently asked questions (FAQs) regarding personalized busulfan dosing. This "Considerations" document is a list of these FAQs and their responses, addressing topics of practical relevance to hematopoietic cell transplantation clinicians.
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Busulfano/administración & dosificación , Medicina de Precisión/métodos , Acondicionamiento Pretrasplante/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Agonistas Mieloablativos/uso terapéuticoRESUMEN
BACKGROUND: We aimed to understand the dependence of MEK and m-TOR inhibition in EGFR(WT)/ALK(non-rearranged) NSCLC cell lines. METHODS: In a panel of KRAS(M) and KRAS(WT) NSCLC cell lines, we determined growth inhibition (GI) following maximal reduction in p-ERK and p-S6RP caused by trametinib (MEK inhibitor) and AZD2014 (m-TOR inhibitor), respectively. RESULTS: GI caused by maximal m-TOR inhibition was significantly greater than GI caused by maximal MEK inhibition in the cell line panel (52% vs 18%, P<10(-4)). There was no significant difference in GI caused by maximal m-TOR compared with maximal m-TOR+MEK inhibition. However, GI caused by the combination was significantly greater in the KRAS(M) cell lines (79% vs 61%, P=0.017). CONCLUSIONS: m-TOR inhibition was more critical to GI than MEK inhibition in EGFR(WT)/ALK(non-rearranged) NSCLC cells. The combination of MEK and m-TOR inhibition was most effective in KRAS(M) cells.
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Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Genes ras , Neoplasias Pulmonares/metabolismo , Quinasas Quinasa Quinasa PAM/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/genéticaRESUMEN
Isocitrate dehydrogenase IDH 1 and IDH 2 mutations were reported in several cancer forms, especially in hematological malignancies, but were never been investigated in familial aggregation. The aim of this study is to determine whether germline isocitrate dehydrogenase genes mutations are involved.We targeted IDH1 and IDH2 genes in 104 familial cases belonging to Tunisian and French populations, including several forms of hematological malignancies and cosegregated solid tumors.We report one IDH1 variant: c.315 G>T, p.Gly105Gly in 15 % of cases, which was assigned to the worst outcome in several studies. Three IDH2 variants were found, among them, one intronic substitution c.543+45 G>A (rs142033117) and two new variants not previously described: c.389 A>T, p.Lys130Met and c.414 T>C, p.Thr138Thr. The p.Lys130Met was found in one case diagnosed with Waldenstrom's disease with familial history of cancer. The enrolled in silico analysis, the functional study, and the absence of this variant in control population strengthen the hypothesis of its deleterious effect.From an extended number of candidate genes analyzed in familial hematological malignancies, IDH2 might be considerably involved since we reported a potential damaging effect.
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Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Isocitrato Deshidrogenasa/genética , Mutación/genética , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: Busulfan-melphalan high-dose chemotherapy followed by autologous stem cell transplantation is an essential consolidation treatment of high-risk neuroblastoma in children. Main treatment limitation is hepatic veno-occlusive disease, the most severe and frequent extra-hematological toxicity. This life threatening toxicity has been related to a drug interaction between busulfan and melphalan which might be increased by prior disturbance of iron homeostasis, i.e. an increased plasma ferritin level. METHODS: We performed an experimental study of busulfan and melphalan pharmacodynamic and pharmacokinetics in iron overloaded mice. RESULTS: Iron excess dramatically increased the toxicity of melphalan or busulfan melphalan combination in mice but it did not modify the clearance of either busulfan or melphalan. We show that prior busulfan treatment impairs the clearance of melphalan. This clearance alteration was exacerbated in iron overloaded mice demonstrating a pharmacokinetic interaction. Additionally, iron overload increased melphalan toxicity without altering its pharmacokinetics, suggesting a pharmacodynamic interaction between iron and melphalan. Based on iron homeostasis disturbance, we postulated that prior induction of ferritin, through Nrf2 activation after oxidative stress, may be associated with the alteration of melphalan metabolism. CONCLUSION: Iron overload increases melphalan and busulfan-melphalan toxicity through a pharmacodynamic interaction and reveals a pharmacokinetic drug interaction between busulfan and melphalan.
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Busulfano/metabolismo , Busulfano/toxicidad , Sobrecarga de Hierro/metabolismo , Melfalán/metabolismo , Melfalán/toxicidad , Animales , Antineoplásicos Alquilantes/metabolismo , Antineoplásicos Alquilantes/toxicidad , Interacciones Farmacológicas/fisiología , Sobrecarga de Hierro/patología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
PURPOSE: To compare irinotecan-eluting HepaSphere (BioSphere Medical, Roissy-en-France, France) and DC Bead (Biocompatibles UK Ltd, London, United Kingdom) embolization microspheres for distribution in tumors, release properties, tolerance, and antitumor effects in a model of liver metastases in the rabbit. MATERIALS AND METHODS: Multiple liver tumors were created by injection of a VX2 cell suspension in the portal vein of rabbits. After 2 weeks, embolization of the proper hepatic artery was performed with a fixed volume of bland HepaSphere (n = 5), irinotecan-loaded HepaSphere (n = 6), or irinotecan-loaded DC Bead (n = 5) microspheres. Untreated animals injected with VX2 cells served as control animals (n = 5). Plasma pharmacokinetics of irinotecan and its metabolite SN38 were assessed. Histopathology and gene expression analysis were performed 3 days after treatment. RESULTS: Among all treated groups, there was no significant difference in liver enzymes or liver damage on histology. Irinotecan-loaded HepaSphere microspheres showed a faster release of drug than DC Bead microspheres leading to a twofold higher concentration of drug in plasma for HepaSphere microspheres. HepaSphere microspheres were less frequently found inside tumor nodules on histology than DC Bead microspheres (11% vs 48%, P < .001) because of their larger size. Tumor necrosis was significantly greater for rabbits given irinotecan-loaded HepaSphere microspheres (69% of total tumor surface) and rabbits given DC Bead microspheres (50% of total tumor surface) compared with control animals (24% of total tumor surface, P = .006 and P = .047). CONCLUSIONS: HepaSphere and DC Bead microspheres loaded with irinotecan caused significant necrosis of tumor nodules in a model of VX2 liver metastases. This outcome was mostly due to irinotecan delivery rather than vascular occlusion by the microspheres and was greater for HepaSphere microspheres compared with DC Bead microspheres.
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Antineoplásicos Fitogénicos/administración & dosificación , Camptotecina/análogos & derivados , Quimioembolización Terapéutica/métodos , Portadores de Fármacos , Neoplasias Hepáticas Experimentales/secundario , Neoplasias Hepáticas Experimentales/terapia , Activación Metabólica , Animales , Antineoplásicos Fitogénicos/sangre , Antineoplásicos Fitogénicos/farmacocinética , Camptotecina/administración & dosificación , Camptotecina/sangre , Camptotecina/farmacocinética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Arteria Hepática , Inyecciones Intraarteriales , Irinotecán , Neoplasias Hepáticas Experimentales/irrigación sanguínea , Neoplasias Hepáticas Experimentales/genética , Neoplasias Hepáticas Experimentales/metabolismo , Masculino , Microesferas , Necrosis , Tamaño de la Partícula , Conejos , Distribución TisularRESUMEN
We present three pediatric patients with BRAFV600E mutant high-grade gliomas treated by vemurafenib on a nominative authorization level at our institution. One patient with anaplastic ganglioglioma experienced confirmed partial tumor response and significant clinical improvement and she is alive 20 months after start of treatment. A second patient with ganglioglioma responded transiently to re-introduction of vemurafenib after immunotherapy. Pharmacokinetic studies suggest that maximum concentration and exposure of vemurafenib at steady-state is dose-dependent and similar in children to that reported in adults. These cases suggest that BRAFV600 is an oncogenic driver in pediatric gliomas. Further exploration in clinical studies is ongoing.
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Antineoplásicos/uso terapéutico , Astrocitoma/tratamiento farmacológico , Neoplasias Encefálicas/tratamiento farmacológico , Ganglioglioma/tratamiento farmacológico , Indoles/uso terapéutico , Mutación Missense , Proteínas de Neoplasias/antagonistas & inhibidores , Mutación Puntual , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Sulfonamidas/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Astrocitoma/enzimología , Bevacizumab , Neoplasias Encefálicas/enzimología , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Vacunas contra el Cáncer/uso terapéutico , Niño , Terapia Combinada , Irradiación Craneana , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Evaluación de Medicamentos , Resultado Fatal , Ganglioglioma/enzimología , Ganglioglioma/radioterapia , Ganglioglioma/cirugía , Humanos , Inmunoterapia , Indoles/efectos adversos , Indoles/farmacocinética , Lactante , Irinotecán , Masculino , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiología , Polietilenglicoles/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/fisiología , Terapia Recuperativa , Sulfonamidas/efectos adversos , Sulfonamidas/farmacocinética , Temozolomida , Tálamo , Resultado del Tratamiento , VemurafenibRESUMEN
Cyclophosphamide and ifosfamide are major alkylating agents but their therapeutics uses are limiting by the toxicity due to several toxicities. Indeed conventional chemotherapies are generally used with the maximum tolerated dose. In contrast, metronomic schedule aims to get a minimum dose for efficacy with a good safety. Depending on the dose, their mechanisms of action are different and offer a dual activity: at high dose, cyclophosphamide is mainly used in graft conditioning for its immunosuppressive properties, while at metronomic dose it is used as an immunoactive agent. Currently, at metronomic dose, cyclophosphamide is studied in clinic against various types of cancer, alone or in combination with others anticancer drugs (anti-angiogenic, immune-modulating agents, immune checkpoints blockers, vaccines, radiotherapy, others conventional anticancer agents), as a nth-line or first-line treatment. More than three quarters of clinical studies show promising results, mostly in breast, ovarian and prostate cancers. Taking advantage of the immune system, use dual antitumor action's chemotherapy is clearly a therapeutic strategy that deserves to be confirmed in order to improve the efficacy/toxicity balance of anticancer treatments, and to use CPM or analogues as a standard of care.
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Ciclofosfamida , Neoplasias , Humanos , Ciclofosfamida/farmacología , Ciclofosfamida/administración & dosificación , Neoplasias/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/administración & dosificación , Administración Metronómica , Ifosfamida/administración & dosificación , Relación Dosis-Respuesta a DrogaRESUMEN
CONTEXT: Obesity prevalence is persistently increasing worldwide. Among surgical therapeutic procedures, bypass surgery and sleeve gastrectomy have shown the best results regarding weight loss, prevention, and treatment of secondary complications. However, these surgeries are associated with an increased risk of malabsorption and metabolic changes that could further affect the pharmacokinetics of drugs. On the other hand, patients with a history of such surgeries are more likely to experience pain and request analgesic initiation or adaptation. The question of how to manage pain medication in these patients is challenging due to their narrow therapeutic indexes. OBJECTIVES: To summarize the current literature on the impact of bariatric surgery on the subsequent pharmacokinetics of analgesics and propose a multidisciplinary therapeutic attitude to optimize pain management in these patients. METHODS: We conducted a systematic review that included all pharmacological studies published after 2000. RESULTS: Unexpectedly, these surgeries seem to increase the bioavailability of drugs by long-term improvement of hepatic function. Yet, the medical community drastically lacks robust guidelines for pain management in those patients. This systematic review aims to bring together pharmacological studies related to the use of pain treatments in patients who underwent bypass surgery or sleeve gastrectomy. CONCLUSIONS: Caution should be exercised regarding the risk of overdose in every circumstance: treatment initiation, change of doses, or change of molecule. More prospective trials comparing the pharmacokinetics of medications in obese patients with and without prior bariatric surgery are needed.
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Analgésicos , Cirugía Bariátrica , Manejo del Dolor , Humanos , Analgésicos/uso terapéutico , Analgésicos/farmacocinética , Manejo del Dolor/métodos , Obesidad/cirugía , Obesidad/complicaciones , Dolor/tratamiento farmacológicoRESUMEN
A multitude of TKI has been developed and approved targeting various oncogenetic alterations. While these have provided improvements in efficacy compared with conventional chemotherapies, resistance to targeted therapies occurs. Mutations in the kinase domain result in the inability of TKI to inactivate the protein kinase. Also, gene amplification, increased protein expression and downstream activation or bypassing of signalling pathways are commonly reported mechanisms of resistance. Improved understanding of mechanisms involved in TKI resistance has resulted in the development of new generations of targeted agents. In a race against time, the search for new, more potent and efficient drugs, and/or combinations of drugs, remains necessary as new resistance mechanisms to the latest generation of TKI emerge. This review examines the various generations of TKI approved to date and their common mechanisms of resistance, focusing on TKI targeting BCR-ABL, epidermal growth factor receptor, anaplastic lymphoma kinase and BRAF/MEK tyrosine kinases.
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Resistencia a Antineoplásicos , Neoplasias , Inhibidores de Proteínas Quinasas , Humanos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Terapia Molecular Dirigida/métodos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismoRESUMEN
Real-life populations are more heterogeneous than those included in prospective clinical studies. In cancer patients, comorbidities and co-medications favor the appearance of severe adverse effects which can significantly impact quality of life and treatment effectiveness. Most of tyrosine kinase inhibitors (TKI) have been developed with flat oral dosing exposing patients to the risk of poor adherence due to side effects. Additionally, genetic or physiological factors, differences in diet, and drug-drug interactions can lead to inter-individual variability affecting treatment outcomes and increasing the risk of adverse events. Knowledge of the different factors of variability allows individualized patient management. This review examines the effects of adherence, food intake, and pharmaceutical form on the pharmacokinetics of oral TKI, as well as evaluating pharmacokinetics considerations improving TKI management. Concentration-effectiveness and concentration-toxicity data are presented for the selected TKI, and a simple therapeutic drug monitoring schema is outlined to help individualize dosing of oral TKI.
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Neoplasias , Inhibidores de Proteínas Quinasas , Humanos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Neoplasias/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Interacciones Farmacológicas , Monitoreo de DrogasRESUMEN
INTRODUCTION: Busulfan is an alkylating agent widely used in the conditioning of hematopoietic stem cell transplantation possessing a complex metabolism and a large interindividual and intra-individual variability, especially in children. Combined with the strong rationale of busulfan PK/PD relationships, factors altering its clearance (e.g. weight, age, and GST-A genetic polymorphism mainly) can also affect clinical outcomes. AREAS COVERED: This review aims to provide an overview of the current knowledge on busulfan pharmacokinetics, its pharmacokinetics variabilities in pediatric populations, drug-drug interactions (DDI), and their consequences regarding dose individualization. This review was based on medical literature up until October 2021. EXPERT OPINION: To ensure effective busulfan exposure in pediatrics, different weight-based nomograms have been established to determine busulfan dosage and provided improved results (65-80% of patients correctly exposed). In addition to nomograms, therapeutic drug monitoring (TDM) of busulfan measuring plasmatic concentrations to estimate busulfan pharmacokinetic parameters can be used. TDM is now widely carried out in routine practices and aims to ensure the targeting of the reported therapeutic windows by individualizing busulfan dosing based on the clearance estimations from a previous dose.
Asunto(s)
Busulfano , Trasplante de Células Madre Hematopoyéticas , Niño , Humanos , Busulfano/farmacocinética , Trasplante de Células Madre Hematopoyéticas/métodos , Interacciones Farmacológicas , Monitoreo de Drogas/métodos , CinéticaRESUMEN
Purinergic receptors and NOD-like receptor protein 3 (NLRP3) inflammasome regulate inflammation and viral infection, but their effects on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remain poorly understood. Here, we report that the purinergic receptor P2X7 and NLRP3 inflammasome are cellular host factors required for SARS-CoV-2 infection. Lung autopsies from patients with severe coronavirus disease 2019 (COVID-19) reveal that NLRP3 expression is increased in host cellular targets of SARS-CoV-2 including alveolar macrophages, type II pneumocytes and syncytia arising from the fusion of infected macrophages, thus suggesting a potential role of NLRP3 and associated signaling pathways to both inflammation and viral replication. In vitro studies demonstrate that NLRP3-dependent inflammasome activation is detected upon macrophage abortive infection. More importantly, a weak activation of NLRP3 inflammasome is also detected during the early steps of SARS-CoV-2 infection of epithelial cells and promotes the viral replication in these cells. Interestingly, the purinergic receptor P2X7, which is known to control NLRP3 inflammasome activation, also favors the replication of D614G and alpha SARS-CoV-2 variants. Altogether, our results reveal an unexpected relationship between the purinergic receptor P2X7, the NLRP3 inflammasome and the permissiveness to SARS-CoV-2 infection that offers novel opportunities for COVID-19 treatment.
Asunto(s)
COVID-19 , Inflamasomas , Humanos , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas NLR , Tratamiento Farmacológico de COVID-19 , SARS-CoV-2/metabolismo , Inflamación , Receptores PurinérgicosRESUMEN
PURPOSE: To assess the efficacy of isolated pelvic perfusion (IPP) with tumor necrosis factor (TNF)-α and melphalan in patients with locally advanced cancers in the pelvic and groin area requiring mutilating surgery. METHODS: A total of 27 patients were enrolled (carcinoma, n = 17; sarcoma/melanoma, n = 4; and endocrine tumor, n = 6). They were candidates for exarticulation (n = 3) or exenteration (n = 11) or were judged unresectable (n = 13). In installing IPP, tourniquets were positioned around both thighs, and an inflated pressure suit was placed at a subthoracic position. Tumor necrosis factor-α (300 µg) was injected in the perfusate, followed 5 minutes later by melphalan at 1.5 mg/kg. After 30 minutes, the remaining drugs were washed out. Leakage was assessed with technetium Tc 99m radiolabeled human serum albumin, and a pharmacokinetic study was performed. Efficacy was based on the complete response rate observed on magnetic resonance imaging. RESULTS: Pelvic/systemic ratios of melphalan/TNF/technetium Tc 99m were 14.2/7/3.6. Responses on magnetic resonance imaging were as follows: 30% complete, 30% partial, 19% no change, and 15% progression. Two patients were not evaluable because they did not receive the treatment. Pre-IPP/post-IPP median percentage of necrosis on magnetic resonance imaging was 10%/70%. Median follow-up was 43 months. Median overall survival was 17 months. Twelve-month survival rate, disease-free survival, and local and metastatic recurrence rates were 67%, 30%, 57%, and 26%, respectively. CONCLUSIONS: Isolated pelvic perfusion with TNF-α compares favorably with historical data, as it was observed in limb perfusion and could provide a chance to translate its successful combination with chemotherapy into treatment of locally advanced pelvic cancers.