Facultad de Ciencias de la Salud

Discovery and clinical development of monoclonal antibodies with the ability to interfere in the regulation of the immune response have significantly changed the landscape of oncology in recent years. Among the active agents licensed by the regulatory agencies, nivolumab and pembrolizumab are paradigmatic as the most relevant ones according to the magnitude of available data derived from the extensive preclinical and clinical experience. Although in both cases the respective data sheets indicate well-defined dosage regimens, a review of the literature permits to verify the existence of many issues still unresolved about dosing the two agents, so it must be considered an open question of potentially important consequences, in which to work to improve the effectiveness and efficiency of use.

Background: Anidulafungin is an antifungal agent. The development of determination techniques can be a useful tool to realize stability and quality control studies. Methods: The determination was performed on an analytical Mediterranea SEA18 (15x0.4 cm, 5 μm) C18 column at 35 ºC. The selected wavelength was 304 nm. The mobile phase was a mixture of 0.037 M sodium dihydrogen phosphate buffer, acetonitrile and methanol (40:50:10, v/v/v) at a flow rate of 2.0 mL min–1. Dasatinib (12.5 μg mL-1) was used as internal standard. Results: The assay enables the measurement of anidulafungin with a linear calibration curve (r2= 0.999) over the concentration range 15–300 μg mL-1. Accuracy, intra-day repeatability (n = 5), and inter-day precision (n = 3) were found to be satisfactory, being the accuracy 5.8% and precisions were intra-day and inter-day, 0.6% and 4.2%, respectively. Conclusions: A rapid, simple and sensitive high-performance liquid chromatography (HPLC) method with ultra violet detection has been developed for quantification of anidulafungin in perfusion solution. The retention time was clearly minor than the previous published HPLC determination methods of anidulafungin.

Nilotinib, a second-generation tyrosine kinase inhibitor, has demonstrated clinical activity in chronic myeloid leukemia. As an exposure–response relationship has been observed for nilotinib, its therapeutic drug monitoring could be a valuable tool in clinical practice. Therefore, the aim of this study was to develop and validate a selective and precise high performance liquid chromatography–ultraviolet method for the measurement of nilotinib in plasma from patients with cancer. After protein precipitation extraction with acetonitrile, nilotinib and rilpivirine were separated using isocratic elution on a Tracer Excel 120 ODS C18 column using a mobile phase consisting of a mixture of potassium dihydrogen phosphate-buffered solution (pH 5.5; 0.037 M)–methanol–acetonitrile (45:45:10, v/v/v), pumped at a flow rate of 1.7 mL·min−1. A wavelength of 254 nm was selected for the quantification of the analyte and the internal standard (IS). The technique was validated following the guidelines for the validation of analytical methods of regulatory agencies (Food and Drug Administration (FDA) and the European Medicines Agency (EMA)). Linearity was established in a concentration range between 125 and 7000 ng/mL. The detection limit was 90 ng/mL, and the lower limit of quantification was 125 ng/mL. For all concentrations in the calibration curve, the intraday and interday coefficients of variation were less than 4.1%. Median recovery of nilotinib from plasma was ≥65.1% (±21.4%). The method described is sensitive, selective, reproducible, and rapid, and can be used for the accurate determination of nilotinib in human plasma for pharmacokinetics studies and for therapeutic drug monitoring (TDM) of nilotinib in routine clinical practice.

Background: Diagnosis and treatment of differentiated thyroid carcinomas (DTC) cause anxiety and depression. Additionally, these patients suffer hormonal alterations that are associated with psychological symptoms (e.g., changes in mood, emotional instability, and memory loss). This study aims to evaluate the effectiveness of a psycho-oncological intervention based on counseling to reduce anxiety and depression related to the treatment in patients with DTC. Methods: A non-randomized controlled study, with two groups [experimental group (EG), n = 37, and control group (CG), n = 38] and baseline and posttreatment measures, was designed. Patients in the EG received a psycho-oncological intervention based on counseling in addition to the standard treatment. The independent variable was the assigned group and the dependent one was the evolution of anxiety and depression, which were analyzed separately, and both were evaluated using the Hospital Anxiety and Depression Scale. Other relevant covariables related to the quality of life (QoL) were also analyzed using Short Form-36 Health Survey and Psychological General Wellbeing Index scales. Results: The difference of the posttreatment-baseline variation showed a statistically significant reduction in anxiety and depression in the EG in relation to the CG (p < 0.001). The mean of the Psychological General Wellbeing Index scales score increased significantly in the EG (p < 0.001) and decreased significantly in the CG (p < 0.001). All the baseline and the posttreatment scores of the variables evaluated showed a statistically significant improvement in the EG vs. the CG. Conclusion: This study demonstrates significant benefits of psycho-oncological intervention based on counseling in anxiety, depression, QoL, and wellbeing of the patient with differentiated thyroid carcinomas.

Introduction: The main goal of treatment in cancer patients is to achieve the highest therapeutic effectiveness with the least iatrogenic toxicity. Tyrosine kinase inhibitors (TKIs) are anticancer oral agents, usually administered at fixed doses, which present high inter- and intraindividual variability due to their pharmacokinetic characteristics. Therapeutic drug monitoring (TDM) can be used to optimize the use of several types of medication. Objective: We evaluated the use of TDM of TKIs in routine clinical practice through studying the variability in exposure to erlotinib, imatinib, lapatinib, and sorafenib and dose adjustment. Materials and methods: We conducted a retrospective analytical study involving patients who received treatment with TKIs, guided by TDM and with subsequent recommendation of dose adjustment. The quantification of the plasma levels of the different drugs was performed using high-performance liquid chromatography (HPLC). The Clinical Research Ethics Committee of the Hospital Quirónsalud Torrevieja approved this study. Results: The inter-individual variability in the first cycle and in the last monitored cycle was 46.2% and 44.0% for erlotinib, 48.9 and 50.8% for imatinib, 60.7% and 56.0% for lapatinib and 89.7% and 72.5% for sorafenib. Relationships between exposure and baseline characteristics for erlotinib, imatinib, lapatinib and sorafenib were not statistically significant for any of the variables evaluated (weight, height, body surface area (BSA), age and sex). Relationships between height (p = 0.021) and BSA (p = 0.022) were statistically significant for sorafenib. No significant relationships were observed between Ctrough and progression-free survival (PFS) or overall survival (OS) for any drug, except in the case of sunitinib (correlation between Ctrough and PFS p = 0.023) in the exposure–efficacy analysis. Conclusions: Erlotinib, imatinib, lapatinib and sorafenib show large inter-individual variability in exposure. TDM entails a significant improvement in exposure and enables more effective and safe use of TKIs in routine clinical practice.

Objective: A review of the literature about the anti-programmed death 1 monoclonal antibody nivolumab permits to verify the existence of several issues still unresolved about their dosing schedule. The aim of the present work was to explore possibilities of nivolumab treatment personalization through therapeutic drug monitoring, in order to improve their effectiveness and efficiency. Method: Observational, prospective study carried out from May 2017 through June 2019 in patients with different tumor diagnoses treated with nivolumab. Blood samples were obtained in the routine clinical practice, once nivolumab steady state was reached. Serum nivolumab levels were determined by means of quantitative ELISA. The standard schedule of 3 mg/kg every two weeks (Q2W) was modified in some patients due to different circumstances, and resulting serum concentrations were compared with those from the non-modified patients and the published data. Results: Blood samples from 19 patients in treatment with nivolumab were analyzed. A total of 39 samples of nivolumab were analyzed between 6th and 27th cycles. The standard schedule of 3 mg/kg every two weeks was modified in 12/19 (60%) patients, with intervals of 3, 4, 5, 6 or 7 weeks, once the steady state was reached. No statistically significant differences were detected when comparing every two weeks and every four week intervals. When the intervals were six or seven weeks, mean plasma concentration showed a statistically significant difference compared with every two weeks. Conclusions: Current data contribute to confirm former suspects about the possibilities of exploring new scenarios to improve and personalize nivolumab dosage. Additional studies to confirm it in bigger series and correlate it with clinical results, and to better define the role of therapeutic drug monitoring in the treatment, are warranted, not only by financial concerns but also for improving quality of life of patients and clinical management aspects. / Objetivo: Una revisión de la literatura sobre nivolumab permite verificar la existencia de diversos aspectos sin resolver sobre su intervalo de dosificación. El objetivo del presente estudio ha sido explorar las posibilidades de personalización del tratamiento con nivolumab mediante la monitorización terapéutica de sus concentraciones séricas para mejorar su efectividad y eficiencia. Método: Estudio observacional, prospectivo, realizado entre mayo de 2017 y junio de 2019 en pacientes tratados con nivolumab que estaban diagnosticados de diferentes tumores. Se obtuvieron muestras de sangre en la práctica clínica habitual, una vez alcanzado el estado de equilibrio de nivolumab. Las concentraciones séricas de nivolumab fueron determinadas mediante ELISA cuantitativo. La pauta posológica habitual de 3 mg/kg cada dos semanas tuvo que ser modificada en algunos pacientes debido a diferentes circunstancias, y las concentraciones séricas resultantes se compararon con las correspondientes a los pacientes en los que no se modificó y con datos publicados. Resultados: Se analizaron muestras de 19 pacientes que recibieron inicialmente 3 mg/kg de nivolumab cada dos semanas. Se analizó un total de 39 muestras, entre los ciclos 6 y 27. La pauta habitual se modificó, una vez alcanzado el estado de equilibrio, en 12/19 (60%) pacientes, en los que se amplió el intervalo a 3, 4, 5, 6 o 7 semanas. No se encontraron diferencias estadísticamente significativas al comparar la maadministración cada dos semanas y cada cuatro semanas. Cuando los intervalos fueron de seis o siete semanas, la concentración sérica media mostró una diferencia estadísticamente significativa en comparación con la administración cada dos semanas. Conclusiones: La información recogida parece confirmar la necesidad de explorar nuevos escenarios para personalizar la dosificación de nivolumab. Se necesitan estudios adicionales en series de mayor tamaño para confirmar esta información, correlacionarla con los resultados clínicos y definir mejor el papel de la monitorización terapéutica, no solo por motivos económicos, sino también para mejorar la calidad de vida de los pacientes y facilitar la administración clínica del tratamiento.