Facultad de Ciencias de la Salud

Background: Pazopanib, a new oral angiogenesis inhibitor, has demonstrated clinical activity against multiple solid tumors and was approved for the treatment of patients with advanced renal cell carcinoma. As an exposure-response relationship has been observed for pazopanib, 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 pazopanib in plasma from patients with cancer. Methods: After liquid-liquid extraction with diethyl ether, pazopanib and gefitinib (internal standard) were separated using isocratic elution on an Ultrabase C18 column using a mobile phase consisting of a mixture in vol/vol proportion of 47:53 of ammonium acetate (pH, 7; 0.02 mol/L) and acetonitrile/methanol (70:30, vol/vol) pumped at a constant flow rate of 1 mL/min. Quantification was performed at 260 nm. Method validation was undertaken as per the guidelines for Bioanalytical Method Validation published by the Food and Drug Administration and European Medicines Agency. Results: Calibration curves were linear over the range 0.5-100 mcg/mL. Interday and intraday coefficients of variations were less than 4.5%. The limit of detection and the lower limit of quantification were 0.2 and 0.5 mcg/mL, respectively. Recovery of pazopanib from plasma was >80%. Conclusions: This is the first high performance liquid chromatography-ultraviolet method for pazopanib quantification that has been validated within a wide range of plasma concentrations and is a suitable method for therapeutic drug monitoring of pazopanib.

The aim of the study was to characterize the platelet count (PLT) dynamics in peritoneal carcinomatosis patients treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal oxaliplatin (HIO). Data from patients treated with CRS alone (N = 18) or CRS and HIO (N = 62) were used to estimate the baseline platelet count (PLT0), rate constants for platelet maturation (k tr ) and platelet random destruction (k s ), feedback on progenitor cell proliferation (γ), and the drug-specific model parameters (α, β). Plasma oxaliplatin concentrations, C p , reduced the proliferation rate of progenitor cells (k prol) according to a power function α × C p (β) . The surgery effect on k prol and k s was explored. The typical values (between subject variability) of the PLT0, k tr , k s , γ, α, and β were estimated to be 237 × 10(9) cells/L (32.9%), 7.09 × 10(-3) h(-1) (47.1%), 8.86 × 10(-3) h(-1) (80.0%), 0.621, 0.88 L/mg (56.9%), and 2.63. Surgery induced a maximal 2.09-fold increase in k prol that was attenuated with a half-life of 8.42 days. Splenectomy decreased k s by 47.5%. Age, sex, body surface area, sex, total proteins, and HIO carrier solution did not impact the model parameters. The model developed suggests that, following CRS and HIO, thrombocytopenia and thrombocytosis were reversible and short-lasting; the severity of the thrombocytopenia and thrombocytosis was inversely correlated, with splenectomized patients having thrombocytopenia of lower severity and thrombocytosis of higher severity; and the HIO dose and treatment duration determine the severity and duration of the thrombocytopenia. Higher HIO dose or longer treatment duration could be used without substantially increasing the risk of major hematological toxicity.

We describe a clinical case of an 84-year-old man diagnosed with non-small cell lung carcinoma and epidermal growth factor receptor mutation, who was treated with erlotinib, with doses adjusted by therapeutic drug monitoring. This case involved a clearance fluctuation leading to over-therapeutic drug concentrations of erlotinib and toxicity. The intrapatient and interpatient variability of erlotinib, in addition to other factors such as age or variations in liver clearance, create situations that are challenging in clinical practice. During treatment, erlotinib serum concentrations were measured, and the dose was accordingly adjusted. The erlotinib dose required to reduce toxicity (rash grade III) and maintain effective plasma concentrations, as well as clinical and radiological responses, was 50% of the initial dose, underscoring the relevance of therapeutic drug monitoring for tyrosine kinase inhibitors in routine clinical practice.

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.