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Escudero-Ortiz V.,Platform of Oncology | Escudero-Ortiz V.,San Antonio de Murcia Catholic University | Perez-Ruixo J.J.,Amgen | Perez-Ruixo J.J.,Consulting Projects for Research | And 2 more authors.
Therapeutic Drug Monitoring | Year: 2015

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 C 18 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. Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved. Source

Perez-Ruixo C.,University of Valencia | Perez-Ruixo C.,Consulting Projects for Research | Peris J.E.,University of Valencia | Escudero-Ortiz V.,Platform of Oncology | And 9 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2014

Purpose: To determine the rate and extent of hyperthermic intraperitoneal oxaliplatin (HIO) absorption in peritoneal carcinomatosis patients treated with cytoreductive surgery (CRS) and the effect of the isotonic carrier solution on HIO absorption parameters. Methods: Full pharmacokinetic profiles collected in peritoneum and plasma from 57 subjects treated with CRS followed by 30 min of HIO were pooled with sparse plasma concentrations collected from 50 patients with solid tumors treated with intravenous oxaliplatin. Pharmacokinetic data were jointly analyzed with nonlinear mixed-effect model (NONMEM VII software). The effect of carrier solution (icodextrin 4 % vs. dextrose 5 %) and selected patient covariates on oxaliplatin pharmacokinetics was investigated. Model evaluation was performed using predictive checks and nonparametric bootstrap. Results: An open linear two-compartment disposition model with linear absorption from peritoneum to plasma was used to characterize the oxaliplatin pharmacokinetics in peritoneum and plasma. No patient-related covariates were associated with oxaliplatin pharmacokinetics. The volume of distribution in the peritoneum (Va) exponentially decreased due to the carrier solute absorption. The reduction in Va was 1.76-fold faster when HIO was administered in dextrose 5 %, relative to icodextrin 4 %. For HIO durations of 30 min, the rate of oxaliplatin absorption ranges from 0.84 to 0.96 h -1 for icodextrin 4 % and from 0.86 to 1.09 h-1 for dextrose 5 %. The extent of HIO absorption was 38 %, regardless of the carrier solution. Conclusions: Hyperthermic intraperitoneal oxaliplatin absorption is fast and incomplete. The small difference in oxaliplatin exposure between both carrier solutions evaluated is not clinically relevant for HIO durations of 30 min. © 2014 Springer-Verlag. Source

Escudero-Ortiz V.,Plataforma de Oncologia | Duart-Duart Ma.J.,University Miguel Hernandez | Perez-Ruixo C.,University of Valencia | Perez-Ruixo C.,Consulting Projects for Research | And 2 more authors.
Farmacia Hospitalaria | Year: 2014

Objective: To evaluate the in vitro physicochemical stability of oxaliplatin and doxorubicin when the in vivo hyperthermic intraperitoneal conditions are reproduced. Methods: Three solutions were prepared, A (oxaliplatin 200 mg/L), B (doxorubicin 15 mg/L) and C (oxaliplatin 200 mg/L with doxorubicin 15 mg/L) in glucose 5%. The three solutions were subjected to the maximum temperature reached in vivo (49°C) for two hours. Physical stability was focused on visual control of particles or precipitates in solutions, discharge of gases, odor and color. Samples were taken every 15 minutes and the chemical stability was evaluated by determining the concentration of oxaliplatin and doxorubicin remaining in the samples. Oxaliplatin concentrations were determined by atomic absorption graphite chamber while doxorubicin was determined by high performance liquid chromatography. The chemical stability criteria selected was the one described by the American Pharmacopoeia, which sets a permissible variation range between the 90-110% of the initial concentration. Results: During the assay there was no appearance of particles, precipitates in the samples, discharge of gases, nor colour changes in the solutions. The samples showed a remaining concentration of oxaliplatin and doxorubicin within the 90-110% limit. The stability of the samples that follow to two cycles of freeze-thaw after hyperthermia was also found within the specified limits. Conclusion: A, B and c solutions in 5% glucose, are physically and chemically stable at 49°C for two hours. Under these conditions, these solutions could be used with guarantees of stability in patients with peritoneal carcinomatosis subsidiary of intraperitoneal hyperthermic chemotherapy based in these antineoplastic agents. Source

Gonzalez-Sales M.,Consulting Projects for Research | Valenzuela B.,Platform of Oncology | Perez-Ruixo C.,Consulting Projects for Research | Fernandez Teruel C.,PharmaMar S.A | And 3 more authors.
Clinical Pharmacokinetics | Year: 2012

Background and Objective: PM00104 (Zalypsis®) is a novel marine-derived compound that has shown antineoplastic activity against a number of human tumour cell lines. Myelosuppression was found to be a PM00104 dose-limiting toxicity during phase I studies. The objective of this study was to characterize the time course of neutropenia after intravenous PM00104 administration in cancer patients. Methods: Absolute neutrophil counts (ANCs) and pharmacokinetic data from 144 patients receiving PM00104 doses ranging from 0.053 to 5 mg/m 2 were used to estimate the system-related (baseline ANC [Circ 0], mean transit time [MTT], feedback on proliferation [γ] and maturation [δ]) and drug-specific (first-order elimination rate constant from effect compartment [ke0] [α and β]) parameters of a modified Friberg's model. The concentrations in the effect compartment (C e) were assumed to reduce the proliferation rate of the progenitor cells according to the function α×Ceβ. Model evaluation and simulations were undertaken to evaluate the effect of dose intensity, dose density and the intravenous infusion duration on severe neutropenia incidence. Results: The typical values (between-subject variability [%]) of the Circ0, MTT, γ, δ, ke0, α and β were estimated to be 5.66 × 109 cells/L (13 %), 149 h (29 %), 0.136, 0.191, 0.00639 h-1 (32 %), 0.332 L/μg (24 %) and 1.47, respectively. Age, bodyweight, sex, serum albumin, total protein, liver metastases, number of previous chemotherapy lines and performance status were not associated with model parameters. The model evaluation evidenced an accurate prediction of the neutropenia grade 3 and/or 4 incidence. Simulations indicated that PM00104 dose and dosing interval, but not infusion duration, were the main determinants of the neutropenia severity and duration. Conclusions: The time course of neutropenia following PM00104 was well characterized by the model developed. The model-predicted time course of the ANCs and its variability confirmed that neutropenia is reversible, of short duration and non-cumulative. © 2012 Springer International Publishing Switzerland. Source

Perez-Ruixo C.,Consulting Projects for Research | Valenzuela B.,University Miguel Hernandez | Fernandez Teruel C.,PharmaMar S.A | Gonzalez-Sales M.,Consulting Projects for Research | And 4 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2012

Objective: The aim of this study was to characterize the population pharmacokinetics of PM00104 (Zalypsis®) in cancer patients. Methods: A total of 135 patients included in four phase I clinical trials who receive intravenous PM00104 at doses ranging from 53 to 5,000 μg/m 2 and administered as 1-, 3-, or 24-h infusion every 3 weeks or as 1-h infusion on days 1, 8, and 15 of a 28-day cycle, or 1-h infusion daily during 5 consecutive days every 3 weeks were included in the analysis. Pharmacokinetic data were analyzed with non-linear mixed effect model using NONMEM VI software. The effect of selected patient covariates on PM00104 pharmacokinetics was investigated. Model evaluation was performed using predictive checks and non-parametric bootstrap. Results: An open four-compartment catenary linear model with first-order elimination was developed to best describe the data. Plasma clearance and its between-subject variability was 43.7 L/h (34%). Volume of distribution at steady state was 822 L (117%). Within the range of covariates studied, age, sex, body size variables, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, lactate dehydrogenase, creatinine clearance, albumin, total protein, hemoglobin, performance status, liver metastases, dose-limiting toxicity, and stable disease for 3 months were not statistically related to PM00104 pharmacokinetic parameters. Bootstrap and posterior predictive check evidenced the model was deemed appropriate to describe the time course of PM00104 plasma concentrations in cancer patients. Conclusions: The integration of phase I pharmacokinetic data demonstrated PM00104 linear elimination from plasma, dose proportionality up to 5,000 μg/m 2, and time-independent pharmacokinetics. No clinically relevant covariates were identified as predictors of PM00104 pharmacokinetics. © 2011 Springer-Verlag. Source

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