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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

Fernandez-Ballester G.,University Miguel Hernandez | Fernandez-Carvajal A.,University Miguel Hernandez | Devesa I.,University Miguel Hernandez | Valenzuela B.,Platform of Oncology | And 3 more authors.
Current Topics in Pharmacology | Year: 2011

Because drug discovery efforts have experienced a pronounced decline in productivity, novel approaches to the rational design of new drugs are being introduced and developed. An exciting solution is the use of natural or synthetic peptides and peptidomimetics targeting protein-protein interactions essential for signaling networks function. The combination of several bioinformatic approaches (docking, virtual screening, pharmacophore models, etc.) allows for the use of the vast amount of information on protein-protein interactions deposited in structural databases. In this respect, interacting peptides are susceptible to optimization in order to stabilize or disrupt protein-protein interactions, providing a promising use of peptides and derivatives as therapeutics. In this review we illustrate tools and strategies currently used in peptidomic drug discovery as well as trends in the area of molecular pharmacology. Source

Miguel-Lillo B.,Clinical Pharmacology | Miguel-Lillo B.,Clinical Research and Development of Pharma Mar | Valenzuela B.,Platform of Oncology | Valenzuela B.,San Antonio de Murcia Catholic University | And 3 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2015

Abstract Purpose: In this study, we characterize the population pharmacokinetics of kahalalide F (KF), a novel marine anticancer drug, after intravenous (i.v.) administration in advanced cancer patients. Methods: Data from 240 patients included in three Phase I and three Phase II trials receiving i.v. weekly and every 3 weeks infusions of KF, at doses ranging 266-6650 μg/m2, were analyzed using NONMEM™ VII. The effect of demographics and/or pathophysiologically relevant factors on KF pharmacokinetic parameters was evaluated. Model evaluation was conducted using nonparametric bootstrap and visual predictive check (in both internal and external datasets). Results: An open two-compartment model with linear distribution and elimination from central compartment was suitable to describe the data. Volume of distribution at steady state and its between-subject variability (CV%) was estimated to be 6.56 L (28 %). Plasma clearance was estimated to be 6.25 L/h (43 %). Within the range of covariates evaluated, age, weight, body surface area, gender, ECOG performance status, presence of liver metastases, creatinine clearance, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, total protein and serum albumin did not contribute to explain KF pharmacokinetic variability to a significant extent. The developed model was deemed appropriate to describe the time course of KF plasma concentrations and its variability in advanced cancer patients. Conclusion: The integration of pharmacokinetic data from six clinical studies demonstrated KF linear elimination from plasma, dose-proportional exposure and time-independent pharmacokinetics. Based on analyzed data, no clinically relevant covariates were identified as predictors of KF pharmacokinetics. © 2015 Springer-Verlag Berlin Heidelberg. Source

Escudero-Ortiz V.,Platform of Oncology | Perez-Ruixo J.J.,Amgen Inc. | Valenzuela B.,Platform of Oncology
Therapeutic Drug Monitoring | Year: 2013

A selective and precise high-performance liquid chromatography ultraviolet method was developed and validated for the determination of lapatinib in human plasma. After protein precipitation with acetonitrile, lapatinib and sorafenib were separated using isocratic elution (on a C18 Ultrabase column using a mobile phase of acetonitrile/20 mM ammonium acetate in a proportion 53:47 (v/v) pumped at a constant flow rate of 1.2 mL/min). Quantification was performed at 260 nm. Calibration curves were linear over the range 0.2-10 μg/mL. Inter- and intraday coefficients of variation were less than 7%. The limit of detection and the lower limit of quantification were 0.1 and 0.2 μg/mL, respectively. Recoveries of lapatinib from plasma were higher than 86.7% in all cases. The assay was applied to the determination of the drug in the plasma of 2 cancer patients receiving lapatinib, 1000 and 1250 mg orally, and could be useful for therapeutic drug monitoring of lapatinib in routine clinical practice. Copyright © 2013 by Lippincott Williams & Wilkins. Source

Perez-Ruixo C.,University of Valencia | Valenzuela B.,Platform of Oncology | Peris J.E.,University of Valencia | Bretcha-Boix P.,Platform of Oncology | And 3 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2013

Purpose: To characterize the hyperthermic intraperitoneal oxaliplatin (HIO) pharmacokinetics in peritoneum and plasma in patients with peritoneal carcinomatosis (PC) after cytoreductive surgery (CRS). Methods: Data from 36 patients receiving HIO diluted in isotonic 4 % icodextrin were combined with data from 13 patients receiving HIO diluted in isotonic 5 % dextrose. Total oxaliplatin in peritoneal and plasma fluids were used to characterize an open two-compartment disposition model with linear distribution and elimination and first-order absorption from peritoneum to plasma using NONMEM software. The effect of patient- and treatment-related covariates on oxaliplatin pharmacokinetic parameters was explored. Results: The typical value (interindividual variability, %) in k a, CL, and V ss were 0.57 h-1 (43 %), 1.71 L h-1 (39 %), and 77 L (65 %), respectively. No significant effect of age, body surface area, sex, creatinine clearance, liver metastases, PC index, and complete cytoreduction on pharmacokinetic parameters was found. A 12-15 % reduction in peritoneal volume of distribution was observed in patients receiving HIO diluted in 5 % dextrose relative to those patients receiving HIO diluted in 4 % icodextrin. Conclusions: The integration of peritoneal and plasma data demonstrated oxaliplatin linear absorption from peritoneum to plasma, non-specific distribution to a peripheral compartment, and linear elimination from the central compartment when HIO was administered with isotonic carrier solutions to PC patients who underwent CRS. Only the effect of the carrier solution had an impact in the peritoneal volume of distribution, but its clinical relevance seems to be limited, especially for short HIO infusions (<60 min). © 2012 Springer-Verlag Berlin Heidelberg. Source

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