112 research outputs found
A pharmacometrics model to define docetaxel target in early breast cancer
Aims: We aimed to study the relation between pharmacokinetics (PK) and pharmacodynamics (PD) of docetaxel in early breast cancer and recommend a target exposure. Methods: A PK/PD study was performed in 27 early breast cancer patients treated with doxorubicin and cyclophosphamide for 4 cycles followed by 4 cycles of docetaxel 75–100 mg/m2 infused every 21 days. Individual Bayesian estimates of docetaxel PK parameters were obtained using a nonparametric population PK model developed with data from patients with metastatic breast cancer who received dose-intensified docetaxel (300–350 mg/m2). Docetaxel area under the curve (AUC) and maximum concentration (Cmax) in each cycle and total cumulative AUC (AUCcum) were calculated and related to the incidence of adverse effects and tumour recurrence. Results: Docetaxel clearance showed no change over the 4 treatment cycles, but a gradual increase in the volume of distribution was observed. One third of the patients had at least 1 dose reduction of docetaxel due to toxicity. The mean AUC, AUCcum and Cmax in patients showing docetaxel-associated adverse events were significantly higher than in patients free of toxicity (P 4.5 mg*h/L and 3.5 mg/L, respectively, were risk factors for docetaxel toxicity, while an AUC <4.5 mg*h/L was associated with tumour recurrence. Conclusion: We report for the first time a relation between docetaxel exposure and toxicity and recommend specific targets of drug exposure with implications for the clinical management of early breast cancer patients.Fil: Aldaz, Azucena. Universidad de Navarra; EspañaFil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: AramendĂa, JosĂ© Manuel. Universidad de Navarra; Españ
Importancia de la excrecion biliar en la farmacocinetica del paracetamol en la rata
El presente trabajo reporta el estudio de la farmacocinĂ©tica del paracetamol en ratas (100 mg/kg, p.o) con flujo biliar modificado, interrumpido por canulaciĂłn del conducto biliar o estimulado por acciĂłn farmacolĂłgica con ácido ursodesoxicĂłlico. A pesar de que el paracetamol sufre recirculaciĂłn enterohepática y que la excreciĂłn biliar de la droga es una vĂa importante de eliminaciĂłn en la rata, la alteraciĂłn del flujo biliar no provocĂł diferencias estadĂsticamente significativas en el tiempo de vida medio de eliminaciĂłn de la droga. Por el contrario, se observĂł una modificaciĂłn de los parámetros farmacocinĂ©ticos relacionados con la biodisponibilidad del paracetamol.Importance of Biliary Excretion in Paracetamol Pharmacokinetics in the Rat”. The present work reports the study of paracetamol pharmacokinetics in the rat (100 mg/kg, p.o) with modified bile flow, interrupted by bile duct cannulation or pharmacologically stimulated by ursodeoxycholic acid. Even if paracetamol undergoes enterohepatic recycling and the biliary excretion has been reported to be an important pathway of drug elimination in the rat, the modification of the bile flow lead to no statistical significant difference in the elimination half life time of the drug. On the contrary, it was observed a change in the pharmacokinetic parameters related to the bioavailability of paracetamolFil: Schaiquevich, Paula Susana. ININFA; Argentina. ININFA; ArgentinaFil: Viviana Niselman. ININFA; ArgentinaFil: Rubio, Modesto Carlos. ININFA; Argentin
A pharmacometrics model to define docetaxel target in early breast cancer
Aims: We aimed to study the relation between pharmacokinetics (PK) and pharmacodynamics (PD) of docetaxel in early breast cancer and recommend a target exposure.
Methods: A PK/PD study was performed in 27 early breast cancer patients treated with doxorubicin and cyclophosphamide for 4 cycles followed by 4 cycles of docetaxel 75-100 mg/m2 infused every 21 days. Individual Bayesian estimates of docetaxel PK parameters were obtained using a nonparametric population PK model developed with data from patients with metastatic breast cancer who received dose-intensified docetaxel (300-350 mg/m2 ). Docetaxel area under the curve (AUC) and maximum concentration (Cmax) in each cycle and total cumulative AUC (AUCcum) were calculated and related to the incidence of adverse effects and tumour recurrence.
Results: Docetaxel clearance showed no change over the 4 treatment cycles, but a gradual increase in the volume of distribution was observed. One third of the patients had at least 1 dose reduction of docetaxel due to toxicity. The mean AUC, AUCcum and Cmax in patients showing docetaxel-associated adverse events were significantly higher than in patients free of toxicity (P 4.5 mg*h/L and 3.5 mg/L, respectively, were risk factors for docetaxel toxicity, while an AUC <4.5 mg*h/L was associated with tumour recurrence.
Conclusion: We report for the first time a relation between docetaxel exposure and toxicity and recommend specific targets of drug exposure with implications for the clinical management of early breast cancer patients
Population pharmacokinetics of amikacin in neonatal intensive care unit patients
Background Amikacin treatment requires close monitoring of blood concentrations to increase the probability that levels achieved are both effective and safe. Aims We described population pharmacokinetics parameters of amikacin in newborns from a Neonatal Intensive Care Unit with suspected or documented sepsis. Methods A nonlinear mixed-effect model approach was used to analyse the data. Results Twenty seven neonates were enrolled. Final parameter estimates were: Ke(h-1)=0.232x(CR) Exp-0.85; V(mL/kg)=497. Conclusion Weight and serum creatinine are associated with neonatal amikacin volume of distribution and elimination constant rate, respectively. The presence of sepsis may decrease amikacin elimination, although this observation should be further explored. These results could help to individualize amikacin dosage for neonates
Pharmacovigilance of calcineurin inhibitors in pediatric kidney and liver transplantation
Objetivo: Desarrollar un programa de farmacovigilancia de pacientes pediátricos trasplantados hepáticos y renales centrado en inmunosupresores calcineurĂnicos del Hospital de PediatrĂa JP Garrahan de Argentina. MĂ©todos: Se evaluaron las reacciones adversas a medicamentos (RAM) de los pacientes pediátricos trasplantados renales y hepáticos de nuestro hospital tratados con inhibidores de calcineurina (ciclosporina y tacrolimus) por revisiĂłn retrospectiva de historias clĂnicas de pacientes trasplantados en 2010-2011, y análisis prospectivo por farmacovigilancia activa de trasplantados fuera de dicho perĂodo, cuyas complicaciones se hayan presentado en los ateneos semanales del Servicio de Trasplante desde marzo de 2011. Las RAM se notificaron a la autoridad sanitaria nacional. Resultados: Se analizaron un total de 59 pacientes, 28 trasplantados renales y 31 hepáticos. Se notificaron, en ambos trasplantes, 60 RAM a ciclosporina destacándose (nĂşmero de casos) hipertensiĂłn arterial (19) y nefrotoxicidad (6). Asimismo, se registraron 46 RAM a tacrolimus, incluyendo hipomagnesemia (25), hipertensiĂłn (7) y nefrotoxicidad (5). El 95% y 96% de los eventos adversos a ciclosporina y a tacrolimus, respectivamente, han sido agrupados como probables o definitivos. El 70% y 98% de los eventos adversos a ciclosporina y a tacrolimus respectivamente, han sido de severidad moderada o grave. Conclusiones: Este es el primer proyecto en AmĂ©rica Latina que propone y desarrolla el estudio cuali-cuantitativo intensivo de RAM a inhibidores de calcineurina en trasplante pediátrico renal y hepático. Es necesario estimular la notificaciĂłn espontánea asĂ como continuar el seguimiento de RAM a mediano y largo plazo para mejorar la calidad de vida del paciente trasplantado.Aim: To develop a pharmacovigilance program of calcineurin inhibitors used in pediatric renal and liver transplant patients at Hospital de PediatrĂa JP Garrahan, Argentina. Methods: Adverse drug reactions (ADRs) of pediatric patients with kidney and liver transplantation treated with calcineurin inhibitors (cyclosporine and tacrolimus) were evaluated by retrospective review of medical records of patients transplanted between 2010 and 2011. In addition, we carried out active pharmacovigilance since March, 2011. ADRs were reported to the National Health Authority. Results: A total of 59 patients, 28 kidney transplant and 31 liver tarnsplant patients were analyzed. In both transplants, 60 ADRs to cyclosporine were reported including (number of cases), hypertension (19) and nephrotoxicity (6). In addition, 46 ADRs to tacrolimus were registered as hypomagnesemia (25), hypertension (7) and nephrotoxicity (5). A total of 95% and 96% of the adverse events to cyclosporine and tacrolimus, respectively, were defined as probable or definitive. Lastly, 70% and 98% of the events to cyclosporine and tacrolimus respectively, have been moderately severe or severe. Conclusions: This is the first study in Latin America that developed an intensive qualitative and quantitative analysis of the ADRs to calcineruin inhibitors in pediatric kidney and liver transplant patients. Spontaneous reporting should be motivated as well as monitoring ADRs should continue in the medium and long term for improving patient's quality of life.Fil: Riva, Natalia. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Caceres Guido, Paulo Arturo. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Rousseau, Marcela. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Dip, Marcelo. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Monteverde, Marta. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Imventarza, Oscar. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Mato, Gabriel. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; Argentin
A molecular biology and phase II trial of lapatinib in children with refractory CNS malignancies: a pediatric brain tumor consortium study.
High expression of ERBB2 has been reported in medulloblastoma and ependymoma; EGFR is amplified and over-expressed in brainstem glioma suggesting these proteins as potential therapeutic targets. We conducted a molecular biology (MB) and phase II study to estimate inhibition of tumor ERBB signaling and sustained responses by lapatinib in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, ependymoma, and high-grade glioma (HGG) undergoing resection were stratified and randomized to pre-resection treatment with lapatinib 900 mg/m(2) dose bid for 7-14 days or no treatment. Western blot analysis of ERBB expression and pathway activity in fresh tumor obtained at surgery estimated ERBB receptor signaling inhibition in vivo. Drug concentration was simultaneously assessed in tumor and plasma. In the phase II study, patients, stratified by histology, received lapatinib continuously, to assess sustained response. Eight patients, on the MB trial (four medulloblastomas, four ependymomas), received a median of two courses (range 1-6+). No intratumoral target inhibition by lapatinib was noted in any patient. Tumor-to-plasma ratios of lapatinib were 10-20 %. In the 34 patients (14 MB, 10 HGG, 10 ependymoma) in the phase II study, lapatinib was well-tolerated at 900 mg/m(2) dose bid. The median number of courses in the phase II trial was two (range 1-12). Seven patients (three medulloblastoma, four ependymoma) remained on therapy for at least four courses range (4-26). Lapatinib was well-tolerated in children with recurrent or CNS malignancies, but did not inhibit target in tumor and had little single agent activity.Fil: Fouladi, Maryam. St. Jude Children’s Research Hospital; Estados UnidosFil: Stewart, Clinton F.. St. Jude Children’s Research Hospital; Estados UnidosFil: Blaney, Susan M.. Baylor College of Medicine. Texas Children’s Cancer Center; Estados UnidosFil: Onar Thomas, Arzu. St. Jude Children’s Research Hospital; Estados UnidosFil: Schaiquevich, Paula Susana. St. Jude Children’s Research Hospital; Estados Unidos. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Packer, Roger J.. Children’s National Medical Center; Estados UnidosFil: Goldman, Stewart. Anne and Robert H. Lurie Children’s Hospital of Chicago; Estados UnidosFil: Geyer, J. Rusell. Children’s Hospital and Regional Medical Center; Estados UnidosFil: Gajjar, Amar. St. Jude Children’s Research Hospital; Estados UnidosFil: Kun, Larry E.. St. Jude Children’s Research Hospital; Estados UnidosFil: Boyett, James M.. St. Jude Children’s Research Hospital; Estados UnidosFil: Gilbertson, Richard J.. St. Jude Children’s Research Hospital; Estados Unido
Pharmacokinetics, Safety, and Efficacy of Intravitreal Digoxin in Preclinical Models for Retinoblastoma
PURPOSE:To assess in vitro cytotoxic activity and antiangiogenic effect, ocular and systemic disposition, and toxicity of digoxin in rabbits after intravitreal injection as a potential candidate for retinoblastoma treatment.METHODS:A panel of two retinoblastoma and three endothelial cell types were exposed to increasing concentrations of digoxin in a conventional (72-hour exposure) and metronomic (daily exposure) treatment scheme. Cytotoxicity was defined as the digoxin concentration that killed 50% of the cells (IC50) and was assessed with a vital dye in all cell types. Induction of apoptosis and cell-cycle status were evaluated by flow cytometry after both treatment schemes. Ocular and systemic disposition after intravitreal injection as well as toxicity was assessed in rabbits. Electroretinograms (ERGs) were recorded before and after digoxin doses and histopathological examinations were performed after enucleation.RESULTS:Digoxin was cytotoxic to retinoblastoma and endothelial cells under conventional and metronomic treatment. IC50 was comparable between both schedules and induced apoptosis in all cell lines. Calculated vitreous digoxin Cmax was 8.5 ÎĽg/mL and the levels remained above the IC50 for at least 24 hours after intravitreal injection. Plasma digoxin concentration was below 0.5 ng/ml. Retinal toxicity was evident after the third intravitreal dose with considerable changes in the ERG and histologic damage to the retina.CONCLUSIONS:Digoxin has antitumor activity for retinoblastoma while exerting antiangiogenic activity in vitro at similar concentrations. Metronomic treatment showed no advantage in terms of dose for cytotoxic effect. Four biweekly injections of digoxin led to local toxicity to the retina but no systemic toxicity in rabbits.Fil: Winter, Ursula Andrea. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Buitrago, Emiliano. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Mena, Hebe Agustina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: del Sole, Maria Jose. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de FisiopatologĂa. Laboratorio de FarmacologĂa; ArgentinaFil: Laurent, Viviana Eunice. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Negrotto, Soledad. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Francis, Jasmine. Memorial Sloan-Kettering Cancer Center; Estados UnidosFil: Arana, Eloisa. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay. Instituto de InmunologĂa, GenĂ©tica y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de InmunologĂa, GenĂ©tica y Metabolismo; ArgentinaFil: Sgroi, Mariana. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Croxatto, Juan Oscar. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; Argentina. FundaciĂłn OftalmologĂa Argentina "J. Malbrán"; ArgentinaFil: Djaballah, Hakim. Core Facility Memorial Sloan-Kettering Cancer Center; Estados UnidosFil: Chantada, Guillermo Luis. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Abramson, David. Memorial Sloan-Kettering Cancer Center; Estados UnidosFil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; Argentin
A Population Pharmacokinetic Approach to Describe Cephalexin Disposition in Adult and Aged Dogs
This study was conducted in order to characterize the pharmacokinetics of orally administered cephalexin to healthy adult and aged dogs, using a population pharmacokinetic approach. Two hundred and eighty-six cephalexin plasma concentrations obtained from previous pharmacokinetic studies were used. Sex, age, pharmaceutical formulation, and breed were evaluated as covariates. A one-compartment model with an absorption lag-time (Tlag) best described the data. The final model included age (adult; aged) on apparent volume of distribution (Vd/F), apparent elimination rate (ke/F), and Tlag; sex (female; male) on ke/F, and breed (Beagle; mixed-breed) on Vd/F. Addition of the covariates to the model explained 78% of the interindividal variability (IIV) in Vd/F, 36% in ke/F, and 24% in Tlag, respectively. Formulation did not affect the variability of any of the pharmacokinetic parameters. Tlag was longer, whereas Vd/F and ke/F were lower in aged compared to adult animals; in female aged dogs ke/F was lower than in male aged dogs; however, the differences were of low magnitude. Different disposition of cephalexin may be expected in aged dogs
Pharmacokinetic analysis of topotecan after superselective ophthalmic artery infusion and periocular administration in a porcine mode
Purpose: To characterize the vitreous and plasma pharmacokinetics of topotecan after ophthalmic artery infusion (OAI) subsequent to superselective artery catheterization and to compare it with periocular injection (POI). Methods: The ophthalmic artery of 4 pigs was catheterized and 1 mg of topotecan infused over a period of 30 minutes. The contralateral eye was subsequently used for administering topotecan by POI. Serial vitreous specimens were obtained by microdialysis and plasma samples collected and assayed for total and lactone topotecan. Results: Maximum total topotecan concentration in the vitreous (median, range) was significantly higher after OAI compared with POI (131.8 ng/mL [112.9–138.7] vs. 13.6 ng/mL [5.5–15.3], respectively; P , 0.005). Median vitreous exposure calculated as area under the curve for total topotecan attained after OAI was significantly higher than after POI (299.8 nghour/mL [247.6–347.2] and 48.9 nghour/mL [11.8–63.4], respectively; P , 0.05). The vitreous to plasma exposure ratio was 29 after OAI and 3.4 after POI. Systemic exposure for total topotecan was low after both modalities of administration, with a trend to be lower after OAI compared with POI (10.6 nghour/mL [6.8–13.4] vs. 18.7 nghour/mL [6.3–21.7]; P = 0.54). Conclusion: Superselective OAI resulted in significantly higher vitreous concentrations and exposure and a trend toward lower systemic exposure than POI.Fil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Buitrago, Emiliano. Universidad de Buenos Aires; ArgentinaFil: Ceciliano, Alejandro. No especifĂca;Fil: Fandino, Adriana C.. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Asprea, Marcelo. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Sierre, Sergio. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Abramson, David H.. No especifĂca;Fil: Bramuglia, Guillermo Federico. Universidad de Buenos Aires; ArgentinaFil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; Argentin
Pharmacokinetic analysis of topotecan after superselective ophthalmic artery infusion and periocular administration in a porcine mode
Purpose: To characterize the vitreous and plasma pharmacokinetics of topotecan after ophthalmic artery infusion (OAI) subsequent to superselective artery catheterization and to compare it with periocular injection (POI). Methods: The ophthalmic artery of 4 pigs was catheterized and 1 mg of topotecan infused over a period of 30 minutes. The contralateral eye was subsequently used for administering topotecan by POI. Serial vitreous specimens were obtained by microdialysis and plasma samples collected and assayed for total and lactone topotecan. Results: Maximum total topotecan concentration in the vitreous (median, range) was significantly higher after OAI compared with POI (131.8 ng/mL [112.9–138.7] vs. 13.6 ng/mL [5.5–15.3], respectively; P , 0.005). Median vitreous exposure calculated as area under the curve for total topotecan attained after OAI was significantly higher than after POI (299.8 nghour/mL [247.6–347.2] and 48.9 nghour/mL [11.8–63.4], respectively; P , 0.05). The vitreous to plasma exposure ratio was 29 after OAI and 3.4 after POI. Systemic exposure for total topotecan was low after both modalities of administration, with a trend to be lower after OAI compared with POI (10.6 nghour/mL [6.8–13.4] vs. 18.7 nghour/mL [6.3–21.7]; P = 0.54). Conclusion: Superselective OAI resulted in significantly higher vitreous concentrations and exposure and a trend toward lower systemic exposure than POI.Fil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Buitrago, Emiliano. Universidad de Buenos Aires; ArgentinaFil: Ceciliano, Alejandro. No especifĂca;Fil: Fandino, Adriana C.. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Asprea, Marcelo. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Sierre, Sergio. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Abramson, David H.. No especifĂca;Fil: Bramuglia, Guillermo Federico. Universidad de Buenos Aires; ArgentinaFil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; Argentin
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