Chemical stability and physical compatibility of meropenem in admixtures for continuous and extended intravenous infusions / Estabilidad química y compatibilidad física de meropenem en mezclas para infusión intravenosa continua y extendida

Introduction: Prolonged intravenous infusion of beta-lactams increase the clinical cure rate compared to conventional administration in critical or septic patients. This study aimed to determine chemical stability and physical compatibility of meropenem at conditions used in clinical practice to evaluate the stability of the preparation during its administration and the possibility of anticipated preparation. Methods: Admixtures in study were: (i) meropenem 6g in 0.9% sodium chloride (NS) in infusor of 2mL/h 50mL or 10mL/h 240mL; (ii) meropenem 1 or 2g in NS in infusion bag of 250mL. Temperatures of study were: (i) infusor: 4.5°C, 32°C or 12h at 4.5°C followed by 32°C; (ii) Infusion bag: 4.5°C, 24.5°C or 6h at 4.5°C followed by 24.5°C. Time of study was 5–6 days in infusor and 1 day in infusion bag. Chemical stability was evaluated by high performance liquid chromatography and physical compatibility by measuring pH and visual inspection. Results: Chemical stability and physical compatibility of meropenem in admixtures in infusors were reduced at high meropenem concentration and high temperature. Admixtures in infusion bag show chemical stability and physical compatibility for at least 1 day. Conclusion: Administration of meropenem 6g in infusion of 24h in 240mL of 0.9% NaCl in infusor of 10mL/h could be possible if the admixture is infused at 4.5°C. Extended infusion of meropenem 1 or 2g in 0.9% NaCl in infusion bag (250mL) in 3–4h is also feasible. Anticipated preparation of the admixtures in infusion bag is possible with a stability of 24h.(AU)

Introducción: La infusión intravenosa prolongada de beta-lactámicos aumenta la velocidad de curación clínica comparada con la administración convencional en pacientes críticos o sépticos. Este estudio tiene como objetivo determinar la estabilidad química y la compatibilidad física de meropenem en condiciones utilizadas en la práctica clínica para evaluar la estabilidad de la preparación durante su administración y la posibilidad de la preparación anticipada. Métodos: Las mezclas en estudio fueron: (I) meropenem 6g en cloruro sódico 0,9% (SN) en infusor de 2mL/h 50 mL o 10mL/h 240mL; (iii) meropenem 1 o 2g en SN en bolsa de infusión de 250mL. Las temperaturas de estudio fueron: (i) infusor: 4,5°C, 32°C o 12h a 4,5°c seguido de 32°C; (ii) bolsa de infusión: 4,5°C, 24,5°C o 6h a 4,5°c seguido de 24,5°C. El tiempo de estudio fue de 5-6 días en infusor y 1 día en bolsa de infusión. Se evaluó la estabilidad química mediante cromatografía líquida de alta resolución y la compatibilidad física por medida de pH e inspección visual. Resultados: La estabilidad química y la compatibilidad física de meropenem en las mezclas en infusores disminuyeron al aumentar la concentración de meropenem y la temperatura. Las mezclas en bolsas de infusión mostraron estabilidad química y compatibilidad física durante al menos 1 día. Conclusión: La administración de meropenem 6g en infusión de 24h en 240 mL de cloruro sódico 0,9% en infusor de 10ml/h podría ser posible si la mezcla es administrada a 4,5°C. La infusión extendida de 1 o 2g en cloruro sódico 0,9% en bolsa de infusión (250 mL) en 3-4h es también viable. Puede realizarse la preparación anticipada de mezclas de meropenem en bolsas de infusión con una estabilidad de 1 día.(AU)

Chemical stability and physical compatibility of meropenem in admixtures for continuous and extended intravenous infusions.

INTRODUCTION: Prolonged intravenous infusion of beta-lactams increase the clinical cure rate compared to conventional administration in critical or septic patients. This study aimed to determine chemical stability and physical compatibility of meropenem at conditions used in clinical practice to evaluate the stability of the preparation during its administration and the possibility of anticipated preparation. METHODS: Admixtures in study were: (i) meropenem 6g in 0.9% sodium chloride (NS) in infusor of 2mL/h 50mL or 10mL/h 240mL; (ii) meropenem 1 or 2g in NS in infusion bag of 250mL. Temperatures of study were: (i) infusor: 4.5°C, 32°C or 12h at 4.5°C followed by 32°C; (ii) Infusion bag: 4.5°C, 24.5°C or 6h at 4.5°C followed by 24.5°C. Time of study was 5-6 days in infusor and 1 day in infusion bag. Chemical stability was evaluated by high performance liquid chromatography and physical compatibility by measuring pH and visual inspection. RESULTS: Chemical stability and physical compatibility of meropenem in admixtures in infusors were reduced at high meropenem concentration and high temperature. Admixtures in infusion bag show chemical stability and physical compatibility for at least 1 day. CONCLUSION: Administration of meropenem 6g in infusion of 24h in 240mL of 0.9% NaCl in infusor of 10mL/h could be possible if the admixture is infused at 4.5°C. Extended infusion of meropenem 1 or 2g in 0.9% NaCl in infusion bag (250mL) in 3-4h is also feasible. Anticipated preparation of the admixtures in infusion bag is possible with a stability of 24h.

Physico-Chemical Stability of Admixtures of Vinflunine Used in Clinical Practice.

Procedure of administration of vinflunine is complex and consists of an Y-site injection with fluid at different speeds. Dose is diluted with 100 mL of 0.9% sodium chloride or 5% glucose and infused with half of the 500 mL bag of the fluid over 20 min; after that, the remaining fluid is administered at 300 mL/h. In this study, chemical stability and physical compatibility of vinflunine diluted with in 500 mL of both fluids were evaluated to simplify the administration procedure (infusion of mixture on 20 min followed by 250 mL of fluid at 300 mL/h). Physical compatibility and chemical stability were evaluated at two temperatures and protected from and exposed to light. Physical compatibility was evaluated by visual inspection, gravimetric control and measure of pH. A chromatographic method was developed to evaluate chemical stability. The dilution of vinflunine with 500 mL of fluid to final concentrations of 0.75 and 1.54 mg/mL is viable at doses used in clinical practice since admixtures are stable for 2 days at room temperature and at least 7 days under refrigeration. These results extend the expiration date of mixtures of vinflunine administered by the usual procedure and confirm the viability of the proposed procedure since administration is simplified and stability of vinflunine is guaranteed.

Personalized pharmacotherapy in oncology: Application of pharmacokinetic-pharmacodynamic criteria.

OBJECTIVE: Indication of personalized pharmacotherapy in oncologic patients is  based on the selection of the optimal treatment (drugs, dosing, routes and  methods of administration and duration) and on the most appropriate dosing  method to achieve maximum antineoplastic efficacy, expressed in terms of  remission or relapse-free time and acceptable toxicity for the patients. The aim  of this study was to explore the contribution of therapeutic monitoring of  plasma concentrations and of the application of the pharmacokinetic and  pharmacodynamic information available for some widely used drugs to  therapeutic personalization to the care of oncologic patients. METHOD: A complete non-systematic literature review was carried out of the  pharmacokinetic and pharmacodynamic properties of antineoplastic agents, as  well as of the results of their use in clinical practice. The search for high quality  articles included primary and secondary bibliographic sources. The  benefits of therapeutic monitoring were evaluated for parenteral cytotoxic  rugs, oral antineoplastic drugs, monoclonal antibodies and other biological  therapies used in clinical practice. RESULTS: Therapeutic personalization of antineoplastic drugs based on therapeutic monitoring of plasma concentrations together with the information provided by pharmacokinetic-pharmacodynamic models makes it  possible to reduce toxicity and increase the effectiveness of treatment. When  personalized treatment is established with high-dose methotrexate in patients  with osteosarcoma, target maximum concentrations are reached in 70% of the  cycles (49% when fixed doses are used). When 5-fluorouracil is used in  patients with colorectal cancer, the response rate is 33.7% (18.3% with fixed  doses). Similar benefit rates are obtained with asparaginase, busulfan, oral  antineoplastics and monoclonal antibodies. CONCLUSIONS: Due to the narrow therapeutic range of antineoplastic drugs and  the highly variable clinical response they elicit, both in terms of  effectiveness and safety, the monitoring of their plasma concentrations and the  application of pharmacokinetic and pharmacodynamic principles and  models constitute feasible and promising tools in the personalization of  oncologic treatment.

OBJETIVO: La indicación de una farmacoterapia personalizada en oncología se  sustenta en la selección del tratamiento óptimo (fármacos, dosis, vías y  métodos de administración y duración) y en el método de ajuste de la dosis  para alcanzar la máxima eficacia antineoplásica, expresada en términos de  remisión de la enfermedad o de tiempo libre de recaída, con una toxicidad  aceptable para el paciente. El objetivo de este trabajo es explorar la  contribución, en la personalización terapéutica en oncología clínica asistencial,  de la monitorización terapéutica de las concentraciones plasmáticas y la  aplicación de la información farmacocinética y farmacodinámica disponible para  algunos fármacos ampliamente utilizados.Método: Se ha realizado una revisión bibliográfica no sistemática completa de  los criterios farmacocinéticos y farmacodinámicos de los antineoplásicos, así  como de los resultados derivados de su utilización en la práctica clínica  asistencial. En la búsqueda de artículos de alta calidad sobre los temas  planteados se han incluido fuentes bibliográficas primarias y secundarias. La  tilidad de la monitorización terapéutica se ha centrado en fármacos citotóxicos  parenterales, antineoplásicos orales, anticuerpos monoclonales y otras terapias  biológicas utilizadas en la práctica clínica asistencial. Resultados: La personalización terapéutica de fármacos antineoplásicos basada en la monitorización terapéutica de las  oncentraciones  plasmáticas, y la información que proporcionan los modelos farmacocinéticos- farmacodinámicos, permite reducir la toxicidad y aumentar la efectividad  asociada al tratamiento. Cuando se instaura un tratamiento personalizado con  metotrexato a altas dosis en pacientes con osteosarcoma se alcanza la  concentración máxima objetivo en un 70% de los ciclos (49% en dosis fijas), y  con 5-fluorouracilo en pacientes con cáncer colorrectal la tasa de respuesta es  del 33,7% (18,3% en dosis fijas). Con asparaginasa, busulfán, antineoplásicos  orales y anticuerpos monoclonales se obtienen tasas de beneficios similares. CONCLUSIONES: Debido al bajo intervalo terapéutico de los medicamentos antineoplásicos y a su alta variabilidad en la respuesta clínica,  tanto en términos de efectividad como de seguridad, la monitorización de sus  concentraciones plasmáticas, y la aplicación de los principios y de los modelos farmacocinéticos y farmacodinámicos, constituyen herramientas  actibles y prometedoras en la personalización de los tratamientos en oncología.

Farmacoterapia personalizada en oncología: Aplicación de criterios farmacocinéticos-farmacodinámicos / Personalized pharmacotherapy in oncology: Application of pharmacokinetic-pharmacodynamic criteria

Objetivo: La indicación de una farmacoterapia personalizada en oncología se sustenta en la selección del tratamiento óptimo (fármacos, dosis,vías y métodos de administración y duración) y en el método de ajuste dela dosis para alcanzar la máxima eficacia antineoplásica, expresada entérminos de remisión de la enfermedad o de tiempo libre de recaída, conuna toxicidad aceptable para el paciente. El objetivo de este trabajo esexplorar la contribución, en la personalización terapéutica en oncologíaclínica asistencial, de la monitorización terapéutica de las concentraciones plasmáticas y la aplicación de la información farmacocinética y farmacodinámica disponible para algunos fármacos ampliamente utilizados.Método: Se ha realizado una revisión bibliográfica no sistemática completa de los criterios farmacocinéticos y farmacodinámicos de los antineoplásicos, así como de los resultados derivados de su utilización en la prácticaclínica asistencial. En la búsqueda de artículos de alta calidad sobre lostemas planteados se han incluido fuentes bibliográficas primarias y secundarias. La utilidad de la monitorización terapéutica se ha centrado en fármacoscitotóxicos parenterales, antineoplásicos orales, anticuerpos monoclonales yotras terapias biológicas utilizadas en la práctica clínica asistencial.Resultados: La personalización terapéutica de fármacos antineoplásicos basada en la monitorización terapéutica de las concentraciones plasmáticas, y la información que proporcionan los modelos farmacocinéticos-farmacodinámicos, permite reducir la toxicidad y aumentar laefectividad asociada al tratamiento. (AU)

Objective: Indication of personalized pharmacotherapy in oncologicpatients is based on the selection of the optimal treatment (drugs, dosing,routes and methods of administration and duration) and on the mostappropriate dosing method to achieve maximum antineoplastic efficacy,expressed in terms of remission or relapse-free time and acceptable toxicity for the patients. The aim of this study was to explore the contribution oftherapeutic monitoring of plasma concentrations and of the applicationof the pharmacokinetic and pharmacodynamic information available forsome widely used drugs to therapeutic personalization to the care ofoncologic patients.Method: A complete non-systematic literature review was carried outof the pharmacokinetic and pharmacodynamic properties of antineoplastic agents, as well as of the results of their use in clinical practice.The search for high quality articles included primary and secondarybibliographic sources. The benefits of therapeutic monitoring wereevaluated for parenteral cytotoxic drugs, oral antineoplastic drugs,monoclonal antibodies and other biological therapies used in clinicalpractice.Results: Therapeutic personalization of antineoplastic drugs based ontherapeutic monitoring of plasma concentrations together with the information provided by pharmacokinetic-pharmacodynamic models makesit possible to reduce toxicity and increase the effectiveness of treatment.When personalized treatment is established with high-dose methotrexatein patients with osteosarcoma, target maximum concentrations are reached in 70% of the cycles (49% when fixed doses are used). When5-fluorouracil is used in patients with colorectal cancer, the responserate is 33.7% (18.3% with fixed doses). Similar benefit rates are obtained with asparaginase, busulfan, oral antineoplastics and monoclonalantibodies. (AU)

Population pharmacokinetics of lenalidomide in multiple myeloma patients.

PURPOSE: Lenalidomide disease-specific toxicity profiles and potentially life-threatening adverse events support the consideration of diversity in starting doses. The aim of this study was to conduct a population pharmacokinetic analysis of lenalidomide in multiple myeloma patients to identify and evaluate non-studied covariates that could be used for dose individualization. METHODS: Blood samples were collected from 15 multiple myeloma patients. Nonlinear mixed-effects modeling was used to develop a population pharmacokinetic model and perform covariate analysis. The developed model was used to simulate dose schedules in order to explore the need of different dosing regimens in patients with different covariate values. RESULTS: The data were accurately described by a one-compartment model with first-order elimination. Absorption was best described using three transit compartments. Creatinine clearance and body surface area were identified as covariates affecting apparent clearance and apparent volume of distribution, respectively. Simulations revealed that lower starting doses than the standard 25 mg/daily could be used in patients with body surface area below 1.8 m2 and even higher doses might be necessary for patients with normal renal function and large body surface area. CONCLUSIONS: This study identified creatinine clearance and body surface area as covariates that have a clinically relevant impact on lenalidomide pharmacokinetics using population pharmacokinetics. In addition, the developed population pharmacokinetic model can be used to individualize lenalidomide dose in multiple myeloma patients, taking into account not only creatinine clearance but also body surface area.

Effectiveness, toxicity, and economic evaluation of ipilimumab for the treatment of patients with metastatic melanoma in the Spanish outpatient setting.

To evaluate the effectiveness and toxicity profile of ipilimumab treatment and to examine the cost-effectiveness relation in a real-world sample of patients with metastasic melanoma. This was a multicenter, observational, retrospective cohorts study. To assess the effectiveness and safety of ipilimumab treatment progression-free survival (PFS), overall survival (OS) and adverse events were registered. An economic evaluation was performed and cost-effectiveness ratios (CERs) were calculated. Eleven patients were included, mean age 59 (SD=11) years. The median PFS was 3.83 months (95% confidence interval 0.98-9.80) and the median OS was 5.15 months (95% confidence interval 1.70-8.48). None of the patients included in the study achieved an objective response. A stable disease was achieved in four (36%) patients. The most commonly reported analytical adverse event was anemia, with all patients developing anemia in any grade. The most severe adverse event was neutropenia (n=6; 55%), with three patients developing grade 4 neutropenia (3/11; 27%). The total cost of ipilimumab treatment was &OV0556;483 397, with a median of 43 033 (interquartile range=9555) euros per patient. The median-based CER was 136 675 (28 539-474 865) euros per progression-free year gained and the median-based CER was 100 112 (23 107-374 893) euros per life-year gained. PFS observed in real-world patients was higher than that reported in clinical trials and OS was lower. The incidence of adverse events was higher. The additional cost per progression-free year gained was ∼&OV0556;136 675. The data from this study fill an important need for information on the relative value of this treatment in terms of cost-effectiveness.

A Wide Linearity Range Method for the Determination of Lenalidomide in Plasma by High-Performance Liquid Chromatography: Application to Pharmacokinetic Studies.

A wide linearity range analytical method for the determination of lenalidomide in patients with multiple myeloma for pharmacokinetic studies is required. Plasma samples were ultrasonicated for protein precipitation. A solid-phase extraction was performed. The eluted samples were evaporated to dryness under vacuum, and the solid obtained was diluted and injected into the high-performance liquid chromatography (HPLC) system. Separation of lenalidomide was performed on an Xterra RP C18 (250 mm length × 4.6 mm i.d., 5 µm) using a mobile phase consisting of phosphate buffer/acetonitrile (85:15, v/v, pH 3.2) at a flow rate of 0.5 mL · min-1 The samples were monitored at a wavelength of 311 nm. A linear relationship with good correlation coefficient (r = 0.997, n = 9) was found between the peak area and lenalidomide concentrations in the range of 100 to 950 ng · mL-1 The limits of detection and quantitation were 28 and 100 ng · mL-1, respectively. The intra- and interassay precisions were satisfactory, and the accuracy of the method was proved. In conclusion, the proposed method is suitable for the accurate quantification of lenalidomide in human plasma with a wide linear range, from 100 to 950 ng · mL-1 This is a valuable method for pharmacokinetic studies of lenalidomide in human subjects.

[Evaluation of two closed-system drug transfer device in the antineoplastic drug elaboration process]. / Evaluación de dos sistemas cerrados en el proceso de elaboración de quimioterapia parenteral.

OBJECTIVE: to assess the impact of two closed-system drug transfer device on the local and environmental contamination and preparation times in the process of preparation of parenteral chemotherapy compared to the standard system. METHOD: prospective observational study. Two different closed- systems providers, Care Fusion® and Icu Medical®, were compared to standard preparation. 15 nurses of Pharmacy Department prepared 5 preparations each one, one with the standard procedure and four using closed-systems. To evaluate the contamination, a fluorescein solution 0.5% was prepared. Two kind of contamination were evaluated, local (three points connection: closed-system connect vial, syringe and final infusion bags) and environmental (gloves and countertop). Percentage of contaminated preparations was obtained in each one. Time taken by each nurse in each preparation was recorded. RESULTS: 75 preparations were prepared. Local contamination was reduced 21% and 75% in closed-system Icu Medical® and Care Fusion® respectively. Care Fusion® closed system, local contamination was significantly lower than the standard system to the vial, syringe and final package, while Icu Medical® closed-systems only was significantly lower in the connection to the vial. Time of preparation was increased significantly with the use of closed-system between 23.4 and 30.5 seconds. CONCLUSIONS: both closed-systems drug transfer device have shown an improvement in contamination than the use of the standard system. However, preparation time has been significantly increased with the use of both systems.

Objetivo: evaluar el impacto del uso de dos sistemas cerrados sobre el proceso de preparación de quimioterapia parenteral, con respecto al sistema estándar, en términos de contaminación local y ambiental, y tiempos de preparación. Método: estudio observacional prospectivo. Se compararon dos proveedores distintos de sistemas cerrados, Icu Medical® y Care Fusion®, frente al sistema estándar de preparación de quimioterapia parenteral. Quince enfermeros del Servicio de Farmacia elaboraron cada uno de ellos 5 preparaciones, una siguiendo el procedimiento estándar y cuatro usando los sistemas cerrados. Para evaluar la aparición de contaminación se elaboró una solución de fluoresceína al 0,5%. Se evaluaron dos tipos de contaminación: local (en tres puntos: sistema acoplado a vial, jeringa y envase final) y ambiental (guantes y mesa de trabajo), obteniéndose el porcentaje de preparaciones contaminadas en cada uno de ellos. Se registró el tiempo empleado por cada enfermero en cada una de las preparaciones. Resultados: se elaboraron 75 preparaciones. Se produjo una reducción global de la contaminación local para los SC Icu Medical® y Care Fusion® del 24% y 74%, respectivamente. En el sistema cerrado Care Fusion® la contaminación local fue significativamente menor que en el sistema estándar en vial, jeringa y envase final; mientras que en el sistema cerrado Icu Medical® solo fue significativamente menor en la conexión al vial. Se produjo un incremento significativo del tiempo de preparación con la utilización de sistemas cerrados de los entre 23,4 y 30,5 segundos. Conclusiones: ambos sistemas cerrados han mostrado un beneficio con respecto a la utilización del sistema estándar. Sin embargo, se han visto incrementados significativamente los tiempos de preparación con ambos sistemas.

Evaluación de dos sistemas cerrados en el proceso de elaboración de quimioterapia parenteral / Evaluation of two closed-system drug transfer device in the antineoplastic drug elaboration process

Objetivo: evaluar el impacto del uso de dos sistemas cerrados sobre el proceso de preparación de quimioterapia parenteral, con respecto al sistema estándar, en términos de contaminación local y ambiental, y tiempos de preparación. Método: estudio observacional prospectivo. Se compararon dos proveedores distintos de sistemas cerrados, Icu Medical® y Care Fusion®, frente al sistema estándar de preparación de quimioterapia parenteral. Quince enfermeros del Servicio de Farmacia elaboraron cada uno de ellos 5 preparaciones, una siguiendo el procedimiento estándar y cuatro usando los sistemas cerrados. Para evaluar la aparición de contaminación se elaboró una solución de fluoresceína al 0,5%. Se evaluaron dos tipos de contaminación: local (en tres puntos: sistema acoplado a vial, jeringa y envase final) y ambiental (guantes y mesa de trabajo), obteniéndose el porcentaje de preparaciones contaminadas en cada uno de ellos. Se registró el tiempo empleado por cada enfermero en cada una de las preparaciones. Resultados: se elaboraron 75 preparaciones. Se produjo una reducción global de la contaminación local para los SC Icu Medical® y Care Fusion® del 24% y 74%, respectivamente. En el sistema cerrado Care Fusion® la contaminación local fue significativamente menor que en el sistema estándar en vial, jeringa y envase final; mientras que en el sistema cerrado Icu Medical® solo fue significativamente menor en la conexión al vial. Se produjo un incremento significativo del tiempo de preparación con la utilización de sistemas cerrados de los entre 23,4 y 30,5 segundos. Conclusiones: ambos sistemas cerrados han mostrado un beneficio con respecto a la utilización del sistema estándar. Sin embargo, se han visto incrementados significativamente los tiempos de preparación con ambos sistemas (AU)

Objective: to assess the impact of two closed-system drug transfer device on the local and environmental contamination and preparation times in the process of preparation of parenteral chemotherapy compared to the standard system. Method: prospective observational study. Two different closed-systems providers, Care Fusion® and Icu Medical®, were compared to standard preparation. 15 nurses of Pharmacy Department prepared 5 preparations each one, one with the standard procedure and four using closed-systems. To evaluate the contamination, a fluorescein solution 0.5% was prepared. Two kind of contamination were evaluated, local (three points connection: closed-system connect vial, syringe and final infusion bags) and environmental (gloves and countertop). Percentage of contaminated preparations was obtained in each one. Time taken by each nurse in each preparation was recorded. Results: 75 preparations were prepared. Local contamination was reduced 21% and 75% in closed-system Icu Medical® and Care Fusion® respectively. Care Fusion® closed system, local contamination was significantly lower than the standard system to the vial, syringe and final package, while Icu Medical® closed-systems only was significantly lower in the connection to the vial. Time of preparation was increased significantly with the use of closed-system between 23.4 and 30.5 seconds. Conclusions: both closed-systems drug transfer device have shown an improvement in contamination than the use of the standard system. However, preparation time has been significantly increased with the use of both systems (AU)

Effectiveness, toxicity, and economic evaluation of vinflunine for the treatment of patients with transitional cell carcinoma in the Spanish outpatient setting.

The aim of this study was to evaluate the effectiveness and toxicity profile of the vinflunine chemotherapy regimen and to examine the cost-effectiveness relation in a real-world sample of patients with transitional cell carcinoma of the bladder. This is a multicenter, observational, retrospective cohort study. To assess the effectiveness and safety of vinflunine treatment, progression-free survival, overall survival, and adverse events were registered. An economic evaluation was performed and cost-effectiveness ratios were calculated. A total of 37 patients were included in the study, with a mean age of 67 (SD=9) years. The median progression-free survival was 2.61 months (95% confidence interval 1.79-4.23) and the median overall survival was 5.72 months (95% confidence interval 3.34-10.35). An objective response was achieved in eight (22%) patients. Statistically significant differences were found between patients treated with vinflunine as a second-line therapy and those treated with vinflunine as a third-line therapy (P=0.036). The most commonly reported analytical adverse event was anemia (n=34; 92%), and the most severe was neutropenia (n=19; 51%), with nine patients developing grade 4 neutropenia (9/19; 47%). The total cost of vinflunine treatment was &OV0556;553 873, with a median of &OV0556;8524 (interquartile range, &OV0556;9220) per patient. The median-based cost-effectiveness ratio was &OV0556;44 789 (&OV0556;31 706-58 022) per progression-free year gained and &OV0556;22 750 (&OV0556;14 526-34 085) per life-year gained. The data from this study fill an important need for information on the relative value of this treatment in terms of cost-effectiveness and might help achieve an optimal quality healthcare system.

Effect of age on systemic exposure and haematological toxicity of carboplatin in advanced non-small cell lung cancer patients.

The aim of this study was to evaluate systemic exposure to carboplatin and its haematological toxicity in patients with advanced non-small cell lung cancer both older and younger than 70 years when the target area under the curve (AUC) in elderly patients was reduced by 20%. For this purpose, a population pharmacokinetic model was developed and the haematological toxicity of the drug was assessed. A total of 33 patients received carboplatin on day 1 and gemcitabine (1250 mg/m(2) ) on days 1 and 8. This schedule was repeated every 21 days. The Calvert-Crokcoft-Gault formula was employed to calculate a dose of carboplatin with a target AUC of 5 mg/min./mL in patients under 70 years and 4 mg/min./mL in patients aged 70 or older. The data of 24 patients were treated for population modelling performed with the nonmem (University of California, San Francisco, CA, USA) approach. Haematological toxicity was evaluated for all 33 patients enrolled in the study. The carboplatin systemic exposure measured by the AUC (mg/min./mL) was 5.98 (5.45; 6.51) and 5.36 (5.02; 5.69) for the younger patients and older groups, respectively. No significant differences were observed between the two groups with respect to rates of grade 3+ anaemia, neutropenia or thrombocytopenia. In clinical practice, a target AUC of 4 mg/min./mL carboplatin is applied to patients aged 70 and over, but the actual systemic exposure to the drug is higher. This supports a target AUC of 4 mg/min./mL carboplatin for patients older than 70 years when the dose is calculated by means of the Calvert-Crokcoft-Gault formula.

Prediction of cyclosporine dosage in patients after kidney transplantation using neural networks.

This paper proposes the use of neural networks for individualizing the dosage of cyclosporine A (CyA) in patients who have undergone kidney transplantation. Since the dosing of CyA usually requires intensive therapeutic drug monitoring, the accurate prediction of CyA blood concentrations would decrease the monitoring frequency and, thus, improve clinical outcomes. Thirty-two patients and different factors were studied to obtain the models. Three kinds of networks (multilayer perceptron, finite impulse response (FIR) network, and Elman recurrent network) and the formation of neural-network ensembles are used in a scheme of two chained models where the blood concentration predicted by the first model constitutes an input to the dosage prediction model. This approach is designed to aid in the process of clinical decision making. The FIR network, yielding root-mean-square errors (RMSEs) of 52.80 ng/mL and mean errors (MEs) of 0.18 ng/mL in validation (10 patients) showed the best blood concentration predictions and a committee of trained networks improved the results (RMSE = 46.97 ng/mL, ME = 0.091 ng/mL). The Elman network was the selected model for dosage prediction (RMSE = 0.27 mg/Kg/d, ME = 0.07 mg/Kg/d). However, in both cases, no statistical differences on the accuracy of neural methods were found. The models' robustness is also analyzed by evaluating their performance when noise is introduced at input nodes, and it results in a helpful test for models' selection. We conclude that neural networks can be used to predict both dose and blood concentrations of cyclosporine in steady-state. This novel approach has produced accurate and validated models to be used as decision-aid tools.