[Antineoplastic oral agents and drug-nutrient interactions: a sistematic review]. / Interacción de los antineoplásicos orales con los alimentos: revisión sistemática.

INTRODUCTION: Studies on bioavailability are part of the clinical development of drugs for oral use in order to identify potential drug-food interactions. For oral antitumor drugs, their clinical importance is currently recognized although regrettably the information available presents variability concerning the scientific evidence. OBJECTIVES: To review the available scientific evidence about oral anti-tumor medications and establish the recommendations for their administration with foods. METHODS: We carried out a bibliographic search in Medline and The Cochrane Library for the period January of 1966 to March of 2008, focused on identifying those publications about drug-food interactions with oral antitumor medications. The bibliographical analysis was made in two steps. During the first phase, we excluded those articles in which the title or their content did not correspond with the objective settled; during the second phase, we deleted all the references duplicated in both databases. The inclusion criteria to select the articles were: design (systematic reviews, meta-analysis, Phase I and Phase II randomized clinical trials), population (adult patients; >19 years of age), intervention evaluated (administration of oral anti-tumor drugs under fasting conditions or with food) and measurement of the iFA results (calculation of the 90% CI of the odds ratio between the geometric mean of the values under the curve of the plasma concentrations (ABC) or the maximal plasma concentration (Cmax) with and without foods). We excluded those publications that did not make reference to the bioequivalence dictamen established by the Food and Drugs Administration (FDA) in their outcomes measurement. A critical appraisal of the selected articles was done according to the recommendations that the FDA established to be met by these studies. RESULTS: At the initial search we obtained 850 references (98.5% Medline + and 1.4% Cochrane). During the first phase, we excluded 87.7% (746) of the articles, 100% of them corresponding to the search in Medline. During the second phase, 40 studies remained (5.2% of the initial ones) for full-text critical appraisal, to which four studies were added not indexed in Medline. From the critical appraisal of the 44 final articles, 25 were excluded (20 original articles, 4 short communications, and 1 meta-analysis) because they did not include as an outcome measure the bioequivalence dictamen. The 19 (2.2%) remaining articles provided information on 19 oral anti-tumor drugs in 210 patients and 146 healthy volunteers. Of these 19 drugs, 63% did not present drug-food interactions, with the possibility of administering them either with or without food; 21% have to be administered with foods and only 16% present drug-food interactions, so they have to be administered without foods. DISCUSSION: Currently, the clinical importance of drug-food interactions with oral anti-tumor drugs is identified more directly with the patient's safety than with the efficacy of the therapy. Given the development of these oral agents, their incorporation into the oncologic strategy displacing parenteral therapy, with monthly costs of thousands of Euros, it is necessary to perform well-designed studies on pharmacokinetics and pharmacodynamics. Their goal has to be comparing their bioavailability in the presence or absence of foods with the clinical response. In the meanwhile, to establish recommendations for their administration in relation to foods is inconsistent for some of these drugs and their results is uncertain given the lack of studies based on the FDA bioequivalence dictamen.

Management of returned anti-neoplastic treatments and their reuse in oncology patients.

OBJECTIVE: Analyse the profile of parenteral preparation and treatment (anti-neoplastic and supplementary) that were dispensed and returned to the Pharmacy Department, the reasons why they were not administered, their reuse and the associated direct costs. METHOD: Longitudinal study over eight months (October 2004-May 2005) in a tertiary hospital with centre for preparing anti-neoplastic agents (including supplementary treatment) in its Pharmacy Department. The variables studied, downloaded from the Oncofarm® application, are as follows: (a) patients and diagnostics; (b) returned treatments, classified by reason returned, pharmaco-therapeutic scheme, cycle and day; (c) returned preparations (anti-neoplastic and supplementary) that were reused; and (d) direct costs. Data is presented with its absolute and relative frequencies and confidence intervals of 95% normalised at 1000 patients/day. RESULTS: 84 treatments were returned by 66 patients for a total of 139 preparations corresponding to 3,429 patients/day. This figure represents 24.5 (CI 95%, 19.6 to 30.2) treatments that were prepared and not administered per 1,000 patients/day, mainly due to clinical causes (n = 47). Colon neoplasia and treatment with 5-fluorouracil and levofolinic acid presented the highest number of returns. The returned preparations made up 1.45 % (CI 95%, 1.2 to 1.7) of those produced. The percentage of reuse is 98%, which results in savings of euro 10,432.55 (90% of the cost of the treatments that are returned). CONCLUSIONS: The application of quality, effectiveness and safety criteria to anti-neoplastic treatments that are prepared and returned to the Pharmacy Department allows a more efficient preparation process.

Gestión de la devolución de tratamientos antineoplásicos y de su reutilización en pacientes oncológicos / Management of returned anti-neoplastic treatments and their reuse in oncology patients

Objetivo: Analizar el perfil de tratamientos y preparaciones parenterales (antineoplásicas y de soporte) dispensados y devueltos al servicio de farmacia, las causas de no administración, su reutilización y los costes directos asociados. Método: Estudio longitudinal, prospectivo, durante 8 meses (octubre 2004-mayo 2005) en un hospital terciario con centralización de la preparación de esquemas antineoplásicos (incluye tratamiento de soporte) en el servicio de farmacia. Las variables estudiadas, descargadas del aplicativo Oncofarm®, fueron: a) pacientes y diagnósticos; b) tratamientos devueltos, diferenciando por causa, esquema farmacoterapéutico, ciclo y día; c) preparaciones devueltas (antineoplásicos y soporte) y reutilizadas, y d) costes directos. Los datos se presentan con sus frecuencias absolutas, relativas e intervalos de confianza (IC) del 95 %, normalizado a 1.000 pacientes/día. Resultados: 84 tratamientos devueltos de 66 pacientes con un total de 139 preparaciones correspondientes a 3.429 pacientes/día. Este dato representa 24,5 (IC del 95 %, 19,6 a 30,2) de tratamientos preparados y no administrados por 1.000 pacientes/día, debido, mayoritariamente, a causas clínicas (n = 47). La neoplasia de colon y el esquema de 5-fluorouracilo y ácido levofolínico presentan el mayor número de devoluciones. Las preparaciones devueltas suponen el 1,45 % (IC del 95 %, 1,2 a 1,7) de las elaboradas. El porcentaje de reutilización es del 98 %, con un coste ahorrado que asciende a 10.432,55 (90 % del coste de los tratamientos devueltos).Conclusiones: La aplicación de criterios de calidad, eficacia y seguridad a los tratamientos antineoplásicos preparados y devueltos al servicio de farmacia permite incrementar la eficiencia en el proceso de preparación (AU)

Objective: Analyse the profile of parenteral preparation and treatment (anti-neoplastic and supplementary) that were dispensed and returned to the Pharmacy Department, the reasons why they were not administered, their reuse and the associated direct costs. Method: Longitudinal study over eight months (October 2004-May 2005) in a tertiary hospital with centre for preparing anti-neoplastic agents (including supplementary treatment) in its Pharmacy Department. The variables studied, downloaded from the Oncofarm® application, are as follows: a) patients and diagnostics; b) returned treatments, classified by reason returned, pharmaco-therapeutic scheme, cycle and day; c) returned preparations (anti-neoplastic and supplementary) that were reused; and d) direct costs. Data is presented with its absolute and relative frequencies and confidence intervals of 95 % normalised at 1000 patients/day. Results: 84 treatments were returned by 66 patients for a total of 139 preparations corresponding to 3,429 patients/day. This figure represents 24.5 (CI 95 %, 19.6 to 30.2) treatments that were prepared and not administered per 1,000 patients/day, mainly due to clinical causes (n = 47). Colon neoplasia and treatment with 5-fluorouracil and levofolinic acid presented the highest number of returns. The returned preparations made up 1.45 % (CI 95 %, 1.2 to 1.7) of those produced. The percentage of reuse is 98 %, which results in savings of € 10,432.55 (90 % of the cost of the treatments that are returned).Conclusions: The application of quality, effectiveness and safety criteria to anti-neoplastic treatments that are prepared and returned to the Pharmacy Department allows a more efficient preparation process (AU)

Interacción de los antineoplásicos orales con los alimentos: revisión sistemática / Antineoplastic oral agents and drug-nutrient interactions: a sistematic review

Introducción: Los estudios de biodisponibilidad son parte integrante del desarrollo clínico de medicamentos para administración oral con el fin de identificar potenciales interacciones fármaco-alimento (iFA). Actualmente, para los antineoplásicos orales se empieza a reconocer su importancia clínica, aun cuando lamentablemente, la información disponible presenta variabilidad en su evidencia científica. Objetivos: Revisar la evidencia científica disponible sobre las interacciones de los alimentos con medicamentos antineoplásicos orales y establecer recomendaciones para su administración. Métodos: Se realizó una búsqueda bibliográfica en Medline y The Cochrane Library para el periodo comprendido entre enero de 1966 a marzo de 2008, enfocada a identificar las publicaciones sobre interacciones fármaco alimento con antineoplásicos orales. El análisis bibliográfico consta de dos fases. En la primera fase se excluyeron los artículos que por título y contenido del resumen no se correspondían con el objetivo planteado; en la segunda fase se eliminaron las referencias duplicadas en ambas bases de datos. Los criterios de inclusión para seleccionar los artículos fueron: diseño (revisiones sistemáticas, metaanálisis, ensayos clínicos randomizados Fase I y II), población (pacientes adultos; >19 años de edad), intervención evaluada (administración de antineoplásicos orales bajo condiciones de ayuno o con alimentos) y medida del resultado de la iFA (cálculo del IC90% de la razón entre la media geométrica de valores del área bajo la curva de concentraciones plasmáticas (ABC) o la concentración plasmática máxima (Cmax) con y sin alimentos). Se excluyeron las publicaciones que como medida de resultado no hacían referencia al dictamen de bioequivalencia establecido por la Food and Drugs Administration (FDA). La valoración crítica de los artículos seleccionados se realizó según las recomendaciones que de acuerdo con la FDA deben cumplir estos estudios. Resultados: En la búsqueda inicial se obtuvieron 850 referencias (98,5% Medline + y 1,4% Cochrane). En la primera fase se excluyeron el 87,7% (746) de los artículos, correspondiendo el 100% a la búsqueda en Medline. En la segunda fase, quedaron 40 artículos (5,2% de los iniciales) para su lectura crítica a texto completo, a los que se añadieron cuatro más no indexados en Medline. De la lectura crítica de los 44 artículos finales, se excluyeron 25 artículos (20 artículos originales, 4 comunicaciones cortas y 1 metanálisis) por no incluir como medida de resultado el dictamen de bioequivalencia. Los 19 (2,2%) artículos restantes proporcionaron información sobre 19 fármacos antineoplásicos orales, en 210 pacientes y 146 voluntarios sanos. De estos 19 fármacos, el 63% no presentan iFA o interacciones fármaco-alimento, pudiéndose administrar indistintamente con/sin alimentos; el 21% se deben administrar con alimentos y sólo el 16% presentan interacción fármaco alimento, por lo que se deben administrar sin alimentos. Discusión: Actualmente, la importancia clínica de las interacciones fármaco alimento con antineoplásicos orales se identifica más directamente con la seguridad del paciente que con la efectividad del tratamiento. Ante el desarrollo de estos agentes orales, su irrupción en la terapia oncológica desplazando a la terapia parenteral, con costes mensuales de miles de euros, hay necesidad de realizar estudios farmacocinéticos y farmacodinámicos bien diseñados. Su objetivo debe de ser comparar su biodisponibilidad en presencia o ausencia de alimentos con la respuesta clínica. Mientras tanto, establecer recomendaciones para su administración en relación con los alimentos, es inconsistente para algunos de estos fármacos y su resultado incierto por la falta de estudios fundamentados en el dictamen de bioequivalencia establecido por la FDA (AU)

Introduction: studies on bioavailability are part of the clinical development of drugs for oral use in order to identify potential drug-food interactions. For oral antitumor drugs, their clinical importance is currently recognized although regrettably the information available presents variability concerning the scientific evidence. Objectives: To review the available scientific evidence about oral anti-tumor medications and establish the recommendations for their administration with foods. Methods: We carried out a bibliographic search in Medline and The Cochrane Library for the period January of 1966 to March of 2008, focused on identifying those publications about drug-food interactions with oral antitumor medications. The bibliographical analysis was made in two steps. During the first phase, we excluded those articles in which the title or their content did not correspond with the objective settled; during the second phase, we deleted all the references duplicated in both databases. The inclusion criteria to select the articles were: design (systematic reviews, meta-analysis, Phase I and Phase II randomized clinical trials), population (adult patients; >19 years of age), intervention evaluated (administration of oral anti-tumor drugs under fasting conditions or with food) and measurement of the iFA results (calculation of the 90% CI of the odds ratio between the geometric mean of the values under the curve of the plasma concentrations (ABC) or the maximal plasma concentration (Cmax) with and without foods). We excluded those publications that did not make reference to the bioequivalence dictamen established by the Food and Drugs Administration (FDA) in their outcomes measurement. A critical appraisal of the selected articles was done according to the recommendations that the FDA established to be met by these studies. Results: At the initial search we obtained 850 references (98.5% Medline + and 1.4% Cochrane). During the first phase, we excluded 87.7% (746) of the articles, 100% of them corresponding to the search in Medline. During the second phase, 40 studies remained (5.2% of the initial ones) for full-text critical appraisal, to which four studies were added not indexed in Medline. From the critical appraisal of the 44 final articles, 25 were excluded (20 original articles, 4 short communications, and 1 meta-analysis) because they did not include as an outcome measure the bioequivalence dictamen. The 19 (2.2%) remaining articles provided information on 19 oral anti-tumor drugs in 210 patients and 146 healthy volunteers. Of these 19 drugs, 63% did not present drugfood interactions, with the possibility of administering them either with or without food; 21% have to be administered with foods and only 16% present drug-food interactions, so they have to be administered without foods. Discussion: Currently, the clinical importance of drugfood interactions with oral anti-tumor drugs is identified more directly with the patient's safety than with the efficacy of the therapy. Given the development of these oral agents, their incorporation into the oncologic strategy displacing parenteral therapy, with monthly costs of thousands of Euros, it is necessary to perform well-designed studies on pharmacokinetics and pharmacodynamics. Their goal has to be comparing their bioavailability in the presence or absence of foods with the clinical response. In the meanwhile, to establish recommendations for their administration in relation to foods is inconsistent for some of these drugs and their results is uncertain given the lack of studies based on the FDAbioequivalence dictamen (AU)