Therapeutic drug monitoring of anti-tumour necrosis factor-α agents in inflammatory bowel disease: Limits and improvements.

AIMS: Since the publication of the American Gastroenterological Association's recommendations in 2017, there have been no significant changes in the biological monitoring recommendations in inflammatory bowel disease. Possible limitations are the lack of evidence to recommend proactive therapeutic drug monitoring (pTDM) over reactive TDM (rTDM), and the limited information about individualized dosing methods. This article aims to review the TDM strategy updates and the use of individualized dosing methods. METHODS: For the analysis of the TDM strategies and individualized dosing method, a search was carried out in PubMed and Cochrane Central. In the TDM case, since August 2017. RESULTS: A total of 263 publications were found, but only 7 related to proactive TDM. Five of these publications directly compared pTDM vs rTDM and 2 were randomized clinical trials. Six studies found benefits of pTDM and 1 found no differences. Regarding the individualized dosing method, 229 distinct results were found. Population pharmacokinetics was the most widely used method to develop individual dosage models and to analyse the influence of factors on drug concentrations (albumin concentration, weight, presence of anti-drug antibodies etc). CONCLUSION: We have found no major changes in TDM strategies. There is a growing trend towards the use of pTDM because it has shown a longer duration of treatment response, lower rates of discontinuation and relapses. However, the available evidence is limited and of low quality. Despite the common use of population pharmacokinetic methods to analyse pharmacokinetic factors, they are not commonly used for personalized dosing.

Automated therapy preparation of isoleucine formulations using 3D printing for the treatment of MSUD: First single-centre, prospective, crossover study in patients.

Maple syrup urine disease (MSUD) is a rare metabolic disorder with a worldwide prevalence of 1 in every 185,000 live births. However, certain populations display a significant overexpression of the disorder where incidence is reported to be 1 in every 52,541 new-borns. The first-line therapy for MSUD involves a strict dietary leucine restriction and oral supplementation of isoleucine and valine. The dose administered to patients requires strict tailoring according to age, weight and blood levels. In current clinical practice, however, practitioners still have to prepare extemporaneous formulations due to the lack of suitable oral treatments for MSUD. Herein, we evaluate the first time use of 3D printing in a hospital setting for the preparation of personalised therapies with the aim of improving safety and acceptability to isoleucine supplementation in paediatric patients suffering from MSUD. This investigation was a single-centre, prospective crossover experimental study. Four paediatric patients with MSUD (aged 3-16 years) were treated at the Clinic University Hospital in Santiago de Compostela, Spain which is a MSUD reference hospital in Europe. The primary objective was to evaluate isoleucine blood levels after six months of treatment with two types of formulations; conventional capsules prepared by manual compounding and personalised chewable formulations prepared by automated 3D printing. A secondary investigation was to evaluate patient acceptability of 3D printed formulations prepared with different flavours and colours. Isoleucine blood levels in patients were well controlled using both types of formulations, however, the 3D printed therapy showed mean levels closer to the target value and with less variability (200-400 µM). The 3D printed formulations were well accepted by patients regarding flavour and colour. The study demonstrates for the first time that 3D printing offers a feasible, rapid and automated approach to prepare oral tailored-dose therapies in a hospital setting. 3D printing has shown to be an effective manufacturing technology in producing chewable isoleucine printlets as a treatment of MSUD with good acceptability.

Pharmacotherapy follow-up of patients under treatment with biologic agents for chronic inflammatory systemic conditions: an agreement among hospital pharmacists for the standardized collection of a minimum set of data.

BACKGROUND AND OBJECTIVE: The objective of this study was to reach a consensus on the minimum set of data that would allow to optimize the pharmacotherapy follow-up of patients on biologic agents for chronic systemic inflammatory conditions, through structured and standardized collection with an electronic tool in the hospital pharmacy. MATERIALS AND METHOD: A scientific committee was formed (n = 5 hospital pharmacists). The Delphi Technique was used, 2 rounds of consultation by e-mail for hospital pharmacists. A structured questionnaire was used, based on a bibliographic review and recommendations by the scientific committee; 37 statements were assessed with the Likert 5-point scale (1= "Strongly Disagree"; 5= "Strongly Agree"). Consensus was reached when 75% or more of panel members assigned a score of 1-2 (rejection consensus) or 4-5 (agreement consensus) to the matter reviewed. Descriptive statistical analyses were conducted. RESULTS: The study included 21 hospital pharmacists (70 were invited, there was 70% response). Consensus was reached for 100% of statements. The minimum set of data was agreed upon, as well as the recommendations that the pharmacist had to collect and make during visits: to document the health status, health-related quality of life, changes in treatment compliance and in patient autonomy, as well as the conditions to make feasible the systematic collection of the minimum data set. CONCLUSIONS: There is consensus among hospital pharmacists about a minimum data set to be collected, through an electronic tool, which will order, standardize and structure the pharmacotherapy follow-up of patients with chronic inflammatory conditions on treatment with biologic agents in the spanish public health system.

Fundamento y objetivo: El objetivo de este estudio fue consensuar un conjunto mínimo de datos cuya recopilación sistemática y estandarizada, mediante una herramienta electrónica en la farmacia hospitalaria, permitiera optimizar el seguimiento farmacoterapéutico de los pacientes tratados con agentes biológicos por enfermedades sistémicas inflamatorias crónicas. Material y método: Se constituyó un comité científico (n = 5 farmacéuticos hospitalarios). Se empleó la técnica Delphi, 2 rondas de consulta, por correo electrónico entre farmacéuticos hospitalarios. Se utilizó un cuestionario estructurado basado en una revisión bibliográfica y en recomendaciones del comité científico, valorándose 37 afirmaciones en una escala Likert de 5 puntos (1 = "En total desacuerdo"; 5 = "Totalmente de acuerdo"). Se alcanzó consenso cuando el 75% o más de los panelistas puntuaron 1-2 (consenso-rechazo) o 4-5 (consenso- acuerdo) la cuestión planteada. Se realizaron análisis estadísticos descriptivos. Resultados: Participaron 21 farmacéuticos hospitalarios (70 invitados, 70% respuesta). Se logró consenso en el 100% de las afirmaciones. Se acordó el conjunto mínimo de datos y de recomendaciones que el farmacéutico debe recoger y hacer en las visitas; documentar el estado de salud, la calidad de vida relacionada con la salud, los cambios en la adherencia al tratamiento y en la autonomía de los pacientes, así como las condiciones para hacer factible la recopilación sistemática del conjunto mínimo de datos. Conclusiones: Existe consenso entre los farmacéuticos hospitalarios en un conjunto mínimo de datos cuya recopilación, mediante una herramienta electrónica, ordenará, estandarizará y sistematizará el seguimiento farmacoterapéutico de los pacientes con enfermedades inflamatorias crónicas en tratamiento con agentes biológicos en el entorno sanitario público español.

Evaluation of the in vitro ocular toxicity of the fortified antibiotic eye drops prepared at the Hospital Pharmacy Departments.

The use of parenteral antibiotic eye drop formulations with non-marketed compositions or concentrations, commonly called fortified antibiotic eye drops, is a common practice in Ophthalmology in the hospital setting. The aim of this study was to evaluate the in vitro ocular toxicity of the main fortified antibiotic eye drops prepared in the Hospital Pharmacy Departments. We have conducted an in vitro experimental study in order to test the toxicity of gentamicin, amikacin, cefazolin, ceftazidime, vancomycin, colistimethate sodium and imipenem-cilastatin eye drops; their cytotoxicity and acute tissue irritation have been evaluated. Cell-based assays were performed on human stromal keratocytes, using a cell-based impedance biosensor system [xCELLigence Real-Time System Cell Analyzer (RTCA)], and the Hen's Egg Test for the ocular irritation tests. All the eye drops, except for vancomycin and imipenem, have shown a cytotoxic effect dependent on concentration and time; higher concentrations and longer exposure times will cause a steeper decline in the population of stromal keratocytes. Vancomycin showed a major initial cytotoxic effect, which was reverted over time; and imipenem appeared as a non-toxic compound for stromal cells. The eye drops with the highest irritating effect on the ocular surface were gentamicin and vancomycin. Those antibiotic eye drops prepared at the Hospital Pharmacy Departments included in this study were considered as compounds potentially cytotoxic for the ocular surface; this toxicity was dependent on the concentration used.

El uso de reformulaciones de antibioticos parenterales en forma de colirios de composicion o concentraciones no comercializadas, comunmente denominados colirios antibioticos reforzados, es una practica habitual en oftalmologia a nivel hospitalario. El objetivo del presente trabajo ha consistido en evaluar la toxicidad ocular in vitro de los principales colirios antibioticos reforzados elaborados en los Servicios de Farmacia Hospitalaria. Hemos realizado un estudio experimental in vitro para evaluar la toxicidad de los colirios de gentamicina, amikacina, cefazolina, ceftazidima, vancomicina, colistimetato de sodio e imipenem- cilastatina en el que se ha evaluado su citotoxicidad y la irritacion tisular aguda. Los ensayos celulares se realizan sobre queratocitos estromales humanos, mediante la utilizacion de un sistema biosensor de impedancia celular [(xCELLigence Real- Time System Cell Analyzer (RTCA)] y los ensayos de irritacion ocular mediante el ensayo Hen/s Egg Test. Todos los colirios, excepto vancomicina e imipenem, han mostrado un efecto citotoxico de concentracion y tiempo dependiente, siendo las concentraciones mas altas y los tiempos mas prolongados los que provocan un descenso mas pronunciado en la poblacion de queratocitos estromales. La vancomicina muestra un importante efecto citotoxico inicial que revierte con el transcurso del tiempo y el imipenem se muestra como un compuesto no toxico para las celulas estromales. Los compuestos con mayor efecto irritante para la superficie ocular son la gentamicina y la vancomicina. Los colirios antiinfecciosos elaborados en los Servicios de Farmacia Hospitalaria estudiados se muestran como compuestos potencialmente citotoxicos para la superficie ocular, siendo esta toxicidad dependiente de la concentracion utilizada.