Aproximación al análisis de las relaciones causales en las ciencias de la salud

Trabajo de Fin de Máster en Investigación en Lógica y Filosofía de la Ciencia, curso 2017-2018[ES] Un adecuado análisis de la causalidad adquiere particular relevancia en áreas de conocimiento en las que son necesarios grados de confianza elevados a la hora de adoptar decisiones frente a ciertos problemas/conflictos sociales, económicos o sanitarios. Una revisión de la investigación publicada sobre causalidad en el ámbito de la salud pública en las últimas décadas revela que en la mayoría de los escenarios planteados en las ciencias de la salud, las relaciones causa-efecto no son deterministas, ni absolutamente ciertas y completas, a lo que se suma el hecho de que en el caso de muchas disciplinas biomédicas, como la epidemiología o la farmacovigilancia, no es posible realizar experimentos para aislar el factor causal de interés (manteniendo todas la condiciones iguales y asegurando la restricción ceteris paribus), lo que incrementa la complejidad del análisis causal. Quizá por ello, la mayoría de epidemiólogos prefieren hablar de determinantes, exposiciones y factores de riesgo y categorizan las causas de forma descriptiva sin enfrentar los problemas de la definición de causa, a pesar de que muchos son conscientes de la trascendencia que puede tener sobre las intervenciones sanitarias la adopción de una definición determinada de causalidad, que razonablemente debería ser la de mayor utilidad.[EN] A suitable analysis of causality acquires a particular relevance in areas of knowledge in which high degrees of confidence are required when making decisions regarding certain social, economic or health issues. A review of published research on causality in the field of public health in recent decades reveals that in most of the scenarios posed in the health sciences, cause-effect relationships are not deterministic, nor absolutely certain and complete, to which is added the fact that in many biomedical disciplines, such as epidemiology or pharmacovigilance, it is not possible to carry out experiments to isolate the causal factor of interest (keeping all the conditions unchanged and thus ensuring the ceteris paribus restriction), which increases the complexity of the causal analysis. Perhaps for this reason, most epidemiologists prefer to talk about determinants, exposures and risk factors and they categorize the causes in a descriptive way without facing the problems of definition of cause, although many are aware of the transcendence that can have on the health interventions the adoption of a specific definition of causality, which reasonably should be the most useful

Elaboración de píldoras audiovisuales de apoyo a las clases prácticas en el laboratorio de biofarmacia y farmacocinética

Memoria ID-095. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2019-2020

Population pharmacokinetics of phenytoin in adult patients

Phenytoin (DPH) is an antiepileptic drug used in the first line of focal seizures and tonic-clonic seizures treatments. Phenytoin shows a highly protein binding, non-lineal dose-dependent kinetics, large pharmacokinetic variability and narrow therapeutic index; reasons why this antiepileptic is commonly monitored to optimize the efficacy/toxicity balance. The aim of the present work was to characterize the DPH pharmacokinetics in adult population./nDrug plasma levels at steady-state from 215 adult patients were used to develop a population pharmacokinetic model (PopPK) using a non-linear mixed effect modelling approach with NONMEM v.7.3./nPharmacokinetics of DPH were described following one-compartment distribution model with zero-order absorption and Michaelis-Menten non-lineal saturable elimination. Age, weight, magnitude of DPH dose and co-medication with valproic acid have been shown influence on maximum velocity of PHT elimination, significantly decreasing the variability of this pharmacokinetic parameter./nThis preliminary PopPK developed, has shown an adequate evaluation of the descriptive and predictive performance in adult population within a large dose range (50-800 mg/day). However, its implementation in the clinical setting is required to confirm its suitability.La fenitoína (DPH) es un antiepiléptico considerado de primera elección en el tratamiento de las crisis focales y convulsiones tónico-clónicas. DPH presenta elevada unión a proteínas plasmáticas, un comportamiento cinético no lineal dependiente de la dosis, elevada variabilidad cinética interindividual y un estrecho margen terapéutico; estas características aconsejan su monitorización para optimizar su balance eficacia/toxicidad. El objetivo de este trabajo fue la caracterización de la farmacocinética de DPH en población adulta./nConcentraciones en estado de equilibrio de DPH procedentes de 215 pacientes adultos fueron utilizadas para desarrollar un modelo farmacocinético poblacional (PopPK) aplicando una metodología de efectos mixtos no lineales con el programa NONMEM v.7.3./nLa cinética de DPH fue descrita adecuadamente mediante un modelo monocompartimental con absorción de orden cero y cinética de eliminación no lineal ajustada a la ecuación de Michaelis-Menten. Edad, peso, magnitud de dosis y comedicación con ácido valproico han mostrado influencia sobre la velocidad de eliminación de DPH, reduciendo su variabilidad de forma considerable./nSe ha obtenido un modelo PopPK preliminar que ha mostrado una adecuada capacidad descriptiva y predictiva en población adulta en un amplio rango de dosis (50-800 mg/día). No obstante, se precisa su aplicación en el contexto clínico para confirmar su validez

In silico prediction of drug absorption in celiac disease

Celiac disease is known to cause impaired oral drug absorption as a consequence of the abnormal gastrointestinal function present in such patients. Nevertheless, the causes underlying this phenomenon remain relatively uncertain. The aim of this study was to determine by means of in silico methods, which factors are more likely to cause absorption irregularities in celiac patients. A simulation tool – Simcyp V14 – was used to predict absorption defects. Jejunum luminal pH and gastric emptying time data was collected from past reports to generate two pairs of virtual populations (celiac and control). Four drugs (desipramine, clozapine, digoxin and warfarin) with different physical-chemical properties were tested. Eight pairs of simulations were performed, divided in two sets to analyse separately the prospective influential factors pH and gastric emptying time. The absorption profiles were compared in terms of Cmax, tmax and AUC. No statistically significant differences (p<0.01) were found between control and celiac populations regarding jejunal pH differences. However, statistically significant differences (p<0.01) in terms of tmax were found regarding gastric emptying time differences with all drugs tested. Further studies need to be conducted to determine the clinical relevance of these results, and to analyse other possible factors involved.La disfunción gastrointestinal presente en la enfermedad celiaca induce alteraciones en la absorción oral de fármacos. No obstante, las causas permanecen relativamente desconocidas. El objetivo del estudio fue determinar mediante métodos in silico los factores más propensos a alterar la absorción en pacientes celiacos. Se utilizó una herramienta de simulación – Simcyp V14 – para predecir alteraciones en la absorción. Se recogieron datos de pH luminal intestinal y tiempo de vaciamiento gástrico de la bibliografía para generar cuatro poblaciones virtuales (celiaca y control). Se estudiaron cuatro fármacos (desipramina, clozapina, digoxina y warfarina) con diferentes propiedades fisico-químicas. Se llevaron a cabo dieciséis simulaciones, divididas en dos bloques, para analizar independientemente la influencia de los factores pH y tiempo de vaciamiento gástrico. Los perfiles de absorción se compararon contrastando Cmax, tmax y AUC. No se encontraron diferencias estadísticamente significativas (p<0,01) entre las poblaciones celiaca y control en base a diferencias en el pH luminal intestinal. No obstante, se encontraron diferencias estadísticamente significativas (p<0,01) en tmax atribuidas a diferencias en el tiempo de vaciamiento gástrico para todos los fármacos estudiados. Se precisan estudios posteriores para determinar la relevancia clínica de estos resultados, y analizar otros posibles factores involucrados.

Puesta en marcha de la asignatura “Información y metodología científica” de primer curso del nuevo título de Graduado/a en Farmacia

Memoria ID-0093. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2008-2009.La asignatura “Información y metodología científica” es de nueva creación y ha surgido este curso académico tras haber sido verificado por la ANECA el nuevo título de Graduado/a en Farmacia por la Universidad de Salamanca. Es una asignatura obligatoria que se imparte en el primer semestre de primer curso y que este curso ha tenido 190 alumnos matriculados. Es una asignatura de carácter transversal que desarrolla competencias fundamentales para que los alumnos se adapten al resto de las materias de la titulación. Consideramos que esta asignatura es fundamental para que los alumnos de primer curso adquieran una preparación básica en competencias transversales y objetivos generales de la titulación de manera que puedan aprovechar al máximo su paso por el resto de asignaturas de la titulación

Incorporación de tabletas digitalizadoras en la corrección de las tareas enviadas por los estudiantes a la plataforma Moodle de apoyo a la docencia (Studium) en la asignatura "Información y Metodología Científica" del Grado de Farmacia

Memoria ID-160. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2010-2011.Este proyecto, se plantea combinar la corrección de tareas a través de Studium con el uso de tabletas digitalizadoras de modo que se agilicen las respuestas que los tres profesores dan a los estudiantes y se reduzca el tiempo y esfuerzo del profesorado en la evaluación de las prácticas y los trabajos tutelados

Elaboración de contenidos en formato Usal-Media para la asignatura "Información y Metodología Científica" del Grado en Farmacia (ampliado con "y análisis del plagio en los trabajos elaborados por estudiantes de nuevo ingreso en la Facultad de Farmacia")

Memoria ID12-0309. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2012-2013

Population Pharmacokinetics of Valproic Acid in Pediatric and Adult Caucasian Patients

(1) Background: The aim of this study was to explore the valproic acid (VPA) pharmacokinetic characteristics in a large population of pediatric and adult Caucasian patients and to establish a robust population pharmacokinetic (PopPK) model. (2) Methods: A total of 2527 serum VPA samples collected from 1204 patients included in a therapeutic drug monitoring program were retrospectively analyzed. Patients were randomly assigned to either a model development group or an external evaluation group. PopPK analysis was performed on 1751 samples from 776 patients with NONMEM using a nonlinear mixed-effect modelling approach. The influence of demographic, anthropometric, treatment and comedication variables on the apparent clearance (CL/F) of VPA was studied. The bootstrap method was used to evaluate the final model internally. External evaluation was carried out using 776 VPA serum samples from 368 patients. (3) Results: A one-compartment model with first-order absorption and elimination successfully described the data. The final model included total body weight, age and comedication with phenytoin, phenobarbital and carbamazepine with a significant impact on VPA elimination. Internal and external evaluations demonstrated the good predictability of the model. (4) Conclusions: A PopPK model of VPA in Caucasian patients was successfully established, which will be helpful for model-informed precision dosing approaches in clinical patient care

Population Pharmacokinetic Analysis of Vancomycin in Patients with Hematological Malignancies

This study determines vancomycin (VAN) population pharmacokinetics (PK) in adult patients with hematological malignancies. VAN serum concentration data (n = 1,004) from therapeutic drug monitoring were collected retrospectively from 215 patients. A one-compartment PK model was selected. VAN pharmacokinetics population parameters were generated using the NONMEM program. A graphic approach and stepwise generalized additive modeling were used to elucidate the preliminary relationships between PK parameters and clinical covariates analyzed. Covariate selection revealed that total body weight (TBW) affected V, whereas renal function, estimated by creatinine clearance, and a diagnosis of acute myeloblastic leukemia (AML) influenced VAN clearance. We propose one general and two AML-specific models. The former was defined by CL (liters/h) = 1.08 × CL(CR(Cockcroft and Gault)) (liters/h); CV(CL) = 28.16% and V (liters) = 0.98 × TBW; CV(V) =37.15%. AML models confirmed this structure but with a higher clearance coefficient (1.17). The a priori performance of the models was evaluated in another 59 patients, and clinical suitability was confirmed. The models were fairly accurate, with more than 33% of the measured concentrations being within ±20% of the predicted value. This therapeutic precision is twofold higher than that of a noncustomized population model (16.1%). The corresponding standardized prediction errors included zero and a standard deviation close to unity. The models could be used to estimate appropriate VAN dosage guidelines, which are not clearly defined for this high-risk population. Their simple structure should allow easy implementation in clinical software and application in dosage individualization using the Bayesian approach

Population pharmacokinetics of doxorubicin and doxorubicinol in patients diagnosed with non-Hodgkin's lymphoma

[Aims]: The aims of the study were: (i) to characterize the pharmacokinetics (PK) of doxorubicin (DOX) and doxorubicinol (DOXol) in patients diagnosed with non-Hodgkin's lymphoma (NHL) using a population approach; (ii) to evaluate the influence of various covariates on the PK of DOX; and (iii) to evaluate the role of DOX and DOXol exposure in haematological toxicity. [Methods]: Population PK modelling (using NONMEM) was performed using DOX and DOXol plasma concentration-time data from 45 NHL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). The influence of drug exposure on haematological toxicity was analysed using the Mann-Whitney-Wilcoxon test. [Results]: A five-compartment model, three for DOX and two for DOXol, with first-order distribution and elimination for both entities best described the data. Population estimates for parent drug (CL) and metabolite (CLm ) clearance were 62 l h-1 and 27 l h-1 , respectively. The fraction metabolized to DOXol (Fm ) was estimated at 0.22. While bilirubin and aspartate aminotransferase showed an influence on the CL and CLm , the objective function value decrease was not statistically significant. A trend towards an association between the total area under the concentration-time curve (AUCtotal ), the area under the concentration-time curve for DOX (AUC) plus the area under the concentration-time curve for DOXol (AUCm ), and the neutropenia grade (P = 0.068) and the neutrophil counts (P = 0.089) was observed, according to an exponential relationship. [Conclusions]: The PK of DOX and DOXol were well characterized by the model developed, which could be used as a helpful tool to optimize the dosage of this drug. The results suggest that the main active metabolite of DOX, DOXol, is involved in the haematological toxicity of the parent drug.Peer Reviewe