A Population Pharmacokinetic Assessment of the Effect of Food on Selumetinib in Patients with Neurofibromatosis Type 1-Related Plexiform Neurofibromas and Healthy Volunteers.

Selumetinib is clinically used for pediatric patients with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas. Until recently, selumetinib had to be taken twice daily, after 2 hours of fasting and followed by 1 hour of fasting, which could be inconvenient. This population analysis evaluated the effect of low- and high-fat meals on the pharmacokinetic (PK) parameters of selumetinib and its active metabolite N-desmethyl selumetinib. The dataset comprised 511 subjects from 15 clinical trials who received ≥1 dose of selumetinib and provided ≥1 measurable postdose concentration of selumetinib and N-desmethyl selumetinib. A 2-compartment model with sequential 0- and 1st-order delayed absorption and 1st-order elimination adequately described selumetinib PK characteristics. A 1-compartment model reasonably described N-desmethyl selumetinib PK characteristics over time simultaneously with selumetinib. Selumetinib geometric mean area under the concentration-time curve ratio (1-sided 90% confidence interval [CI] lower bound) was 76.9% (73.3%) with a low-fat meal and 79.3% (76.3%) with a high-fat meal versus fasting. The lower bound of the 1-sided 90% CI demonstrated a difference of <30% between fed and fasted states. Considering the flat exposure-response relationship within the dose range (20-30 mg/m2), the observed range of exposure, and the variability in the SPRINT trial, this was not considered clinically relevant.

Beneficios metabólicos de realizar ejercicio en estado de ayuno / Metabolic benefits of exercise in the fasted state

The high rate of obesity in sedentary population, coupled with the increase in diseases associated with this lifestyle, have led us to seek new strategies to enhance the physical training that will favor mobilization, uptake and utilization of fats and glucose. Doing exercise in the fasted state is one that has proved more promising. There is sufficient evidence on the benefits of physical activity during fasting producing a favorable hormonal environment, activation of mediators such as AMPKand LPL activation, among others. Performing aerobic exercise of moderate intensity in this environment favors fasting lipid oxidation, decreasing intramyo-cellular triglycerides, visceral fat and LDL cholesterol, compared with the benefits of exercise in the postprandial state. There is an important need for more studies of physical activity in the fasted state that include patients with chronic non-transmissible diseases and resistance training.

El alta tasa de obesidad y sedentarismo de la población, sumado al aumento de las patologías asociadas a éste estilo de vida, nos han llevado a buscar nuevas estrategias de entrenamiento físico que potencien la movilización, captación y utilización de grasas y glucosa. La realización de ejercicio en estado de ayuno es una de las que ha resultado ser más promisoria. Hay evidencia suficiente sobre los beneficios de realizar actividad física en ayunas, ya sea por el ambiente hormonal favorable, la activación de mediadores como el AMPK y la activación de la LPL, entre otros. La realización de ejercicio aeróbico de intensidad moderada en este ambiente de ayuno favorece la oxidación de lípidos, la disminución de los triglicéridos intramiocelulares, la grasa visceral y del colesterol LDL, en comparación con los beneficios del ejercicio realizado en ambiente postprandial. Existe una necesidad de un mayor número de estudios con actividad física en ayuna, donde se incluya a paciente con enfermedades crónicas no transmisibles y los ejercicios de tipo resistido.