Quantification of Pharmacokinetic Profiles of PD-1/PD-L1 Antibodies by Validated ELISAs.

Immunotherapy has changed the paradigm of cancer treatments. In this way, several combinatorial strategies based on monoclonal antibodies (mAb) such as anti (a)-PD-1 or anti (a)-PD-L1 are often reported to yield promising clinical benefits. However, the pharmacokinetic (PK) behavior of these mAbs is a critical issue that requires selective analytical techniques. Indeed, few publications report data on a-PD1/a-PD-L1 exposure and its relationship with therapeutic or toxic effects. In this regard, preclinical assays allow the time profiles of antibody plasma concentrations to be characterized rapidly and easily, which may help to increase PK knowledge. In this study, we have developed and validated two in-house ELISAs to quantify a-PD-1 and a-PD-L1 in plasma collected from tumor-bearing mice. The linear range for the a-PD-1 assay was 2.5-125 ng/mL and 0.11-3.125 ng/mL for the a-PD-L1 assay, whereas the intra-and inter-day precision was lower than 20% for both analytes. The PK characterization revealed a significant decrease in drug exposure after administration of multiple doses. Plasma half-life for a-PD-1 was slightly shorter (22.3 h) than for a-PD-L1 (46.7 h). To our knowledge, this is the first reported preclinical ELISA for these immune checkpoint inhibitors, which is sufficiently robust to be used in different preclinical models. These methods can help to understand the PK behavior of these antibodies under different scenarios and the relationship with response, thus guiding the choice of optimal doses in clinical settings.

Drug Exposure to Establish Pharmacokinetic-Response Relationships in Oncology.

In the oncology field, understanding the relationship between the dose administered and the exerted effect is particularly important because of the narrow therapeutic index associated with anti-cancer drugs and the high interpatient variability. Therefore, in this review, we provide a critical perspective of the different methods of characterising treatment exposure in the oncology setting. The increasing number of modelling applications in oncology reflects the applicability and the impact of pharmacometrics on all phases of the drug development process and patient management as well. Pharmacometric modelling is a worthy component within the current paradigm of model-based drug development, but pharmacometric modelling techniques are also accessible for the clinician in the optimisation of current oncology therapies. Consequently, the application of population models in a hospital setting by generating close collaborations between physicians and pharmacometricians is highly recommended, providing a systematic means of developing and assessing model-based metrics as 'drivers' for various responses to treatments, which can then be evaluated as predictors for treatment success. Characterising the key determinants of variability in exposure is of particular importance for anticancer agents, as efficacy and toxicity are associated with exposure. We present the different strategies to describe and predict drug exposure that can be applied depending on the data available, with the objective of obtaining the most useful information in the patients' favour throughout the full drug cycle. Therefore, the objective of the present article is to review the different approaches used to characterise a patient's exposure to oncology drugs, which will result in a better understanding of the time course of the response and the magnitude of interpatient variability.

Population Pharmacokinetic Analysis of Lanreotide Autogel/Depot in the Treatment of Neuroendocrine Tumors: Pooled Analysis of Four Clinical Trials.

BACKGROUND AND OBJECTIVES: Lanreotide Autogel (lanreotide Depot in the USA) has demonstrated anti-tumor activity and control of the symptoms associated with hormone hypersecretion in patients with neuroendocrine tumors. The objectives of this study were to describe the pharmacokinetics of lanreotide Autogel administered 4-weekly by deep subcutaneous injections of 60, 90, or 120 mg in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs), to quantify the magnitude of inter-patient variability (IPV), and to identify those patient characteristics that impact on pharmacokinetics. METHODS: Analyses were based on pooled data from clinical trials. A total of 1541 serum concentrations from 290 patients were analyzed simultaneously by the population approach using NONMEM version 7.2. Covariates evaluated included demographics, renal and hepatic function markers, and disease-related parameters. RESULTS: Serum profiles were described by a one-compartment disposition model in which the absorption process was characterized by two parallel pathways following first- and zero-order kinetics. The estimated apparent volume of distribution was 18.3 L. The estimated apparent total serum clearance for a typical 74 kg patient was 513 L/day, representing a substantial difference in clearance in this population of patients with respect to healthy volunteers that could not be explained by any of the covariates tested. Body weight was the only covariate to show a statistically significant effect on the pharmacokinetic profile, but due to the overlap between the pharmacokinetic profiles of patients with lower or higher body weights the effect of body weight on clearance was not considered clinically relevant. The IPV was low for clearance (27%) and moderate to high for volume of distribution (150%) and the absorption constant (61%). CONCLUSIONS: Using two mechanisms of absorption, the pharmacokinetics of lanreotide Autogel were well-described in patients with GEP-NET. None of the patient characteristics tested were of clinical relevance to potential dose adjustment in clinical practice.

Impacto de una intervención en alimentación y actividad física sobre la prevalencia de obesidad en escolares / Impact of an intervention on diet and physical activity on obesity prevalence in schoolchildren

En Chile la obesidad infantil es un creciente problema de salud pública. Los programas de intervención al interior de las escuelas han mostrado resultados variables, con mejores resultados cuando se incluyen diversas variables y a toda la comunidad educativa. El objetivo del estudio fue evaluar el efecto sobre el estado nutricional de un programa realizado al interior de las escuelas, de 2 años de duración (Programa Vive Sano). Se estudiaron 2.527 escolares de primero a cuarto año de educación básica, de 3 comunas de la Región Metropolitana de Chile, que fueron intervenidos en alimentación, nutrición, actividad física y autocuidado de la salud con un equipo de Nutricionistas y Profesores de educación física. Se evaluó peso y talla al ingreso al programa y al final del primer y segundo año de intervención, en condiciones estandarizadas. Se calculó puntaje Z del IMC y estado nutricional según la referencia OMS 2007. Al final del segundo año 1.453 niños fueron reevaluados. Hubo una disminución significativa en puntaje Z del IMC-edad en los escolares obesos (-0,3 DE) y la prevalencia global de obesidad disminuyó de 21,8% a 18,4% al final de la intervención. El 75% de los escolares con obesidad y 60,5% con sobrepeso disminuyó su Z score IMC, siendo mayor la reducción en el sexo masculino y en los cursos superiores. El 51,9% de los estudiantes con peso normal aumentó su puntaje Z de IMC-edad, aunque mayoritariamente menos de 0,5 DE. Se puede concluir que la educación en alimentación y actividad física realizada por profesionales fue efectiva en reducir la prevalencia de obesidad (-3,4 puntos porcentuales). El gran desafío es buscar mecanismos para darle continuidad al programa y evaluar los efectos a largo plazo (AU)

In Chile childhood obesity is a growing public health problem. Intervention programs within schools have shown variable results, with better impacts when multiple aspects are involved and included the entire educational community. The objective of the study was to evaluate the effect on the nutritional status of children in intervention schools within 2 years of duration (Healthy Living Program). The sample included 2,527 students first through fourth grade of 3 counties of Santiago. The students were intervened and followed for a period of two years in their food and nutrition habits, physical activity and self-care practices, by a team of nutritionists and physical education teachers. Weight and height were measured at start of program, end of the first and second years of intervention, under standardized conditions and calculated the Z score of BMI and nutritional status according to the WHO reference 2007. At the end of the second year 1,453 children were reassessed. There was a significant decrease in BMI Z score in obese children (-0.3 SD) and obesity decreased from 21.8% to 18.4% at the end of the intervention. 75% of schoolchildren obese and 60.5% overweight decreased their BMI Z score, reduction that was greater in men and students in the upper grades. 51.9% of normal weight children increased their BMI Z-score age, although most less than 0.5 SD. The intervention in education, nutrition and physical activity among schoolchildren in three communes of Greater Santiago was effective in reducing the prevalence of obesity (-3.4 percentage points). The big challenge is to find mechanisms to give continuity to the program and evaluate long-term effects (AU)