Setting up regional diagnostic reference levels for pediatric computed tomography in Latin America: preliminary results, challenges and the work ahead.

We established a framework for collecting radiation doses for head, chest and abdomen-pelvis computed tomography (CT) in children scanned at multiple imaging sites across Latin America with an aim towards establishing diagnostic reference levels (DRLs) and achievable doses (ADs) in pediatric CT in Latin America. Our study included 12 Latin American sites (in Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, Honduras and Panama) contributing data on the four most common pediatric CT examinations (non-contrast head, non-contrast chest, post-contrast chest and post-contrast abdomen-pelvis). Sites contributed data on patients' age, sex and weight, scan factors (tube current and potential), volume CT dose index (CTDIvol) and dose length product (DLP). Data were verified, leading to the exclusion of two sites with missing or incorrect data entries. We estimated overall and site-specific 50th (AD) and 75th (diagnostic reference level [DRL]) percentile CTDIvol and DLP for each CT protocol. Non-normal data were compared using the Kruskal-Wallis test. Sites contributed data from 3,934 children (1,834 females) for different CT exams (head CT 1,568/3,934, 40%; non-contrast chest CT 945/3,934, 24%; post-contrast chest CT 581/3,934, 15%; abdomen-pelvis CT 840/3,934, 21%). There were significant statistical differences in 50th and 75th percentile CTDIvol and DLP values across the participating sites (P<0.001). The 50th and 75th percentile doses for most CT protocols were substantially higher than the corresponding doses reported from the United States of America. Our study demonstrates substantial disparities and variations in pediatric CT examinations performed in multiple sites in Latin America. We will use the collected data to improve scan protocols and perform a follow-up CT study to establish DRLs and ADs based on clinical indications.

Inoculum-Based Dosing: A Novel Concept for Combining Time with Concentration-Dependent Antibiotics to Optimize Clinical and Microbiological Outcomes in Severe Gram Negative Sepsis.

Certain classes of antibiotics show "concentration dependent" antimicrobial activity; higher concentrations result in increased bacterial killing rates, in contrast to "time dependent antibiotics", which show antimicrobial activity that depends on the time that antibiotic concentrations remain above the MIC. Aminoglycosides and fluoroquinolones are still widely used concentration-dependent antibiotics. These antibiotics are not hydrolyzed by beta-lactamases and are less sensitive to the inoculum effect, which can be defined as an increased MIC for the antibiotic in the presence of a relatively higher bacterial load (inoculum). In addition, they possess a relatively long Post-Antibiotic Effect (PAE), which can be defined as the absence of bacterial growth when antibiotic concentrations fall below the MIC. These characteristics make them interesting complementary antibiotics in the management of Multi-Drug Resistant (MDR) bacteria and/or (neutropenic) patients with severe sepsis. Global surveillance studies have shown that up to 90% of MDR Gram-negative bacteria still remain susceptible to aminoglycosides, depending on the susceptibility breakpoint (e.g., CLSI or EUCAST) being applied. This percentage is notably lower for fluoroquinolones but depends on the region, type of organism, and mechanism of resistance involved. Daily (high-dose) dosing of aminoglycosides for less than one week has been associated with significantly less nephro/oto toxicity and improved target attainment. Furthermore, higher-than-conventional dosing of fluoroquinolones has been linked to improved clinical outcomes. Beta-lactam antibiotics are the recommended backbone of therapy for severe sepsis. Since these antibiotics are time-dependent, the addition of a second concentration-dependent antibiotic could serve to quickly lower the bacterial inoculum, create PAE, and reduce Penicillin-Binding Protein (PBP) expression. Inadequate antibiotic levels at the site of infection, especially in the presence of high inoculum infections, have been shown to be important risk factors for inadequate resistance suppression and therapeutic failure. Therefore, in the early phase of severe sepsis, effort should be made to optimize the dose and quickly lower the inoculum. In this article, the authors propose a novel concept of "Inoculum Based Dosing" in which the decision for antibiotic dosing regimens and/or combination therapy is not only based on the PK parameters of the patient, but also on the presumed inoculum size. Once the inoculum has been lowered, indirectly reflected by clinical improvement, treatment simplification should be considered to further treat the infection.

Establishing national clinical diagnostic reference levels and achievable doses for CT examinations in Brazil: A prospective study.

PURPOSE: Diagnostic reference levels (DRL) and achievable doses (AD) are important tools for radiation dose optimization. Therefore, a prospective study was performed which aimed to establish a multi-parametric, clinical indication based - DRL(DRLCI) and clinical indication - AD (ADCI) for adult CT in Brazil. METHODS: The prospective study included 4787 patients (50 ± 18 years old; male:female 2041:2746) at 13 Brazilian sites that have been submitted to head, paranasal sinus, cervical spine, chest, or abdomen-pelvis CT between January and October 2021 for 13 clinical indications. The sites provided the following information: patient age, gender, weight, height, body mass index[BMI], clinical indications, scanner information(vendor, model, detector configuration), scan parameters (number of scan phases, kV, mA, pitch) and dose-related quantities (CT dose index volume- CTDIvol, dose length product- DLP). Median(AD) and 75th(DRL) percentile CTDIvol and DLP values were estimated for each body region and clinical indications. Non-normal data were analyzed with the Kruskal-Wallis test. RESULTS: In majority of Brazilian sites, body region and clinical indications based DRLs were at or lower than the corresponding DRLs in the US and higher than Europe. Although radiation doses varied significantly for patients in different body mass index groups (p < 0.001), within each body region, there were no differences in radiation doses for different clinical indications (p > 0.1). Radiation doses for 7/13 clinical indications were higher using iterative reconstruction technique than for the filtered back projection. CONCLUSIONS: There was substantial variation in Brazil DRLCI across different institutions with higher doses compared to the European standards. There was also a lack of clinical indication-based protocol and dose optimization based on different clinical indications for the same body region.

Oncology phase I trial design and conduct: time for a change - MDICT Guidelines 2022.

In 2021, the Food and Drug Administration Oncology Center of Excellence announced Project Optimus focusing on dose optimization for oncology drugs. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Taskforce met to review and discuss the optimization of dosage for oncology trials and to develop a practical guide for oncology phase I trials. Defining a single recommended phase II dose based on toxicity may define doses that are neither the most effective nor the best tolerated. MDICT recommendations address the need for robust non-clinical data which are needed to inform trial design, as well as an expert team including statisticians and pharmacologists. The protocol must be flexible and adaptive, with clear definition of all endpoints. Health authorities should be consulted early and regularly. Strategies such as randomization, intrapatient dose escalation, and real-world eligibility criteria are encouraged whereas serial tumor sampling is discouraged in the absence of a strong rationale and appropriately validated assay. Endpoints should include consideration of all longitudinal toxicity. The phase I dose escalation trial should define the recommended dose range for later testing in randomized phase II trials, rather than a single recommended phase II dose, and consider scenarios where different populations may require different dosages. The adoption of these recommendations will improve dosage selection in early clinical trials of new anticancer treatments and ultimately, outcomes for patients.

Modelado farmacocinético-farmacodinámico de fármacos antihipertensivos: su aplicación en la práctica clínica / Pharmacokinetic-Pharmacodynamic Modelling of Antihypertensive Drugs: Its Application to Clinical Practice

El conocimiento de las propiedades farmacocinéticas-farmacodinámicas (PK/PD) de los fármacos puede optimizar la terapia antihipertensiva. El modelado PK/PD en la investigación clínica podría contribuir en el desarrollo del fármaco y en la práctica clínica en varios aspectos, entre ellos la evaluación de eficacia y seguridad de los antihipertensivos, mayor información durante el proceso del desarrollo, identificación de factores de variabilidad de la respuesta farmacológica, y permitir además una identificación rápida de malos respondedores o no respondedores y ayudar a determinar requerimientos óptimos del fármaco y dosis en cada paciente hipertenso. Hay algunas limitaciones en el modelado PK/PD de los antihipertensivos en la práctica clínica, entre las que se incluyen el uso de modelos farmacodinámicos inadecuados y la incapacidad de estudiar dosis elevadas de antihipertensivos para determinar el rango farmacodinámico completo del efecto antihipertensivo. El propósito de esta revisión es describir el conocimiento actual del modelado PK/PD de los fármacos antihipertensivos en la investigación clínica y sus usos futuros.

Knowing the pharmacokinetic-pharmacodynamic properties (PK/PD) of drugs might optimize antihypertensive therapy. PK/PD modelling might not only contribute to develop the drug but might also help in clinical practice assessing the efficacy and safety of antihypertensive drugs, bringing more information during the developing process, identifying factors responsible for the variability in pharmacologic response, bad responders or non-responders, and determining the optimal requisites of the drug and doses in each patient with hypertension. There are some limitations in PK/ PD modelling of antihypertensive drugs in clinical practice, such as inadequate pharmacodynamic models and the inability to study high doses of antihypertensive drugs to determine the whole pharmacodynamic range of the antihypertensive effect. The aim of this review is to describe the current knowledge on PK/PD modelling of antihypertensive drugs in clinical research, and its further uses.