Characterization of the Pharmacokinetic and Pharmacodynamic Profile of Apraglutide, a Glucagon-Like Peptide-2 Analog, in Healthy Volunteers.

Apraglutide (FE 203799) is a glucagon-like peptide-2 (GLP-2) analog under development for the treatment of intestinal failure associated with short bowel syndrome (SBS-IF) and graft-versus-host disease (GvHD). Compared with native GLP-2, apraglutide has slower absorption, reduced clearance, and higher protein binding, enabling once-weekly dosing. This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of apraglutide in healthy adults. Healthy volunteers were randomized to receive 6 weekly subcutaneous administrations of 1, 5, or 10 mg apraglutide or placebo. PK and citrulline (an enterocyte mass PD marker) samples were collected at multiple time points. Kinetic parameters of apraglutide and citrulline were calculated using noncompartmental analysis; repeated PD measures were analyzed with a mixed model of covariance. A population PK/PD model was developed that also included data from a previous phase 1 study in healthy volunteers. Twenty-four subjects were randomized; 23 received all study drug administrations. Mean estimated apraglutide clearance was 16.5-20.7 l/day, and mean volume of distribution was 55.4-105.0 liters. A dose-dependent increase in citrulline plasma concentration was observed, with 5-mg and 10-mg doses inducing higher citrulline levels than 1-mg doses and placebo. PK/PD analysis showed that weekly 5-mg apraglutide induced the maximal citrulline response. Increased plasma citrulline levels were sustained for 10-17 days after the final apraglutide administration. Apraglutide displays predictable dose-dependent PK and PD profiles, with a 5-mg dose showing significant PD effects. Results suggest that apraglutide has early and enduring effects on enterocyte mass and supports the continued development of weekly subcutaneous apraglutide for SBS-IF and GvHD patient populations. SIGNIFICANCE STATEMENT: Once-weekly subcutaneous apraglutide results in dose-dependent elevations of plasma citrulline (an enterocyte mass pharmacodynamic marker) with parameters suggesting that apraglutide has lasting effects on enterocyte mass and the potential to provide therapeutic benefits. This is the first report of a model relating glucagon-like peptide-2 (GLP-2) agonism and its effects in intestinal mucosa, affording not only the ability to predict pharmacologic effects of GLP-2 analogs but also the exploration of optimal dosing regimens for this drug class across populations with different body weights.

Development and Technical Validation of a Smartphone-Based Cry Detection Algorithm.

Introduction: The duration and frequency of crying of an infant can be indicative of its health. Manual tracking and labeling of crying is laborious, subjective, and sometimes inaccurate. The aim of this study was to develop and technically validate a smartphone-based algorithm able to automatically detect crying. Methods: For the development of the algorithm a training dataset containing 897 5-s clips of crying infants and 1,263 clips of non-crying infants and common domestic sounds was assembled from various online sources. OpenSMILE software was used to extract 1,591 audio features per audio clip. A random forest classifying algorithm was fitted to identify crying from non-crying in each audio clip. For the validation of the algorithm, an independent dataset consisting of real-life recordings of 15 infants was used. A 29-min audio clip was analyzed repeatedly and under differing circumstances to determine the intra- and inter- device repeatability and robustness of the algorithm. Results: The algorithm obtained an accuracy of 94% in the training dataset and 99% in the validation dataset. The sensitivity in the validation dataset was 83%, with a specificity of 99% and a positive- and negative predictive value of 75 and 100%, respectively. Reliability of the algorithm appeared to be robust within- and across devices, and the performance was robust to distance from the sound source and barriers between the sound source and the microphone. Conclusion: The algorithm was accurate in detecting cry duration and was robust to various changes in ambient settings.

Contemporary Insertion of Central Venous Access Catheters in Pediatric Patients: A Retrospective Record Review Study of 538 Catheters in a Single Center.

OBJECTIVE: To analyze the rate of infections and complications after surgeon-performed, largely ultrasound-guided, central venous catheter (CVC) placement in a pediatric population and to identify patients at high risk of complications. METHODS: All children aged between 4 months and 19 years with a percutaneous CVC inserted between January 1, 2000, and July 31, 2013, were included. Patient records were reviewed retrospectively for the occurrence of infection and other complications until CVC removal or the last outpatient clinic visit and compared between patient groups and with the recent literature. RESULTS: A total of 538 CVCs were placed in 345 patients. Eight patients (1.5%) suffered complications during placement. There were 84 cases of a suspected CVC infection (15.6%). Catheter-related infections with a positive catheter tip culture occurred in 25 cases (4.6%). Older patients (odds ratio [OR] 0.88; 95% confidence interval [CI] 0.78-0.98) or patients with a double-lumen 7 French Bard-Hickman catheter (OR 0.32; 95% CI 0.11-1.00) had a significantly lower risk of infection. Older patients (OR 0.94; 95% CI 0.89-0.99) and patients with beta-thalassemia (OR 0.35; 95% CI 0.17-0.71) also had a significantly lower risk of suspected infection. CONCLUSION: In general, infection rates in our series were similar to those in the recent literature. Younger patients seem to be at higher risk for CVC removal because of infection prior to the end of treatment. Patients with beta-thalassemia or receiving a double-lumen 7F Bard-Hickman catheter had a lower risk of infection.