Characteristics of Pediatric Hospital Medicine Fellowship Program Directors.

BACKGROUND AND OBJECTIVES: Rapid growth in pediatric hospital medicine (PHM) fellowships has occurred, yielding many new program directors (PDs). Characteristics of PDs have potential implications on the field. To describe characteristics (demographic, educational) and scholarly interests of PHM fellowship PDs. METHODS: We developed and distributed a 15-question, cross-sectional national survey to the PHM PDs listserv. Questions were pilot tested. The survey was open for 4 weeks with weekly reminders. Responses were summarized using descriptive statistics. RESULTS: Fifty-six current fellowship leaders (40 PDs, 16 associate PDs [APDs]) responded, including at least 1 from 43 of 59 active PHM fellowship programs (73%). Most respondents identified as female (71%) and ≤50 years old (80%). Four (7%, n = 2 PD, 2 APD) leaders identified as underrepresented in medicine. About half (n = 31, 55.4%) completed a fellowship themselves (APDs > PDs; 87.5% vs 42.5%), and 53.5% (n = 30) had advanced nonmedical degrees (eg, Master of Science, Doctor of Philosophy; APDs > PDs; 62% vs 45%). Most leaders (59%, n = 33) chose multiple domains when asked to select a "primary domain of personal scholarship." Education was the most frequently selected (n = 37), followed by quality improvement (n = 29) and then clinical research (n = 19). CONCLUSIONS: This survey confirms a high percentage of women as PHM fellowship leaders and highlights the need to increase diversity. Less than half of senior PDs completed a fellowship in any specialty. Leaders report interest in multiple domains of scholarship; few focus solely on clinical research.

Behavioural responses of fin whales to military mid-frequency active sonar.

The effect of active sonars on marine mammal behaviour is a topic of considerable interest and scientific investigation. Some whales, including the largest species (blue whales, Balaenoptera musculus), can be impacted by mid-frequency (1-10 kHz) military sonars. Here we apply complementary experimental methods to provide the first experimentally controlled measurements of behavioural responses to military sonar and similar stimuli for a related endangered species, fin whales (Balaenoptera physalus). Analytical methods include: (i) principal component analysis paired with generalized additive mixed models; (ii) hidden Markov models; and (iii) structured expert elicitation using response severity metrics. These approaches provide complementary perspectives on the nature of potential changes within and across individuals. Behavioural changes were detected in five of 15 whales during controlled exposure experiments using mid-frequency active sonar or pseudorandom noise of similar frequency, duration and source and received level. No changes were detected during six control (no noise) sequences. Overall responses were more limited in occurrence, severity and duration than in blue whales and were less dependent upon contextual aspects of exposure and more contingent upon exposure received level. Quantifying the factors influencing marine mammal responses to sonar is critical in assessing and mitigating future impacts.

Inpatient Pediatric Care and Clinician Workforce in Wisconsin: The State of the State.

INTRODUCTION: Availability of inpatient pediatric services declined across the United States from 2008 through 2018, with rural areas experiencing steepest declines. Despite the movement of pediatric care to children's centers, most children are still cared for in community hospitals nationally. Assessing the availability and providers of inpatient pediatric care in Wisconsin is an important step in ensuring the health care needs of children in the state continue to be met. METHODS: A cross-sectional survey was distributed to Wisconsin hospitals to determine pediatric services and physician workforce. The response rate was 130/138 (94%), including 56/58 (97%) critical access hospitals. Results of specific inpatient pediatric subdivisions were analyzed by descriptive statistics. RESULTS: Hospitals that provide inpatient newborn care are mostly staffed by pediatricians and family physicians, while critical access hospitals are staffed by family physicians. Hospitals with neonatal intensive care units are staffed by neonatologists, with telemedicine utilized in critical access hospitals. Hospitals with general pediatric admissions are staffed by pediatricians or family physicians, while critical access hospitals are staffed by family physicians. Hospitals with pediatric intensive care units are staffed by pediatric intensivists. CONCLUSIONS: Despite workforce disparities and shortages, hospitals across Wisconsin, including many critical access hospitals, continue to provide inpatient pediatric services. Family physicians play a major role in the pediatric health care delivery in Wisconsin hospitals. Robust inpatient pediatric training of family physicians may enable rural health authorities to continue addressing the gaps that persist in inpatient pediatric care accessibility.

Gender Difference in Teaching Evaluation Scores of Pediatric Faculty.

OBJECTIVE: To evaluate associations between faculty gender and milestone-based teaching assessment scores assigned by residents. METHODS: We performed a retrospective cohort study of milestone-based clinical teaching assessments of pediatric faculty completed by pediatric residents at a mid-sized residency program from July 2016 to June 2019. Assessments included 3 domains (Clinical Interactions, Teaching Skills, Role Modeling/Professionalism) comprised of a total of 11 sub-competency items. We used multilevel logistic regression accounting for repeat measures and clustering to evaluate associations between faculty gender and assessment scores in the 1) top quartile, 2) bottom quartile, or 3) top-box (highest score). Findings were adjusted for faculty rank and academic track, and resident year and gender. RESULTS: Over 3 years, 2889 assessments of 104 faculty were performed by 91 residents. Between assessments of women and men faculty, there were no significant differences in the odds of receiving a score in the top quartile for the 3 domains (Clinical aOR 0.99, P = .86; Teaching aOR 0.99, P = .93; Role Modeling aOR 0.87, P = .089). However, assessments of women were more likely to receive a score in the bottom quartile in both Teaching (aOR 1.23, P = .019) and Role Modeling (aOR 1.26, P = .008). Assessments of women also had lower odds of receiving the highest score in 6 of 11 sub-competencies. CONCLUSION: Results suggest that gender bias may play a role in resident assessments of pediatric faculty. Future studies are needed to determine if findings are replicated in other settings and to identify opportunities to reduce the gender gap in pediatric academic medicine.

Gender-Based Linguistic Analysis of Pediatric Clinical Faculty Evaluations.

BACKGROUND: Gendered stereotypes are embedded in the culture of medicine. Women are stereotypically expected to act collaboratively and less assertively, while men are expected to act with authority and power. Whether gender-biased language is expressed in academic pediatric teaching evaluations is unknown. OBJECTIVE: Determine whether stereotypic gender-based linguistic differences exist in resident evaluations of pediatric faculty. METHODS: We performed a retrospective cross-sectional study of clinical faculty evaluations by pediatric residents in a single program from July 2016 to June 2019. Using Linguistic Inquiry and Word Count, responses to 2 open-ended questions were analyzed for stereotypic language. Categories were reported as a percent of total words written. Comparisons between gender groups were conducted using nonparametric Wilcoxon rank sum tests. Rates of word use within each category were analyzed using logistic regression where faculty and resident gender were included as predictor variables. RESULTS: A total of 6436 free-text responses from 3218 unique evaluations were included. As hypothesized, evaluations of women faculty were less likely than those of men to include certain agentic language like power (odds ratio [OR] 0.9, P < .001) and insight (OR 0.9, P < .001), and research words (OR 0.6, P = .003). As expected, evaluations of women were more likely to include grindstone words, like "hardworking" (OR 1.2, P = .012). Contrary to our hypothesis, women received fewer teaching words like "mentor" (OR 0.9, P = .048) and communal words like "friendly" (OR 0.6, P = .001). CONCLUSION: Certain stereotypic language was demonstrated in clinical teaching evaluations of pediatric faculty. These findings should be further examined to improve gender inequities in academic pediatrics.

Earlier Hospital Discharge With Prospectively Designated Discharge Time in the Electronic Health Record.

BACKGROUND AND OBJECTIVES: Hospital discharge requires multidisciplinary coordination. Insufficient coordination impacts patient flow, resource use, and postdischarge outcomes. Our objectives were to (1) implement a prospective, multidisciplinary discharge timing designation in the electronic health record (EHR) and (2) evaluate its association with discharge timing. METHODS: This quality-improvement study evaluated the implementation of confirmed discharge time (CDT), an EHR designation representing specific discharge timing developed jointly by a patient's family and the health care team. CDT was intended to support task management and coordination of multidisciplinary discharge processes and could be entered and viewed by all team members. Four plan-do-study-act improvement phases were studied: (1) baseline, (2) provider education, (3) provider feedback, and (4) EHR modification. Statistical process control charts tracked CDT use and the proportion of discharges before noon. Length of stay was used as a balancing measure. RESULTS: During the study period from April 2013 through March 2017, 20 133 pediatric discharges occurred, with similar demographics observed throughout all phases. Mean CDT use increased from 0% to 62%, with special cause variations being detected after the provider education and EHR modification phases. Over the course of the study, the proportion of discharges before noon increased by 6.2 percentage points, from 19.9% to 26.1%, whereas length of stay decreased from 47 (interquartile range: 25-95) to 43 (interquartile range: 24-88) hours (both P < .001). CONCLUSIONS: The implementation of a prospective, multidisciplinary EHR discharge time designation was associated with more before-noon discharges. Next steps include replicating results in other settings and determining populations that are most responsive to discharge coordination efforts.

Feeding during High-Flow Nasal Cannula for Bronchiolitis: Associations with Time to Discharge.

BACKGROUND: High-flow nasal cannula (HFNC) is increasingly used to treat children hospitalized with bronchiolitis; however, the best practices for feeding during HFNC and the impact of feeding on time to discharge and adverse events are unknown. The study objective was to assess whether feeding exposure during HFNC was associated with time to discharge or feeding-related adverse events. METHODS: This retrospective cohort study included inpatients aged 1-24 months receiving HFNC for bronchiolitis at an academic children's hospital from January 1, 2015 to March 1, 2017. Feeding exposures during HFNC were categorized as fed or not fed. Among fed children, we further evaluated mixed (oral and tube) or exclusive oral feeding. The primary outcome was time to discharge after HFNC cessation. Secondary outcomes were aspiration, intubation after HFNC, and seven-day readmission. RESULTS: Of 123 children treated with HFNC, 45 (37 %) were never fed. A total of 78 children (63%) were fed; 50 (41%) were exclusively orally fed and 28 (23 %) had mixed feeding. Median (interquartile range) time to discharge after HFNC was 29.5 hours (23.5-47.9) and 39.8 hours (26.4-61.5) hours in the fed and not fed groups, respectively. In adjusted models, time to discharge was shorter with any feeding (hazard ratio [HR] 2.17; 95% CI: 1.34-3.50) and with exclusive oral feeding (HR 2.13; 95% CI: 1.31-3.45) compared with no feeding. Time to discharge from HFNC initiation was shorter for exclusive oral feeding versus not feeding (propensity weighted HR 1.97 [95% CI: 1.13-3.43]). Adverse events (one intubation, one aspiration pneumonia, one readmission) occurred in both groups. LIMITATIONS: Assessment of feeding exposure did not account for quantity and duration. DISCUSSION: Children fed while receiving HFNC for bronchiolitis may have shorter time to discharge than those not fed. Feeding-related adverse events were rare regardless of the feeding method. Controlled prospective studies addressing residual confounding are needed to justify a change in the current practice.

From Their Perspective: The Connection between Life Stressors and Health Care Service Use Patterns of Homeless Frequent Users of the Emergency Department.

The perspective of homeless adults on their health care service utilization is not well studied. This article describes a study that used in-depth, semistructured interviews with 18 individuals to highlight the viewpoints of homeless people who are frequent users of the emergency department (ED) about the influence of life events on service utilization. Participants reported high levels of pain and comorbid psychiatric, substance use, and medical conditions. They also reported an identifiable pattern of health care utilization, often centered on a crisis event, influenced by high perceived medical needs, inability to cope after crisis, predisposing vulnerability from social determinants of health, and health care system factors. A social work case management intervention often led to a period of stability and use of ED alternatives. Modifiable targets for intervention at the health care system and local levels include improving trust and convenience of ED alternatives, enhancing consistency of care at ED-alternative sites, and educating those at risk of frequent ED use about community alternatives.

Behavioral responses of individual blue whales (Balaenoptera musculus) to mid-frequency military sonar.

This study measured the degree of behavioral responses in blue whales (Balaenoptera musculus) to controlled noise exposure off the southern California coast. High-resolution movement and passive acoustic data were obtained from non-invasive archival tags (n=42) whereas surface positions were obtained with visual focal follows. Controlled exposure experiments (CEEs) were used to obtain direct behavioral measurements before, during and after simulated and operational military mid-frequency active sonar (MFAS), pseudorandom noise (PRN) and controls (no noise exposure). For a subset of deep-feeding animals (n=21), active acoustic measurements of prey were obtained and used as contextual covariates in response analyses. To investigate potential behavioral changes within individuals as a function of controlled noise exposure conditions, two parallel analyses of time-series data for selected behavioral parameters (e.g. diving, horizontal movement and feeding) were conducted. This included expert scoring of responses according to a specified behavioral severity rating paradigm and quantitative change-point analyses using Mahalanobis distance statistics. Both methods identified clear changes in some conditions. More than 50% of blue whales in deep-feeding states responded during CEEs, whereas no changes in behavior were identified in shallow-feeding blue whales. Overall, responses were generally brief, of low to moderate severity, and highly dependent on exposure context such as behavioral state, source-to-whale horizontal range and prey availability. Response probability did not follow a simple exposure-response model based on received exposure level. These results, in combination with additional analytical methods to investigate different aspects of potential responses within and among individuals, provide a comprehensive evaluation of how free-ranging blue whales responded to mid-frequency military sonar.

Romer Labs RapidChek®Listeria monocytogenes Test System for the Detection of L. monocytogenes on Selected Foods and Environmental Surfaces.

The Romer Labs RapidChek® Listeria monocytogenes test system (Performance Tested Method 011805) was validated against the U.S. Department of Agriculture-Food Safety and Inspection Service Microbiology Laboratory Guidebook (USDA-FSIS/MLG), U.S. Food and Drug Association Bacteriological Analytical Manual (FDA/BAM), and AOAC Official Methods of Analysis (AOAC/OMA) cultural reference methods for the detection of L. monocytogenes on selected foods including hot dogs, frozen cooked breaded chicken, frozen cooked shrimp, cured ham, and ice cream, and environmental surfaces including stainless steel and plastic in an unpaired study design. The RapidChek method uses a proprietary enrichment media system, a 44-48 h enrichment at 30 ± 1°C, and detects L. monocytogenes on an immunochromatographic lateral flow device within 10 min. Different L. monocytogenes strains were used to spike each of the matrixes. Samples were confirmed based on the reference method confirmations and an alternate confirmation method. A total of 140 low-level spiked samples were tested by the RapidChek method after enrichment for 44-48 h in parallel with the cultural reference method. There were 88 RapidChek presumptive positives. One of the presumptive positives was not confirmed culturally. Additionally, one of the culturally confirmed samples did not exhibit a presumptive positive. No difference between the alternate confirmation method and reference confirmation method was observed. The respective cultural reference methods (USDA-FSIS/MLG, FDA/BAM, and AOAC/OMA) produced a total of 63 confirmed positive results. Nonspiked samples from all foods were reported as negative for L. monocytogenes by all methods. Probability of detection analysis demonstrated no significant differences in the number of positive samples detected by the RapidChek method and the respective cultural reference method.

Hydrodynamic properties of fin whale flippers predict maximum rolling performance.

Maneuverability is one of the most important and least understood aspects of animal locomotion. The hydrofoil-like flippers of cetaceans are thought to function as control surfaces that effect maneuvers, but quantitative tests of this hypothesis have been lacking. Here, we constructed a simple hydrodynamic model to predict the longitudinal-axis roll performance of fin whales, and we tested its predictions against kinematic data recorded by on-board movement sensors from 27 free-swimming fin whales. We found that for a given swimming speed and roll excursion, the roll velocity of fin whales calculated from our field data agrees well with that predicted by our hydrodynamic model. Although fluke and body torsion may further influence performance, our results indicate that lift generated by the flippers is sufficient to drive most of the longitudinal-axis rolls used by fin whales for feeding and maneuvering.

Pharmacokinetics, Safety, and Tolerability of Once-Daily Intranasal Fluticasone Furoate and Levocabastine Administered Alone or Simultaneously as fluticasone Furoate/Levocabastine Fixed-Dose Combination.

PURPOSE: The purpose of this study was to investigate potential systemic pharmacokinetic interactions between intranasal fluticasone furoate (FF) and levocabastine (LEVO) when delivered simultaneously via a metered atomizing spray pump. METHODS: This was a randomized, open-label, crossover study. Healthy male and female subjects (n = 30) received once-daily repeat doses of FF/LEVO (100/200 µg) as a fixed-dose combination (FDC), FF (110 µg), or LEVO (200 µg) for 7 days. FF and LEVO plasma pharmacokinetics (0-24 hours) were measured on day 7, with safety assessments over the study duration. RESULTS: Systemic exposure to LEVO was similar when administered as FF/LEVO FDC or LEVO alone. Following FF/LEVO FDC or FF alone, the majority (>99%) of FF concentrations were nonquantifiable, that is, below the lower limit of quantification of 10 pg/mL. All treatments were well tolerated, and adverse event incidence was similar across the treatment groups. CONCLUSIONS: These results suggest that in healthy subjects, for LEVO, there is no pharmacokinetic interaction with FF when delivered as FF/LEVO FDC. As the majority of data were below the assay sensitivity for FF, any potential differences in the bioavailability of FF when delivered alone or as FF/LEVO FDC could not be established. There was no clinically relevant impact on safety/tolerability when FF/LEVO was coadministered.

Population pharmacokinetics of inhaled fluticasone furoate and vilanterol in adult and adolescent patients with asthma.

OBJECTIVES: Population pharmacokinetic (PK) methods were used to characterize the PK of fluticasone furoate (FF) and vilanterol (VI) in patients with asthma following once daily inhaled FF/VI and FF and to identify significant covariates that impact the PK. MATERIALS AND METHODS: Four of the five studies in the meta-analysis were conducted in patients with asthma (> 90%), the fifth in healthy subjects. FF data were described by a two-compartment model with first order absorption and elimination. VI data were described by a three-compartment model with zero-order absorption and first order elimination. RESULTS: Race was a significant covariate on inhaled clearance (CL/F) of FF PK. AUC(0-24) for Asian patients was on average 33 - 53% higher than for non-Asians. Race was also a significant covariate on VI PK, with lower (81%) central volume of distribution (Vc/F) for Asian patients compared with non-Asians; VI C(max) was 220 - 287% higher in Asian patients. Treatment (combination or monotherapy), predicted percentage FEV(1), and other demographic variables did not influence the PK of FF or VI. CONCLUSIONS: Combination of FF/VI does not appear to affect the PK of FF or VI. The effect of race on PK of FF or VI does not have impact on dosage adjustments for FF/VI in East Asian patients with asthma.

Impact of the Collaborative Pharmaceutical Care at Tallaght Hospital (PACT) model on medication appropriateness of older patients.

OBJECTIVES: A high prevalence of potentially inappropriate prescribing (PIP) has been identified in older patients in Ireland. The impact of the Collaborative Pharmaceutical Care at Tallaght Hospital (PACT) model on the medication appropriateness of acute hospitalised older patients during admission and at discharge is reported. METHODS: Uncontrolled before-after study. The study population for this study was medical patients aged ≥65 years, using ≥3 regular medicines at admission, taken from a previous before-after study. Standard care involved clinical pharmacists being ward-based, contributing to medication history taking and prescription review, but not involved at discharge. The innovative PACT model involved clinical pharmacists being physician team-based, leading admission and discharge medication reconciliation and undertaking prescription review, with authority to change the prescription during admission or at discharge. The primary outcome was the Medication Appropriateness Index (MAI) score applied pre-admission, during admission and at discharge. RESULTS: Some 108 patients were included (48 PACT, 60 standard). PACT significantly improved the MAI score from pre-admission to admission (mean difference 2.4, 95% CI 1.0 to 3.9, p<0.005), and from pre-admission to discharge (mean difference 4.0, 95 CI 1.7 to 6.4, p<0.005). PACT resulted in significantly fewer drugs with one or more inappropriate rating at discharge (PACT 15.0%, standard 30.5%, p<0.001). The MAI criteria responsible for most inappropriate ratings were 'correct directions' (4.8% PACT, 17.3% standard), expense (5.3% PACT, 5.7% standard) and dosage (0.6% PACT, 4.0% standard). PACT suggestions to optimise medication use were accepted more frequently, and earlier in the hospital episode, than standard care (96.7% PACT, 69.3% standard, p<0.05). CONCLUSIONS: Collaborative pharmaceutical care between physicians and pharmacists from admission to discharge, with authority for pharmacists to amend the prescription, improves medication appropriateness in older hospitalised Irish patients.

Development of an automated method of detecting stereotyped feeding events in multisensor data from tagged rorqual whales.

The introduction of animal-borne, multisensor tags has opened up many opportunities for ecological research, making previously inaccessible species and behaviors observable. The advancement of tag technology and the increasingly widespread use of bio-logging tags are leading to large volumes of sometimes extremely detailed data. With the increasing quantity and duration of tag deployments, a set of tools needs to be developed to aid in facilitating and standardizing the analysis of movement sensor data. Here, we developed an observation-based decision tree method to detect feeding events in data from multisensor movement tags attached to fin whales (Balaenoptera physalus). Fin whales exhibit an energetically costly and kinematically complex foraging behavior called lunge feeding, an intermittent ram filtration mechanism. Using this automated system, we identified feeding lunges in 19 fin whales tagged with multisensor tags, during a total of over 100 h of continuously sampled data. Using movement sensor and hydrophone data, the automated lunge detector correctly identified an average of 92.8% of all lunges, with a false-positive rate of 9.5%. The strong performance of our automated feeding detector demonstrates an effective, straightforward method of activity identification in animal-borne movement tag data. Our method employs a detection algorithm that utilizes a hierarchy of simple thresholds based on knowledge of observed features of feeding behavior, a technique that is readily modifiable to fit a variety of species and behaviors. Using automated methods to detect behavioral events in tag records will significantly decrease data analysis time and aid in standardizing analysis methods, crucial objectives with the rapidly increasing quantity and variety of on-animal tag data. Furthermore, our results have implications for next-generation tag design, especially long-term tags that can be outfitted with on-board processing algorithms that automatically detect kinematic events and transmit ethograms via acoustic or satellite telemetry.

Population Pharmacokinetics of Inhaled Fluticasone Furoate and Vilanterol in Subjects with Chronic Obstructive Pulmonary Disease.

BACKGROUND AND OBJECTIVES: Previous pharmacokinetic studies of the inhaled corticosteroid, fluticasone furoate (FF), and the long-acting, beta2-receptor agonist, vilanterol (VI) have been performed in relatively small populations using non-compartmental pharmacokinetic methods and censored data (due to low drug exposure relative to assay sensitivity). This paper presents a population pharmacokinetic analysis, utilizing pooled concentration-time data from clinical studies in healthy subjects and from global trials in patients with chronic obstructive pulmonary disease (COPD). The objective of this analysis was to characterize the population pharmacokinetics of FF and VI following once-daily inhalation dosing of FF/VI or the individual components (FF and VI) and to identify significant covariates that impact systemic exposure to FF and VI in this population. METHODS: Population pharmacokinetic methods that maximize the likelihood of all data were developed to describe systemic exposure to FF and VI following once-daily FF/VI, FF, or VI, and to identify significant covariates that impact the pharmacokinetics. COPD patients (N = 1225 for the FF analysis and N = 1091 for the VI analysis; 94 and 93 % of total data, respectively) and healthy subjects contributed to the analysis. RESULTS: FF data were described by a two-compartment model with first-order absorption and elimination. The population grouping "race" was a significant covariate on inhaled clearance (CL/F). The area under the curve over 24 h (AUC0-24) for FF was higher for East Asian, Japanese, and South East Asian (average 23-30 %) and Asian Central, White Arabic, American Indian/Native Alaskan, and 'other' (10-26 %) subjects compared with White/Caucasians. VI pharmacokinetics were described by a three-compartment model with zero-order absorption and first-order elimination. Significant demographic covariates identified to affect pharmacokinetics of VI were age [on CL/F and central volume (V 1/F)], bodyweight (on CL/F), sex and smoking (on V 1/F). CONCLUSIONS: While significant effects of the covariates were observed in this study, the magnitude of these effects on systemic exposure is not large enough to warrant FF/VI dosage adjustment in patients with COPD.

Pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol as a triple therapy in healthy volunteers.

OBJECTIVE: Two single-center, four-way, single-dose, crossover studies assessed the systemic exposure, systemic pharmacodynamics (PD), and safety profile of the closed triple fluticasone furoate/ umeclidinium/vilanterol (FF/UMEC/VI) therapy compared with dual therapies. These are the first studies where pharmacokinetic (PK) profile assessment was possible for this inhaled triple fixed-dose combination product. METHODS: Healthy volunteers were randomized to receive 4 consecutive inhalations (each administered as a single dose) via a single ELLIPT® dry powder inhaler: in study 1 (CTT116415/NCT01691547), FF/UMEC/VI at total doses of 400/500/100 µg, FF/UMEC 400/500 µg, UMEC/VI 500/100 µg, or FF/VI 400/100 µg; in study 2 (200587/NCT01894386), FF/UMEC/VI at total doses of 400/500/100 µg or 400/250/100 µg, FF/VI 400/100 µg, or UMEC/VI 250/100 µg. PK and PD parameters and safety were assessed. RESULTS: Of 88 subjects, 95% completed both studies and received all planned treatments. Total systemic exposure was similar for FF, UMEC, and VI when administered as a triple therapy compared with FF/VI and UMEC/VI. No clinically significant systemic PD findings were detected. The incidence of adverse events was low and similar across treatment arms. CONCLUSIONS: Systemic exposure to all three components of the closed triple therapy, following single-dose delivery, was similar to that seen with the dual therapies FF/VI and UMEC/VI. The delivered lung dose and safety profile of all three agents, delivered via a single inhaler, are expected to be similar to those of the dual therapies.

Pharmacodynamics and pharmacokinetics of fluticasone furoate/vilanterol in healthy Chinese subjects.

STUDY OBJECTIVE: To investigate the pharmacodynamic and pharmacokinetic profiles of fluticasone furoate (FF)/vilanterol (VI) - a fixed-dose combination of an inhaled corticosteroid (ICS) and a long-acting ß2 -agonist for the treatment of asthma and chronic obstructive pulmonary disease - after single and repeat administration in healthy Chinese subjects. DESIGN: Double-blind, placebo-controlled, single-site, randomized, four-way crossover study. SETTING: The Clinical Pharmacological Research Centre at Peking Union Medical College Hospital [PUMCH]) in Beijing, China. SUBJECTS: Sixteen healthy, nonsmoking Chinese adults. INTERVENTION: Subjects were randomized to receive FF/VI 50/25, 100/25, or 200/25 µg, or placebo once/daily in the morning, delivered by the Ellipta dry powder inhaler, for 7 consecutive days. The subjects then received the other three treatments, with each treatment period separated by a 7-day washout period. MEASUREMENTS AND MAIN RESULTS: The co-primary outcome measures reflected pharmacodynamic responses relating to recognized class effects of the two drug classes: reduced serum cortisol level (ICSs), and increased Fridericia's corrected QT interval (QTcF) and reduced serum potassium level (long-acting ß2 -agonists). Co-primary pharmacodynamic endpoints were 0-24-hour weighted mean serum cortisol level on day 7 (cortisol0-24 hr, Day 7 ), and 0-4-hour weighted mean and maximum QTcF and weighted mean and minimum serum potassium level on days 1 and 7. Fluticasone furoate and VI plasma concentrations, derived pharmacokinetic parameters, and safety were also assessed. Of the 16 subjects randomized, 15 completed the study. Reductions in cortisol0-24 hour, Day 7 of 15% and 25% were observed with FF/VI 100/25 and 200/25 µg, respectively, versus placebo. Minor increases (< 10 msec) in maximum QTcF on day 7 were seen with FF/VI 50/25 and 100/25 µg but not with 200/25 µg. Slight decreases in serum potassium level were only observed in subjects receiving FF/VI 50/25 µg on day 1 and FF/VI 50/25 and 200/25 µg on day 7. Fluticasone furoate accumulation (day 7 vs day 1) for FF/VI 50/25-200/25 µg ranged from 38 to 54% for maximum observed concentration and 63-71% for area under the concentration-time curve from 0 to 4 hours. Fluticasone furoate pharmacokinetics were less than dose proportional. The VI pharmacokinetic profiles were similar for all three FF/VI doses. Adverse events were all mild in intensity and were reported by 13 (81%) of the 16 subjects. CONCLUSION: In healthy Chinese subjects, minimal and non-clinically relevant ß-adrenergic pharmacodynamic effects were observed with FF/VI doses ranging from 50/25 to 200/25 µg. FF dose-dependent reductions in serum cortisol levels of 15-25% were seen after administration of FF/VI 100/25 and 200/25 µg. FF/VI was safe and well tolerated in these subjects at doses ranging from 50/25 to 200/25 µg.

The pharmacodynamics, pharmacokinetics, safety and tolerability of inhaled fluticasone furoate and vilanterol administered alone or simultaneously as fluticasone furoate/vilanterol.

PURPOSE: To investigate the potential for systemic pharmacokinetic (PK) and pharmacodynamic (PD) interactions between inhaled fluticasone furoate (FF) and vilanterol (VI) when delivered simultaneously via the ELLIPTA™ dry powder inhaler (DPI). METHODS: Randomized, double-blind, placebo-controlled, crossover study. Healthy subjects (n = 16) received single doses of FF (800 mcg), VI (100 mcg), FF/VI (800/100 mcg), and placebo. Endpoints measured were systemic PD (FF: serum cortisol; VI: heart rate), FF and VI plasma PK (0-48 hours), pharyngometry, inhalation and breath hold profiles and safety assessments. RESULTS: Treatment differences [90% confidence interval (CI)] in weighted mean serum cortisol (0-24 hours) were 12.3% [4.4, 20.9] (FF/VI vs. FF) and for maximum heart rate (0-4 hours) were -1.2 bpm [-4.6, 2.1] (FF/VI vs. VI). When delivered simultaneously, FF and VI systemic exposures were slightly lower (<20%) versus delivery of either agent alone (although this was not a formal bioequivalence study). In vitro simulation of selected inhalation profiles and modeling supported the PK and PD findings. FF/VI, FF and VI were well tolerated with an AE incidence comparable to placebo. CONCLUSIONS: These results suggest there was a slight PK interaction and no PD interactions of concern between inhaled FF and VI when delivered simultaneously via the ELLIPTA DPI in healthy subjects.