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Our purpose is to understand patient preferences towards contrast-enhanced imaging such as CEM or MRI for breast cancer screening.An anonymous survey was offered to all patients having screening mammography at a single academic institution from December 27 th 2019 to March 6 th 2020. Survey questions related to: (1) patients' background experiences (2) patients' concern for aspects of MRI and CEM measured using a 5-point Likert scale, and (3) financial considerations.75% (1011/1349) patients completed the survey. 53.0% reported dense breasts and of those, 47.6% had additional screening. 49.6% had experienced a callback, 29.0% had a benign biopsy, and 13.7% had prior CEM/MRI. 34.7% were satisfied with mammography for screening. A majority were neutral or not concerned with radiation exposure, contrast allergy, IV line placement, claustrophobia, and false positive exams. 54.7% were willing to pay at least $250-500 for screening MRI. Those reporting dense breasts were less satisfied with mammography for screening (p0.001) and willing to pay more for MRI (p0.001). If patients had prior CEM/MRI, there was less concern for an allergic reaction (p0.001), IV placement (p=0.025), and claustrophobia (p=0.006). There was less concern for false positives if they had a prior benign biopsy (p=0.029) or prior CEM/MRI (p=0.005) and less concern for IV placement if they had dense breasts (p=0.007) or a previous callback (p=0.013).The screening population may accept CEM or MRI as a screening exam despite its risks and cost, especially patients with dense breasts and patients who have had prior CEM/MRI.

In the United States, silicone and saline breast implants with their familiar radiologic appearance are the mainstays of breast augmentation. However, less well-known sequelae of unconventional injected materials introduced for cosmetic and noncosmetic purposes may also be encountered on breast imaging—for example, free silicone, paraffin and/or oil, polyacrylamide gel, autologous fat, and hyaluronic acid, which are encountered in the setting of breast augmentation. Breast injection of go-yak is not cosmetic but also results in characteristic imaging findings. Breast changes due to extravasation of chemotherapy or interstitial brachytherapy can mimic the appearance of injected noncosmetic materials. Because many of these materials can mimic or obscure imaging findings of breast cancer, it is important to recognize their varied appearances and the limitations of imaging alone in delineating breast injection material from cancer. Given the relatively uncommon incidence of injected materials into the breast, this article aims to review the imaging appearance in order to aid radiologists in maximizing cancer detection and ensuring optimal patient management.

Contrast-enhanced mammography (CEM) is gaining rapid traction following the U.S. Food and Drug Administration approval for diagnostic indications. Contrast-enhanced mammography is an alternative form of mammography that uses a dual-energy technique for image acquisition after the intravenous administration of iodinated contrast material. The resulting exam includes a dual set of images, one that appears similar to a routine 2D mammogram and one that highlights areas of contrast uptake. Studies have shown improved sensitivity compared to mammography and similar performance to contrast-enhanced breast MRI. As radiology groups incorporate CEM into clinical practice they must first select the indications for which CEM will be used. Many practices initially use CEM as an MRI alternative or in cases recommended for biopsy. Practices should then define the CEM clinical workflow and patient selection to include ordering, scheduling, contrast safety screening, and managing imaging on the day of the exam. The main equipment requirements for performing CEM include CEM-capable mammography equipment, a power injector for contrast administration, and imaging-viewing capability. The main staffing requirements include personnel to place the intravenous line, perform the CEM exam, and interpret the CEM. To safely and appropriately perform CEM, staff must be trained in their respective roles and to manage potential contrast-related events. Lastly, informing referring colleagues and patients of CEM through marketing campaigns is helpful for successful implementation.

Background International Medical Graduates (IMG) form a significant part of the paediatric workforce in the UK. IMGs come from diverse cultural and ethnic backgrounds, and some have many years of postgraduate training in their country of origin (COO). The composition of this workforce includes: Speciality Trainees (ST1-ST8), Trust grade (Clinical Fellows), SAS (Speciality and Associate Specialty), and Locums. Due to the heterogeneity of this group, it is hard to find data to characterise this vital part of the workforce. We hope to fill a gap by starting to understand this group and the particular challenges they face, related to adopting to the new environment in their personal, social and work life. During Covid many of these doctors have faced additional challenges of isolation, being separated for long periods from family overseas, and not having the usual opportunities to make connections outside work. Our project, 'Soft Landing' aims to understand and help address these challenges. Objectives To explore the challenges faced by an IMGs in personal, social and working lives and how they progress through their careers in UK. Methods The survey was distributed via email to Training Programme Directors, as well as via social media. It was open to all paediatric IMGs in UK. Results 108 IMGs participated in the survey. 44% of them had worked in the UK for

Breast imaging is an important field within radiology, having made significant strides in helping reduce morbidity and mortality from breast cancer. Historically, breast imaging radiologists learned mammography and ultrasound skills on the job as a part of general radiology training. However, breast imaging as a subspecialty has grown over time with the emergence of breast imaging fellowships across the country. Despite this growth, breast imaging fellowships remain nonaccredited through the American College of Graduate Medical Education, and as a result, there are significant variations in training programs throughout the country. In this article, we will provide guidelines on organizing a breast imaging fellowship to help standardize the experience of fellows entering the breast imaging community. This will include guidelines regarding providing adequate clinical exposure, developing a fund of knowledge, fostering extra-clinical interests, and providing constructive feedback for ongoing improvement.

To perform a pilot evaluation of contrast-enhanced mammography (CEM) for screening to determine whether it can improve accuracy and reader confidence in diagnosis.This institutional review board-approved reader study was comprised of 64 de-identified CEM cases acquired from December 1, 2014, to June 7, 2016, including 48 negative, 5 biopsy-proven benign, and 11 biopsy-proven malignancies. Negative cases were followed for at least 2 years without evidence of cancer. Ten breast imagers of varying experience first rated the low-energy (LE) mammogram and then the CEM examination using BI-RADS categories and a 5-point Likert scale for confidence in diagnosis.There were 635 out a total possible 640 complete reader interpretations included in this analysis. The remaining five incomplete interpretations were excluded. Median sensitivity and specificity improved with the addition of CEM (sensitivity: 0.86 [95% confidence interval {CI}: 0.74-0.95] versus 1 [95% CI: 0.83-1.00], specificity: 0.85 [95% CI: 0.64-0.94] versus 0.88 [95% CI: 0.80-0.92]). Individual receiver operating characteristic curves showed significant improvement with CEM (mean area under the curve increase = 0.056 [95% CI: 0.015-0.097], P = .002). The addition of CEM significantly improved average confidence in 5 of 10 readers when compared with LE (P.0001) and improved pooled confidence across all tissue density categories, except the almost entirely fatty category. There was a trend toward improved confidence with increasing tissue density with CEM. Degree of background parenchymal enhancement did not affect readers' level of improvement in confidence when interpreting CEM.CEM improved reader performance and confidence compared with viewing only LE, suggesting a role for CEM in breast cancer screening for which larger trials are warranted.

IMPORTANCE: Pulmonary hypoplasia affects a very small percentage of preterm neonates, but its presence is associated with high rates of mortality. OBJECTIVE: To determine whether treatment with inhaled nitric oxide during the first week of life was associated with improved in-hospital survival in a cohort of extremely preterm neonates with pulmonary hypoplasia. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from the Pediatrix Medical Group’s Clinical Data Warehouse, a data set containing information from more than 350 neonatal intensive care units in 35 US states and Puerto Rico. Since inhaled nitric oxide was not randomly prescribed, we used 1-to-1 propensity score matching to reduce the imbalance of measured covariates between the 2 treatment groups. The initial, unmatched cohort included singleton neonates who were born between 22 and 29 weeks’ gestation, had a birth weight of 400 g or more, were diagnosed with pulmonary hypoplasia as a cause of their respiratory distress, remained free of major anomalies, and were discharged between January 1, 2000, and December 31, 2014. We defined exposure as the initiation of inhaled nitric oxide on day t in days 0 to 7 of the life of a neonate. Each exposed neonate was matched 1-to-1 to a neonate who had not initiated inhaled nitric oxide on a given day. MAIN OUTCOMES AND MEASURES: The primary outcome was mortality defined as death prior to transfer or discharge home. Secondary outcomes were any-stage necrotizing enterocolitis, retinopathy of prematurity requiring treatment, chronic lung disease, and periventricular leukomalacia. RESULTS: Among 92 635 neonates in our study sample, we identified 767 (0.8%) with pulmonary hypoplasia who met all study inclusion criteria, of whom 185 (0.2%) were exposed to inhaled nitric oxide. Among 151 matched pairs of exposed and unexposed neonates, we did not identify a significant association between inhaled nitric oxide use and mortality (hazard ratio [HR], 0.79; 95% CI, 0.57-1.11). Subgroup analyses of neonates with and without persistent pulmonary hypertension (PPHN) likewise revealed no significant association between inhaled nitric oxide use and mortality (pulmonary hypoplasia with PPHN: HR, 0.67; 95% CI, 0.45-1.01; pulmonary hypoplasia without PPHN: HR, 1.11; 95% CI, 0.61-2.02), but these findings may have been influenced by ascertainment bias. CONCLUSIONS AND RELEVANCE: Early treatment with inhaled nitric oxide is not associated with improved survival among extremely preterm neonates with pulmonary hypoplasia. Clinical trials are warranted to clarify the matter.

The purpose of this study is to review the clinical presentation, multi-modality appearance, and management of the most common benign and malignant fibroepithelial lesions of the breast. Fibroepithelial lesions of the breast may exhibit characteristic features on mammography, ultrasound, and MRI, although definitive diagnosis most often requires biopsy and at times, surgical excision. Knowledge of the imaging features can assist in refining the differential diagnosis and guiding appropriate management.

Background Population pharmacokinetic methods were used to characterize the pharmacokinetics of fluticasone furoate (FF), umeclidinium (UMEC), and vilanterol (VI) in patients with chronic obstructive pulmonary disease (COPD) when administered as a fixed-dose combination via a single closed inhaler. Methods Plasma concentration data from three studies were analyzed using non-linear mixed-effects modeling in NONMEM®. Results The pooled dataset consisted of 2948, 2589, and 3331 FF, UMEC, and VI observations from 714, 622, and 817 patients with COPD, respectively. There were 41%, 13%, and 21% of observations below the quantification limit for FF, UMEC, and VI, respectively. The pharmacokinetics of FF, UMEC, and VI were all adequately described by a two-compartment model with first-order absorption. The following covariates were statistically significant, but none were considered to be clinically relevant. For FF, Japanese heritage and FF/VI treatment on apparent inhaled clearance (CL/F) with FF CL/F 35% lower in patients of Japanese heritage across all treatments and FF CL/F 42% higher in patients with COPD following FF/VI administration. This is in line with the product label. For UMEC, weight, age, and smoking status on CL/F and weight on apparent volume of distribution (V2/F) with every 10% increase in age from 60 years of age leading to approximately a 6% decrease in UMEC CL/F and every 10% increase in weight from 70 kg leading to approximately a 6% increase in UMEC CL/F and approximately an 8% increase in UMEC V2/F. For a subject with COPD who smoked, UMEC CL/F was 28% higher. For VI, weight on CL/F and smoking status on V2/F with an approximately 4% increase in VI CL/F for every 10% increase in weight from 70 kg, and for a subject with COPD who smoked, VI V2/F was 46% higher. The majority of these covariates have been previously identified in historical analyses. None of these effects were clinically relevant in terms of systemic exposures and do not warrant dose adjustment. Conclusions All FF, UMEC, and VI plasma concentrations were well interspersed with historical data and were all adequately described by a two-compartment model with first-order absorption. There were no clinically relevant differences in FF, UMEC, or VI systemic exposures when administered as FF/UMEC/VI, FF/VI + UMEC, or the dual combinations FF/VI and/or UMEC/VI.

Background To evaluate the effects of fluticasone furoate on the hypothalamic–pituitary–adrenocortical axis, and the safety and tolerability of fluticasone furoate treatment in children with asthma. Methods This was a randomized, double-blind, placebo-controlled, multicenter, stratified, parallel-group, non-inferiority study of fluticasone furoate 50 µg inhalation powder administered once daily. The study enrolled children (aged 5–11 years inclusive) with a documented diagnosis of asthma for ≥ 6 months and a Childhood Asthma Control Test score of > 19. After a 7–14-day run-in period, eligible subjects were stratified by age and randomized to fluticasone furoate 50 µg once daily or placebo once daily via ELLIPTA for 6 weeks. The primary endpoint was the change from baseline (expressed as a ratio) in 0–24-h weighted mean serum cortisol at the end of the treatment period. Results Fifty-six randomized subjects received fluticasone furoate 50 µg once daily and 55 received placebo. The primary analysis was performed in the serum cortisol population (n = 104) and demonstrated that fluticasone furoate 50 µg once daily was non-inferior to placebo (ratio = 0.93; 95% confidence interval 0.8096, 1.0620), as the lower limit of the 95% confidence interval for the geometric mean treatment ratio of fluticasone furoate 50 µg once daily versus placebo was greater than 0.80. Findings from the intent-to-treat population (n = 111) were similar. Conclusions Six weeks of treatment with inhaled fluticasone furoate 50 µg once daily had no clinically relevant effect on the hypothalamic–pituitary–adrenocortical axis function of children, as measured by 24-h serum cortisol profiles. The primary analysis showed that fluticasone furoate 50 µg once daily was non-inferior to placebo. Fluticasone furoate 50 µg once daily was well tolerated and no new safety concerns emerged during the study. Trial registration This study is registered in ClinicalTrials.gov (NCT02483975). Date of submission: 25 June 2015.

A complete 2-drug regimen of dolutegravir at 50 mg and rilpivirine at 25 mg was approved to treat HIV-1 infection in virologically suppressed patients after demonstrating acceptable efficacy and tolerability. This study investigated the bioequivalence and pharmacokinetics of the fixed-dose combination tablet compared with those of separate tablets. Secondary endpoints were the tolerability and safety of the fixed-dose combination tablet. In this open-label, randomized-sequence, 2-way crossover trial, single doses of the fixed-dose combination tablet (the test treatment) and the combination of separate tablets (the reference treatment) were administered to healthy adults after a moderate-fat meal, with a 21-day washout between treatments. Pharmacokinetic samples were collected through 12 days after dosing. The primary endpoints were the area under the plasma concentration-time curve (AUC) and the maximum concentration of drug in plasma (Cmax). The study employed a prespecified sample size reestimation based on a blind midpoint review of Cmax variability to update the enrollment size to achieve statistical power. Of 118 participants enrolled, 113 received both treatments and underwent pharmacokinetic assessment. The 90% confidence intervals for the geometric least-squares mean ratios for the AUC from 0 h to infinity, the AUC from 0 h to the last quantifiable measurement, and Cmax (test treatment versus reference treatment) were within the bioequivalence range of 0.80 to 1.25 for both drugs, indicating bioequivalence. In this study, a single dose of either treatment was well tolerated overall, with 4% (n = 5) and 3% (n = 3) of participants reporting adverse events considered related to the test and reference treatments, respectively. The dolutegravir-rilpivirine fixed-dose combination tablet is bioequivalent to a combination of separate tablets, and no new safety signals emerged. (This study has been registered at ClinicalTrials.gov under identifier NCT02741557.).

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 ELLIPTA® dry powder inhaler: in study 1 (CTT116415/{"type":"clinical-trial","attrs":{"text":"NCT01691547","term_id":"NCT01691547"}}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/{"type":"clinical-trial","attrs":{"text":"NCT01894386","term_id":"NCT01894386"}}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.

The Rotacaps®/Rotahaler® system is a single unit dose inhaler being developed to deliver inhaled salmeterol/fluticasone propionate combination (SFC) as an alternative treatment option to the metered dose inhaler and the multi-dose dry powder inhaler, Diskus®. The aim of this study was to compare the systemic exposure of SFC 50/100 µg following delivery via the Rotacaps®/Rotahaler® and the Diskus®. This was an open-label, randomized, cross-over, repeat-dose (3.5 days of twice-daily dosing) study comparing salmeterol and fluticasone propionate systemic exposure following inhaled SFC 50/100 µg delivered via the Rotacaps®/Rotahaler® and Diskus®, in healthy subjects. Pharmacokinetic sampling was conducted over 12 h post-dose on the last day of each treatment. Pharmacokinetic samples were analysed using solid phase extraction followed by high performance liquid chromatography/tandem mass spectrometry. Co-primary endpoints were fluticasone propionate area under the concentration-time curve over the dosing interval (AUC0–τ ) and salmeterol maximum plasma concentration (C max) on the last day of treatment. Following SFC 50/100 µg Rotacaps®/Rotahaler®, fluticasone propionate and salmeterol systemic exposures were comparable with Diskus® in terms of both AUC0–τ [geometric mean ratio (GMR) with 90 % confidence interval (CI) of Rotahaler®/Diskus® for fluticasone propionate: 0.98 (0.91, 1.06) and salmeterol: 1.04 (0.99, 1.10)] and C max [GMR (90 % CI) for fluticasone propionate: 1.04 (0.94, 1.15) and salmeterol: 0.97 (0.87, 1.08)], meeting the pre-defined criteria for comparability (upper limit of the 90 % CI for the GMRs (Rotahaler®/Diskus®) ≤1.25]. SFC delivered from both inhalers was well tolerated. SFC 50/100 µg Rotacaps®/Rotahaler® showed comparable fluticasone propionate and salmeterol systemic exposure to Diskus® for all pharmacokinetic endpoints with GMR and both upper and lower limits of 90 % CIs within conventional acceptance criteria for bioequivalence (0.8, 1.25), sufficient for considering progression of the Rotacaps®/Rotahaler® product for further clinical development.

A population pharmacokinetic analysis was conducted from a subset of samples obtained from the Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy trial to characterize the pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol in patients with symptomatic COPD following treatment with fluticason furoate‐umeclidinium‐vilanterol combined in a single inhaler. This was a randomized, double‐blind, double‐dummy study comparing 24 weeks of once‐daily triple therapy (fluticason furoate‐umeclidinium‐vilanterol, 100 μg/62.5 μg/25 μg; Ellipta inhaler) with twice‐daily dual therapy (budesonide/formoterol 400 μg/12 μg; Turbuhaler). The analyses were conducted in a subset of 74 patients who received fluticason furoate‐umeclidinium‐vilanterol and provided serial or sparse samples. Monte Carlo simulations and a model‐based estimation approach both indicated that systemic drug concentrations of fluticasone furoate, umeclidinium, and vilanterol after administration of fluticason furoate‐umeclidinium‐vilanterol triple combination therapy from a single inhaler were within the ranges observed following administration of these drugs as monotherapy (fluticasone furoate, umeclidinium, and vilanterol) or as dual‐combination therapy (fluticasone furoate/vilanterol or umeclidinium/vilanterol).

Background: FULFIL showed statistically significant improvements in trough FEV 1 and health status with once-daily FF/UMEC/VI 100μg/62.5μg/25μg via the ELLIPTA ® inhaler (n=911) vs twice-daily budesonide/formoterol (BUD/FOR) 400μg/12μg via the Turbuhaler ® (n=899) in patients with advanced COPD (Lomas et al. ERJ 2016;48:PA4629). We report the population PK results for FF/UMEC/VI. Methods: PK blood samples (6mL) were taken from 74 patients in the FF/UMEC/VI arm: two samples (sparse; n=64) at weeks 12 (predose; 5–15min post-dose) and 24 (5–15min; 45–90min post-dose); seven samples (serial; n=10) at week 24 (predose; 5–15min, 45–90min, 2.5–4h, 6–8h, 10–12h, 23–24h post-dose). Derived parameters, including area under the curve (AUC) and maximum observed concentration (C max ), for FF (inhaled corticosteroid), UMEC (long-acting muscarinic antagonist) and VI (long-acting β 2 -agonist) from FULFIL were compared with historical data for FF, UMEC and VI mono-/dual therapy. Results: Steady state AUCs (geometric mean, pg*h/mL) from FULFIL were consistent with historical data for FF (188 vs 181 [FF]/182 [FF/VI]), UMEC (341 vs 312) and VI (666 vs 615). Steady state C max (geometric mean, pg/mL) for FF from FULFIL was also consistent with historical data (13.2 vs 11.5 [FF]/11.9 [FF/VI]). C max for UMEC and VI from FULFIL were lower than historical data (UMEC, 55.7 vs 69.3; VI, 101.4 vs 127.9); this was likely due to higher variability associated with smaller sample sizes and is not clinically relevant. Conclusion: Population PK results for FF/UMEC/VI triple therapy were consistent with data for FF, UMEC and VI mono-/dual therapy. Funding GSK (CTT116853)

The unit dose dry powder inhaler (UD-DPI) is being considered as an alternative inhaler platform that, if developed, has the potential to improve access to inhaled respiratory medicines in developing countries.This study compared the systemic exposure of fluticasone furoate after delivery from the UD-DPI with that from the ELLIPTAThis open-label, five-way cross-over, randomized, single-dose study in healthy subjects evaluated fluticasone furoate systemic exposure of three dose strengths (using four inhalations), 4 × 80 μg [320 μg], 4 × 100 μg [400 μg], and 4 × 140 μg [560 μg]), and two percentages of drug in lactose blends (0.6% and 0.8% by weight) after delivery from the UD-DPI compared with systemic exposures from the ELLIPTA inhaler (4 × 100 μg [400 μg] dose, 0.8% lactose blend). The primary treatment comparisons were area under the concentration-time curve from time 0 to 6 hours [AUCAfter single-dose administration of fluticasone furoate, systemic exposure was lower from all UD-DPI formulations versus the ELLIPTA inhaler in terms of both AUCFluticasone furoate systemic exposure was lower from the UD-DPI than from the ELLIPTA inhaler, but the UD-DPI formulations did demonstrate detectable systemic levels and approximate dose proportionality. Together with the good tolerability shown, these data support further evaluation of the UD-DPI as a potential device for delivering inhaled respiratory drugs.

Introduction The long-acting muscarinic antagonist umeclidinium (UMEC) and the combination of UMEC with the long-acting beta 2 agonist vilanterol (VI) are approved maintenance treatments for chronic obstructive pulmonary disease in the US and EU. Objectives This study investigated the effect of UMEC and UMEC/VI on the QT interval corrected using Fridericia's correction (QTcF) following a 10-day treatment period. Methods Randomized, placebo- and moxifloxacin-controlled, 4-period incomplete block crossover study of healthy non-smokers ( n = 103). All treatments were double blind, except for moxifloxacin/moxifloxacin placebo controls which were single blinded. Subjects were randomized to a treatment sequence which consisted of 4 of 5 regimens. Each regimen consisted of once-daily doses on Days 1–10 via the ELLIPTA™ dry powder inhaler and a single tablet on Day 10 of the following: placebo + placebo; placebo + moxifloxacin; UMEC 500 μg + placebo; UMEC/VI 125/25 μg (delivered dose: 113/22 μg) + placebo; UMEC/VI 500/100 μg + placebo. QT interval, additional cardiac parameters, pharmacokinetics, pharmacodynamics and safety were assessed. Results No clinically significant changes from baseline in QTcF occurred with UMEC 500 μg and UMEC/VI 125/25 μg compared with placebo, however, there was a change in QTcF from baseline of 6.4 ms (90% confidence interval [CI]: 4.3, 8.5) at 10 min and 8.2 ms (90%: 6.2, 10.2) at 30 min post dose following UMEC/VI 500/100 μg compared with placebo. On Day 10, categorical analysis demonstrated absolute QTcF values >450–480 ms for UMEC/VI 125/25 μg (1 subject) and moxifloxacin (3 subjects), and a change from baseline QTcF of >30–60 ms for UMEC/VI 125/25 μg, UMEC 500/100 μg and placebo (1 subject each) and moxifloxacin (2 subjects). On Day 10, the mean change from baseline in heart rate was increased with UMEC/VI 125/25 μg and UMEC 500/100 μg compared with placebo with the maximum increase occurring at 10 min post dose (8.4 bpm [90% CI: 7.0, 9.8] for UMEC/VI 125/25 μg; 20.3 bpm [90% CI: 18.9, 21.7] for UMEC/VI 500/100 μg); after this timepoint, heart rate rapidly returned to normal levels. UMEC and VI systemic exposures following UMEC/VI 500/100 μg were >4-fold higher than those following UMEC/VI 125/25 μg. All treatments were generally well tolerated in terms of adverse events, laboratory, vital signs and electrocardiogram data; the proportion of subjects with any adverse event was similar across treatments arms (39–59%).. Conclusion There was no clinically significant effect on QTcF observed following 10-days' treatment with inhaled UMEC/VI 125/25 μg or UMEC 500 μg compared with placebo. The supratherapeutic dose of UMEC/VI 500/100 μg prolonged QTcF by 6.4 ms (90% CI: 4.3, 8.5) at 10 min and 8.2 ms (90% CI: 6.2, 10.2) at 30 min compared with placebo, following which QTcF interval difference from placebo declined rapidly..

Aim To compare salmeterol (SALM) and fluticasone propionate (FP) systemic exposure following inhaled salmeterol/fluticasone propionate combination (SFC) from a unit-dose capsule-based inhaler (Rotacaps ® /Rotahaler ® ) and a multi-dose dry powder inhaler (Diskus ® ) in healthy volunteers. Methods An open-label, randomised, repeat-dose, cross-over, adaptive design study ( n = 36 in each part) evaluated SFC 50/250 μg and SFC 50/100 μg in Rotacaps used with two types of Rotahaler inhalers (airflow resistance similar to (S) and lower than (L) Diskus) versus the Diskus. Primary endpoints were area under the concentration-time curve over the dosing interval [AUC 0–τ ] and maximum plasma concentration [ C max ]. Results SFC 50/250 μg Rotacaps/Rotahaler (S) showed 1.2–1.9-fold greater FP and SALM systemic exposure compared with Diskus. FP and SALM systemic exposure were comparable to DISKUS following SFC 50/250 μg Rotacaps/Rotahaler (L) (90% CI of ratio of Rotahaler to DISKUS within 0.8–1.25) for salmeterol (AUC 0–τ and C max ) and FP (AUC 0–τ ). Following SFC 50/100 μg Rotacaps/Rotahaler (L), FP and SALM systemic exposures were 1.2–1.4 fold higher in terms of FP (AUC 0–τ and C max ) and salmeterol ( C max ) compared with Diskus. SFC at both doses and via both inhalers was well tolerated. Conclusions SFC 50/250 μg Rotacaps/Rotahaler (L) showed comparable systemic exposure to Diskus in terms of FP AUC and SALM AUC and C max . These results merit further progression of SFC 50/250 μg Rotacaps/Rotahaler (L) to phase 3 clinical evaluation in asthma and COPD patients. The lack of pharmacokinetic comparability between the inhalers for SFC 50/100 μg requires further evaluation.

The object of this study was to assess whether a capsule-based and multidose dry powder inhaler containing salmeterol (as xinafoate salt) 50 μg plus fluticasone propionate (FP) 250 μg [combination (SFC 50/250)] could be equivalent in terms of in vivo drug delivery and systemic exposure.This was a randomized, double-blind, double-dummy, replicate treatment design comparative bioavailability study of SFC 50/250 delivered in a capsule-based inhaler (Rotahaler®) and a multidose dry powder inhaler (Diskus®). Subjects with asthma or chronic obstructive pulmonary (COPD) disease (n=60) were randomized to receive twice-daily SFC 50/250 via a Rotahaler and via Diskus each for two 10-day treatment periods (GlaxoSmithKline Protocol ASR114334).For FP and salmeterol, the in vitro aerodynamic particle size profiles were within±15% of Diskus for the fine particle mass (FPM) and emitted dose (ED) using the Andersen Cascade Impactor, and ED, mass median aerodynamic diameter, and geometric standard deviation using the New Generation Impactor (NGI). This was also the case for FP but not salmeterol for FPM and fine particle dose using the NGI. For the combined asthma and COPD subjects, the plasma AUC and Cmax for FP and salmeterol were higher for Rotahaler:Rotahaler/Diskus geometric mean ratios (90% confidence intervals) for FP AUC0-τ of 1.52 (1.37-1.67) and Cmax of 1.94 (1.75-2.10) and salmeterol AUC0-τ of 1.15 (1.09-1.21) and Cmax of 1.56 (1.42-1.67). Corresponding values for the primary pharmacodynamic endpoint, weighted mean (0-12 hr) serum cortisol, were 0.928 (0.886-0.971). Inhaled FP/salmeterol via both inhalers was well-tolerated. One serious adverse event, considered possibly related to study medication, resulted in subject withdrawal from the study.The in vitro tests and systemic pharmacodynamic endpoints revealed no major differences between the two inhalers, but lacked predictive power and sensitivity to guide in vivo drug delivery performance and systemic exposure. Based on pharmacokinetic endpoints, the inhalers were not considered bioequivalent in terms of systemic exposure. Further studies to refine the Rotahaler performance are ongoing.

Background Combination long-acting bronchodilator therapy may be more effective than long-acting bronchodilator monotherapy in COPD. Our objectives were to compare the efficacy and safety of once-daily umeclidinium bromide (UMEC)/vilanterol (VI) 125/25 μg with placebo and UMEC or VI monotherapy in COPD. Methods This was a double-blind, placebo-controlled, parallel-group study. A total of 1,493 patients were randomized (3:3:3:2) to 24 weeks of treatment with UMEC/VI 125/25 μg, UMEC 125 μg, VI 25 μg, or placebo once daily via dry powder inhaler. Results Primary efficacy end point was trough FEV 1 on day 169 (23-24 h postdose). Additional lung-function, symptomatic, and health-related quality-of-life end points were also assessed. Safety evaluations included adverse events, vital signs, ECG, and clinical laboratory measurements. All active treatments significantly improved trough FEV 1 vs placebo (0.124-0.238 L, all P P ≤ .001). Improvements for UMEC/VI 125/25 μg vs placebo were observed for the Transition Dyspnea Index (1.0 unit, P P Conclusions Once-daily UMEC/VI 125/25 μg was well tolerated and provided greater improvements in lung function, health status, and dyspnea scores compared with monotherapy components and placebo over 24 weeks. This study supports the use of UMEC/VI 125/25 μg for the maintenance treatment of COPD. Trial registry ClinicalTrials.gov ; No.: NCT01313637; URL: www.clinicaltrials.gov .

Efficacy and safety of umeclidinium administered in a dry power inhaler were evaluated in moderate-to-very-severe chronic obstructive pulmonary disease patients. This was a randomised, placebo-controlled study assessing once-daily umeclidinium 62.5 and 125 μg over 12 weeks. The primary end-point was change from baseline in trough forced expiratory volume in 1 s (FEV1) on day 85. Secondary end-points were 0-6-h weighted mean and serial forced expiratory volume in 1 s. Other end-points were transitional dyspnoea index, health outcomes (St George's Respiratory Questionnaire), pharmacokinetics and safety. 246 patients were enrolled; 168 completed the study. On day 85, umeclidinium 62.5 and 125 μg significantly improved least squares mean change from baseline in trough FEV1 (127 and 152 mL, respectively; p

Chronic obstructive pulmonary disease (COPD) has a significant negative impact on quality of life and increases the risk of premature death. Umeclidinium is a long-acting muscarinic receptor antagonist in development for the treatment of COPD with the aim to broaden treatment options for clinicians and patients by providing improved symptom control. To characterize the safety, tolerability, pharmacokinetics and pharmacodynamics of single and repeat inhaled doses of umeclidinium in healthy subjects. Two randomized, placebo-controlled, ascending-dose studies were conducted in healthy ipratropium bromide-responsive subjects. In the single-dose study, subjects (n = 20) received umeclidinium (10–350 μg), tiotropium bromide 18 μg and placebo in a crossover dosing schedule. In this study, lung function was assessed for 24 h by measuring specific airways conductance (sGaw) and forced expiratory volume in 1 s (FEV1). In the repeat-dose study, subjects (n = 36) received umeclidinium (250–1,000 μg) and placebo for 14 days in a parallel-group schedule. Adverse events (AEs) were reported in five subjects (single-dose study) and 23 subjects (repeat-dose study); none were serious. In both studies, no abnormalities in 12-lead electrocardiogram parameters, 24-h Holter monitoring or lead II monitoring were reported as AEs. Umeclidinium was rapidly absorbed following single-dose administration [time to reach the maximum plasma concentration (tmax) 5–15 min] and repeat-dose administration (tmax 5–7 min). Following repeat dosing, the geometric mean plasma elimination half-life was approximately 27 h and statistically significant accumulation was observed for the area under the plasma concentration–time curve, maximum plasma concentration and cumulative amount of unchanged drug excreted into the urine at 24 h (range 1.5- to 4.5-fold). Umeclidinium at doses of 100 μg and above, and tiotropium bromide demonstrated statistically significant bronchodilatory effects relative to placebo at 12 h post-dosing, which lasted up to 24 h for umeclidinium 350 μg and for tiotropium bromide. Relative to placebo, these increases in sGaw were 24–34 % at 12 h post-dose and 13 % at 24 h post-dose. Increases in FEV1 achieved statistical significance at 12 and 24 h for umeclidinium 100 μg and 350 μg compared with placebo. Umeclidinium was well tolerated and demonstrated bronchodilatory effects in healthy subjects for up to 24 h. These bronchodilatory effects can be potentially clinically important in patients with airway obstruction such as COPD. The data obtained have informed dose selection for subsequent trials in subjects with COPD.

To compare the systemic exposure of salbutamol following delivery from the unit dose dry powder inhaler (UD-DPI) system with that from the DiskusThis open-label, two-part, six-way crossover, randomized single-dose study in healthy subjects evaluated salbutamol systemic exposure of three dose strengths (using three inhalations: 3 × 150 μg [450 μg], 3 × 200 μg [600 μg], and 3 × 250 μg [750 μg]) and 2% of drug in lactose blends (1.6% and 1.0% [600 μg dose only] by weight) following delivery through the UD-DPI compared with systemic exposure from the Diskus and MDI (600 μg dose). Systemic exposure in the presence of charcoal block was also evaluated. Primary treatment comparisons were area under the concentration-time curve from time zero to 12 hours [AUCDelivery of salbutamol 600 μg from the UD-DPI resulted in total systemic exposure similar to that from the Diskus and approximately half of that from the MDI (AUCSalbutamol total systemic exposure following UD-DPI was similar to that from the Diskus and was lower than that following the MDI. The different blend formulations tested resulted in consistent salbutamol systemic exposure. The contribution of the lung and gut to systemic exposure revealed a different profile for the three inhaler platforms. These data suggest that the UD-DPI warrants further evaluation.

To characterise the safety, tolerability, pharmacodynamics (bronchodilatory effect) and pharmacokinetics of inhaled umeclidinium in patients with chronic obstructive pulmonary disease (COPD). The first investigation was a single dose, randomised, double-blind, placebo-controlled study (clinicaltrials.gov: NCT00515502) in which ipratropium bromide-sensitive patients received umeclidinium (250μg, 500μg, and 1000μg), tiotropium bromide 18μg or placebo. Patients were randomised to receive four out of five possible treatments as an incomplete block four-way cross-over. A subsequent study (clinicaltrials.gov: NCT700732472) was focused on assessment of safety, tolerability and pharmacokinetics of umeclidinium (250μg and 1000μg) administered once-daily for 7 days in a randomised, double-blind, placebo-controlled, parallel-group design. Of the 24 patients randomised for the single dose study, 20 completed; 31 out of 38 patients completed the repeat dose study. Most adverse events were mild-to-moderate and transient. Examination of heart rate, QTc interval, blood pressure and clinical laboratory assessments raised no concern over the safety of umeclidinium. Evidence of pharmacology was demonstrated in first study by statistically significant increases in specific airway conductance (sGaw) for up to 24h for all active treatments compared with placebo. Increases in forced expiratory volume in 1s were also observed. Pharmacokinetic analysis demonstrated that maximum observed plasma umeclidinium concentration (Cmax) was reached rapidly (time to Cmax: ∼5-15min) after single and repeat doses; 1.5-1.9-fold accumulation was observed after repeat-dosing. Single and repeat doses of umeclidinium were well tolerated and produced clinically relevant lung function improvements over 24h in patients with COPD.

Jutta Beier1, Jan van Noord2, Amanda Deans3, Jean Brooks3, Claire Maden3, Suus Baggen4, Rashmi Mehta5, Anthony Cahn31INSAF Respiratory Research Institute, Germany; 2Atrium Medisch Centrum, The Netherlands; 3GlaxoSmithKline, Stockley Park, UK; 4GlaxoSmithKline, Zeist, The Netherlands; 5GlaxoSmithKline, RTP, NC, USABackground: GSK233705 is an inhaled, long-acting muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease (COPD). This study was performed to see if the addition of GSK233705 to salmeterol would provide greater bronchodilation than salmeterol or tiotropium alone in COPD.Methods: In an incomplete-block, three-period, crossover design, dually responsive patients received three of the following five treatments: GSK233705 20 µg plus salmeterol 50 µg twice-daily; GSK233705 50 µg plus salmeterol 50 µg twice-daily; salmeterol 50 µg or placebo, each twice-daily; and tiotropium 18 µg or placebo once-daily for 7 days. Each treatment period was separated by a 14-day washout. The primary efficacy endpoint was morning (trough) forced expiratory volume in 1 second (FEV1) on Day 8, following 7 days of treatment. Secondary endpoints included pulmonary function, plethysmography, pharmacokinetics of GSK233705 and salmeterol, adverse events (AEs), electrocardiograms (ECGs), vital signs, and laboratory parameters.Results: A total of 47 patients were randomized. The mean % predicted normal postbronchodilator FEV1 was 55% at screening. Compared with placebo (n = 24), the adjusted mean change from baseline in trough FEV1 on Day 8 was 215 mL higher with GSK233705 20 µg + salmeterol (n = 23) and 203 mL higher with GSK233705 50 µg + salmeterol (n = 27), whereas with salmeterol (n = 27) and tiotropium (n = 28) the changes were 101 mL and 118 mL higher, respectively. The primary efficacy results were supported by the results from the other secondary lung function assessments. AEs were reported by similar proportions of patients across the treatment groups, with headache the most frequently reported treatment-related AE reported by one subject receiving each of GSK233705 20 µg + salmeterol, tiotropium, and placebo. No significant differences were seen in vital signs, ECGs, or laboratory parameters between the groups.Conclusion: The addition of GSK233705 to salmeterol in partially reversible COPD patients resulted in greater bronchodilation than salmeterol or tiotropium alone and was well tolerated.Keywords: COPD, bronchodilation, dual therapy, LAMA, LABA

Introduction: GSK233705 is a recently developed inhaled anticholinergic being investigated for the potential treatment of chronic obstructive pulmonary disease (COPD). Objectives: This dose-ranging, parallel-group, double-blind study compared the bronchodilator efficacy, safety and pharmacokinetics of GSK233705 with placebo in patients with moderate-to-severe COPD. Methods: Patients were randomised to receive 12.5 µg, 25 µg, 50 µg, 100 µg or 200 µg of GSK233705 or placebo once daily for 28 days. The primary endpoint was change from baseline in trough forced expiratory volume in 1 s (FEV1) on day 29. Results: The intent-to-treat population consisted of 576 patients (mean predicted FEV1 51%; mean age 62 years). Treatment with GSK233705 produced statistically significant improvements in pulmonary function compared with placebo. Only the 200 µg dose exceeded the predefined target threshold of 130-mL difference compared with placebo for the primary endpoint of change from baseline in trough FEV1 on day 29. No clear pattern of dose response was observed for the other doses. Serial FEV1 (0–24 h) showed a peak effect around 2 h postdose and tended to decline to clinically insignificant levels compared with placebo at 23 and 24 h. Each dose of GSK233705 was well tolerated. The incidence of adverse events was low and similar across all treatment groups. There were no clinically significant effects on laboratory parameters, vital signs or electrocardiograms. Conclusion: All doses of GSK233705 demonstrated bronchodilatory activity and were well tolerated. Although the onset of bronchodilation was rapid, it was not sustained over 24 h making it unsuitable for once-daily dosing. Please cite this paper as: Bateman E, Feldman G, Kilbride S, Brooks J, Mehta R, Harris S, Maden C and Crater G. Efficacy and safety of the long-acting muscarinic antagonist GSK233705 delivered once daily in patients with COPD. Clin Respir J 2012; DOI:10.1111/j.1752-699X.2011.00278.x.

We determined lung bioavailability of a fluticasone propionate (FP) pressurised metred-dose inhaler (Flovent HFA; GlaxoSmithKline, Research Triangle Park, NC, USA) administered via AeroChamber Plus (Monaghan Medical, Plattsburgh, NY, USA) with Facemask and Babyhaler (GlaxoSmithKline) valved holding chambers (VHCs) using a population pharmacokinetic approach. Children from 1 to

The Mini Spacer has been developed for use with Ventolin(®) metered dose inhalers (MDIs) to improve accessibility to affordable spacers in developing countries. To ensure patient safety is not compromised if the Mini Spacer is used off-label with fluticasone propionate (FP) or salmeterol/FP combination (SFC) MDIs (currently not recommended), this study compared the systemic exposure of FP and salmeterol following delivery of FP and SFC MDIs with the Mini Spacer and the Aerochamber Plus(®) spacer (Aerochamber).This was an open-label, randomized, single dose, crossover study in healthy subjects that evaluated four treatments: i) FP 250 μg MDI with Mini Spacer; ii) FP 250 μg MDI with Aerochamber; iii) SFC 25/250 μg with Mini Spacer; iv) SFC 25/250 μg with Aerochamber. There was a minimum 7 day washout between treatments. Pharmacokinetic samples were collected over 24 hours post-dose. The co-primary endpoints were FP area under the concentration-time curve from time zero to 24 h [FP AUC(0-24)] and salmeterol maximum plasma concentration [Cmax].FP systemic exposure in terms of AUC(0-24) was lower following inhalation with the Mini Spacer compared with the Aerochamber for both FP 250 μg (Mini Spacer/Aerochamber Ratio 0.76 [90% CI: 0.57-1.01]) and SFC 25/250 μg (Ratio 0.74 [90% CI: 0.56-0.99]). Salmeterol systemic exposure was also lower following SFC 25/250 μg with Mini Spacer compared with Aerochamber (Cmax Ratio 0.90 [90% CI 0.48-1.66]). The incidence of adverse events was low and similar with each treatment.In the event of use of the Mini Spacer with FP and SFC MDIs, which is not recommended, FP and salmeterol systemic exposure is unlikely to be higher than if MDIs were to be used with the Aerochamber. However, these data do not indicate that the Mini Spacer and Aerochamber are interchangeable.

The long-acting muscarinic antagonist umeclidinium (UMEC) is approved as a once-daily monotherapy and in combination with the long-acting β2 agonist vilanterol (VI) for chronic obstructive pulmonary disease. The objective of this analysis was to assess the relationship between observed plasma UMEC and/or VI concentrations and QT interval corrected using Fridericia's correction (QTcF). 103 subjects were enrolled and 86 (83 %) completed the study. Subjects were randomized to 4 of 5 repeat-dose treatments (days 1-10: n = 77 subjects received placebo, n = 76 UMEC 500 µg, n = 78 UMEC/VI 125/25 µg, or n = 76 UMEC/VI 500/100 µg; day 10: n = 74 oral tablet moxifloxacin 400 mg [positive control]). The concentration-QTcF interval relationship was examined using nonlinear mixed-effects methods. For UMEC, predicted QTcF interval prolongation (at observed geometric mean of maximum plasma concentrations) was -2.38 ms (90 % prediction interval [PI] -3.82, -0.85) with UMEC 500 µg and -0.50 ms (90 % PI -0.80, -0.18) and -2.01 ms (90 % PI -3.22, -0.72) with UMEC/VI 125/25 µg and 500/100 µg, respectively. For VI, estimates were 5.89 ms (90 % PI 4.89, 6.91) and 7.23 ms (90 % PI 5.88, 8.55) with UMEC/VI 125/25 µg and 500/100 µg, respectively. Combined additive mean effects were estimated for UMEC/VI 125/25 µg (5.39 ms [90 % PI 4.40, 6.47]) and 500/100 µg (5.22 ms [90 % PI 3.72, 6.80]). The model-predicted decrease with UMEC and increase with UMEC/VI combination in QTcF interval suggest that the QT effect is likely attributable to VI. These model-predicted results support those of previously-published traditional statistical analyses.

UNLABELLED Inhaled umeclidinium (UMEC) and the combination of inhaled UMEC with vilanterol (UMEC/VI) are approved maintenance treatments for chronic obstructive pulmonary disease in the US and EU. This was a randomized, open-label, three-period crossover, single- and repeat-dose study to assess the pharmacokinetics (PK), safety, and tolerability of inhaled UMEC/VI 62.5/25 μg (delivering 55/22 μg) and UMEC/VI 125/25 μg (delivering 113/22 μg) compared with their monotherapy components (UMEC 62.5 μg, UMEC 125 μg and, VI 25 μg [delivering 55, 113, and 22 μg, respectively]) in healthy Chinese subjects (n=20). UMEC and VI were rapidly absorbed following single and repeat dosing (time to maximum plasma concentration [tmax]: UMEC = 5 min; VI = 5 min). The median tlast was 2–4 h for UMEC and 1–2 h for VI following single doses of UMEC/VI and UMEC monotherapy (both doses). UMEC reached steady-state prior to Day 10; steady-state for VI could not be assessed. UMEC accumulation following repeat dosing was 11–34% based on Cmax and 19–59% based on area under the concentration-time curve from time zero to 2 h (AUC(0-2)). VI accumulation following repeat dosing was 25–66% based on Cmax and 17–43% based on AUC(0-2). The evidence was not sufficient to suggest that systemic exposure was substantially different between UMEC/VI combination therapy and the constituent monotherapies following single or repeat dosing. Following both single- and repeat-dose administration, the inter-subject coefficient of variation for all UMEC PK parameter estimates ranged from 12% to 165% for all treatments, indicating a wide range of variability in inhaled PK parameters. Twelve subjects experienced ≥1 adverse event (AE). Six subjects experienced ≥1 treatment-related AE; the most commonly reported treatment-related AE was chest discomfort (n=3 [15%]). No clinically important changes in vital signs or electrocardiogram parameters were reported. These data suggest that single- and repeat-dose administration of UMEC/VI combination therapy in healthy Chinese subjects did not result in substantial differences in systemic exposure compared with UMEC and VI as monotherapies. TRIAL REGISTRATION Clinicaltrials.gov NCT01899638 NCT01899638.

This was a randomised, double-blind, placebo-controlled, cross-over study comparing the systemic pharmacodynamic effects (heart rate and serum potassium) and pharmacokinetics of salmeterol delivered by the non-CFC hydrofluoralkane (HFA) propellant 134a and the CFC propellant (propellant 11/12) metered dose inhalers (MDI) in healthy subjects. At the therapeutic dose (50 microg), salmeterol-mediated systemic pharmacodynamics were equivalent for the HFA and CFC MDIs. Higher doses of salmeterol (150 and 300 microg) produced dose-related beta-agonist pharmacodynamic effects irrespective of the propellant. However, these effects were lower with salmeterol HFA MDI than with the salmeterol CFC MDI at all dose levels. Overall, salmeterol Cmax and AUC(0-t) values were lower for salmeterol HFA compared with salmeterol CFC MDI. At the highest dose (300 microg), where a full pharmacokinetic profile was obtained, exposure to salmeterol delivered by the HFA MDI compared with the salmeterol CFC MDI was 27% and 30% lower for Cmax and AUC(0-t), respectively. Maximum plasma concentrations were generally seen in the first plasma samples taken 5 min after the start of dosing. Salmeterol HFA was well-tolerated. At supratherapeutic doses, adverse events were typical for high-dose salmeterol with fewer adverse events occurring with the HFA compared with the CFC formulation. These data indicate that the salmeterol HFA MDI would not be associated with a significantly different pharmacodynamic, safety and tolerability profile compared with the salmeterol CFC MDI.

A fixed-dose combination of the bronchodilators umeclidinium and vilanterol is in development for the long-term, once-daily treatment of chronic obstructive pulmonary disease (COPD). We characterized the pharmacokinetics of umeclidinium and vilanterol in ≈1,635 patients with COPD, evaluating the impact of patient demographics and baseline characteristics on umeclidinium and vilanterol exposure. Plasma concentrations of umeclidinium and vilanterol were evaluated in patients enrolled in two phase III, randomized, double-blind, parallel-group, placebo-controlled trials using inhaled umeclidinium/vilanterol combination therapy and inhaled umeclidinium and vilanterol monotherapies as treatments. Population-pharmacokinetic models were developed using non-linear mixed-effects analyses, performed using NONMEM® software. A likelihood-based approach was used to characterize the data below limit of quantification. Umeclidinium and vilanterol exposures at clinical doses were simulated based on the population model. For the umeclidinium and vilanterol population-pharmacokinetic analyses, 1,635 and 1,637 patients provided 8,498 and 8,405 observations, respectively. Umeclidinium and vilanterol pharmacokinetics were best described by a two-compartment model with first-order absorption. For umeclidinium, bodyweight, age, and creatinine clearance (CLCR) were statistically significant covariates for apparent inhaled clearance (CL/F); bodyweight was a statistically significant covariate for volume of distribution of central compartment (V 2/F).The population parameter estimates namely CL/F and V 2/F for umeclidinium were 218 L/h and 1,160 L and 40.9 L/h and 268 L for vilanterol. For vilanterol, bodyweight and age were statistically significant covariates for CL/F. The effect of covariates on umeclidinium and vilanterol systemic exposure was marginal. The population model indicates that a 10 % increase in bodyweight will result in a 2 % increase in CL/F for umeclidinium and vilanterol and 6 % increase in umeclidinium V 2/F. A 10 % increase in age will provide a 7 and 4 % decrease in umeclidinium and vilanterol CL/F, respectively. A 10 % decrease in CLCR will result in a 3 % decrease in umeclidinium CL/F. Umeclidinium and vilanterol population-pharmacokinetic model-based systemic exposure predictions showed no pharmacokinetic interactions between umeclidinium and vilanterol when administered in combination. There were no apparent pharmacokinetic interactions when umeclidinium and vilanterol were co-administered in patients with COPD. The effects of patient demographics, including age, bodyweight, and CLCR, on umeclidinium or vilanterol systemic exposure were minimal, and therefore no dose adjustments are necessary.

Umeclidinium (UMEC) is an inhaled long-acting muscarinic antagonist approved in the US and EU for the once-daily (QD) treatment of chronic obstructive pulmonary disease (COPD); it is not indicated for the treatment of asthma. To fully characterize the dose-response relationship of UMEC in patients with COPD, a pooled analysis of data from two randomized, placebo-controlled, cross-over, dose-ranging studies was performed, evaluating UMEC at doses of 15.6-1000 mcg QD and 15.6-250 mcg twice daily (BID). The primary endpoint was trough forced expiratory volume in one second (FEV(1)) at the end of each study's treatment period (Day 8/Day 15). A population model-based analysis using total daily UMEC dose was used for the primary analysis comparing QD and BID dosing. A physiological effect (E(max)) model was optimal in defining the relationship between UMEC dose and the primary endpoint, demonstrating a clear monotonic dose response over QD and BID dosing regimens. UMEC doses ≥62.5 mcg QD were differentiated from lower doses and BID dosing did not provide benefit over QD dosing. The potency (ED(50)) estimate was 33 mcg with QD dosing. These data indicate that UMEC 62.5 mcg and 125 mcg QD provide lung function benefits that warrant further investigation for the treatment of COPD.

A 6-month-old infant presented to our paediatric department with a low grade pyrexia and rash. There were vesicular lesions over the left chest and abdominal wall in the T6 dermatome distribution (figure 1). Investigations revealed a normal C reactive protein, with raised alanine transaminase of 362 units/l and white cell count of 19.1×109/l. On questioning, the mother revealed …

Rashmi Mehta,1 Dennis Kelleher,1 Andrew Preece,2 Stephen Hughes,3 Glenn Crater4 1Respiratory Medicines Development Center, GlaxoSmithKline, Research Triangle Park, NC, USA; 2Respiratory Medicines Development Center, GlaxoSmithKline, Stockley Park West, UK; 3GlaxoSmithKline R&D, Bioanalytical Sciences and Toxicokinetics, Drug Metabolism and Pharmacokinetics, Ware, UK; 4Respiratory Medicine Development Center, GlaxoSmithKline, Mississauga, ON, Canada Background: The combination of umeclidinium (UMEC), a long-acting muscarinic receptor antagonist, and vilanterol (VI), a selective long-acting ß2 agonist, is in development for the treatment of chronic obstructive pulmonary disease (COPD). This study evaluated the pharmacokinetics, safety and tolerability, and pharmacodynamics of once-daily, inhaled UMEC and UMEC/VI when co-administered with oral verapamil, a moderate P-glycoprotein transporter and moderate cytochrome P450 3A4 (CYP3A4) inhibitor frequently used by patients with COPD and cardiovascular comorbidities. Methods: Subjects were randomized to one of two 13-day treatment regimens: UMEC 500 µg or UMEC 500 µg/VI 25 µg. All subjects received a single tablet containing 240 mg verapamil on each of days 9–13. Results: Repeat doses of UMEC and UMEC/VI in combination with and without verapamil were safe and well tolerated. There was no increase in systemic exposure of UMEC when administered in combination with VI compared to UMEC alone. UMEC maximum concentration was similar with or without verapamil; a moderate increase in UMEC area under the curve (approximately 1.4-fold) was observed with verapamil. Verapamil did not increase systemic exposure to VI following administration of the UMEC/VI combination. Conclusion: Administration of UMEC and UMEC/VI combination was well tolerated and did not show clinically relevant increases in systemic exposure for either drug. The UMEC/VI combination is unlikely to have a clinically meaningful drug–drug interaction with moderate P-glycoprotein transporter and CYP3A4 inhibitor drugs. Keywords: umeclidinium, vilanterol, verapamil, long-acting muscarinic antagonist, long-acting ß2 agonist

Background This study evaluated the dose–response of the new long-acting muscarinic antagonist umeclidinium (GSK573719) in patients with COPD. Methods This randomized, double-blind, placebo-controlled, parallel-group study evaluated three once-daily doses of umeclidinium (125, 250 and 500 μg) for 28 days in 285 patients with COPD having FEV 1 of 35–70% predicted (mean (SD) age = 61.4 (8.41); mean (SD) post-bronchodilator FEV 1 = 1.577 (0.450)). The primary endpoint was morning trough FEV 1 at Day 29. Secondary endpoints included 0–6 h weighted mean FEV 1 and serial FEV 1 measured over 6 h post-dose and at trough. Safety and pharmacokinetics were also assessed. Results All doses of umeclidinium significantly increased trough FEV 1 over placebo from 150 to 168 mL ( p 1 from 113 to 211 mL ( p 1 at each point in time over 24 h. Reductions in salbutamol use and improvements in FVC were noted for all doses. Umeclidinium was well tolerated with no apparent treatment-related changes in vital signs. Conclusion Once-daily umeclidinium provides clinically significant, sustained improvement in lung function and is well tolerated.

Background Umeclidinium (UMEC; GSK573719) is a new long-acting muscarinic antagonist (LAMA) currently in development in combination with vilanterol (VI), an inhaled, long-acting beta 2 agonist for the treatment of chronic obstructive pulmonary disease (COPD). The primary aim of this study was to evaluate the safety and tolerability of repeat dosing of UMEC and VI in combination once daily for 28 days in patients with COPD. Methods This was a multicenter, double-blind, placebo-controlled, parallel group study. Patients aged ≥40 years with post-bronchodilator FEV 1 ≤80% of predicted normal values and FEV 1 /FVC ratio ≤0.70, and a smoking history of ≥10 pack-years, were randomized 4:1 to once-daily UMEC/VI (500/25 mcg; n = 42) or placebo ( n = 9). Results UMEC/VI was non-inferior to placebo in weighted mean pulse rate over 0–6 h at Day 28 (primary endpoint: difference of −0.5 bpm, 95% CI: −5.5 to 4.5). There was no evidence of a difference between UMEC/VI compared with placebo in blood pressure, minimum and maximum pulse rate, or QTcF assessments. Adverse events (AEs) were reported by 11 (26%) patients in the UMEC/VI group and one (11%) patient in the placebo group. No serious AEs were reported. Both UMEC and VI showed rapid absorption (median t max ∼6 min for both drugs) with no evidence of accumulation for AUC or C max on Day 28 compared with Day 1 for UMEC or VI. There was no correlation between individual steady-state C max and pulse rate on Day 28. Change from baseline in trough FEV 1 on Day 29 showed numerically greater improvements with UMEC/VI compared with placebo. Conclusion Once-daily dosing with UMEC in combination with VI in patients with moderate-to-very-severe COPD was well tolerated over 28 days.

The systemic exposure of fluticasone propionate with hydrofluoroalkane propellant compared with chlorofluoro-carbon propellant and the effect of fluticasone propionate hydrofluoroalkane on 24-hour urinary cortisol in children aged 4 to 11 years with asthma were evaluated. Study 1 was an open-label, 2-way crossover study in which 16 subjects were randomized to 7.5 days each of fluticasone propionate hydrofluoroalkane 88 mug twice a day or fluticasone propionate chlorofluorocarbon 88 mug twice a day. In study 2, 63 subjects received 13.5 days of placebo followed by 27.5 days of fluticasone propionate hydrofluoroalkane 88 mug twice a day. The main outcome measure for study 1 was the difference between fluticasone propionate hydrofluoroalkane and fluticasone propionate chlorofluorocarbon in fluticasone propionate AUC(last) (area under the plasma fluticasone propionate concentration-time curve from zero up to the last quantifiable plasma concentration), and for study 2, 24-hour overnight urinary cortisol excretion. In study 1, fluticasone propionate systemic exposure was significantly lower (55%) with hydrofluoroalkane metered dose inhaler compared with chlorofluorocarbon metered dose inhaler. Study 2 showed no statistically significant changes in 24-hour overnight urinary cortisol excretion and no relationship to fluticasone propionate systemic exposure at this dose. The results of these 2 studies showed that in children aged 4 to 11 years with asthma, fluticasone propionate hydrofluoroalkane has lower systemic exposure compared with chlorofluorocarbon and no hypothalamic-pituitary-adrenal axis effects as measured by 24-hour urinary cortisol excretion.

Background The long-acting muscarinic antagonist umeclidinium (UMEC) is approved as a monotherapy, and in combination with the long-acting β2-agonist vilanterol (VI), as a once-daily inhaled maintenance bronchodilator therapy for chronic obstructive pulmonary disease in the US and EU; they are not indicated for the treatment of asthma. Preclinical and clinical data suggest that UMEC and VI are predominantly eliminated by the liver. Objectives The objectives of the study were to evaluate the effects of moderate hepatic impairment on the plasma and urinary pharmacokinetic properties of each drug, and on the tolerability of inhalational UMEC/VI 125/25 µg and UMEC 125 µg. Methods This open-label, nonrandomized study was conducted in patients with moderate hepatic impairment (Child-Pugh score, 7–9) and in healthy volunteers (control). Patients and volunteers were administered a single dose of UMEC/VI 125/25 µg, and, after a 7- to 14-day washout period, repeat-dose UMEC 125 µg once daily for 7 days. Primary end points were the plasma pharmacokinetic properties of single- and repeat-dose UMEC and VI. Secondary end points were the urinary pharmacokinetic properties of UMEC, and the tolerability of each treatment. Results All 18 enrolled patients and volunteers (12 men, 6 women; mean age, 53.6 years) completed the study. Mean systemic exposures of UMEC and VI were similar or numerically lower in patients with moderate hepatic impairment compared with those in healthy volunteers, but the differences were not clinically significant. UMEC accumulations with 7-day dosing of UMEC were similar between patients with moderate hepatic impairment and healthy volunteers. UMEC/VI 125/25 µg and UMEC 125 µg were well-tolerated, with no safety concerns identified. Conclusions The administration of UMEC/VI 125/25 µg or UMEC 125 µg in patients with moderate hepatic impairment did not result in clinically relevant increases in UMEC or VI exposures compared with those in healthy volunteers. Based on these findings, no dose adjustment for UMEC/VI or UMEC is warranted in patients with moderate hepatic impairment.

Background Umeclidinium bromide (UMEC) is an inhaled long-acting muscarinic antagonist in development for chronic obstructive pulmonary disease (COPD). Methods This was a multicentre, randomised, double-blind, placebo-controlled, three-way cross-over, incomplete block study to evaluate UMEC 15.6, 31.25, 62.5, and 125 μg administered once daily (QD), and UMEC 15.6 μg and 31.25 μg administered twice daily (BID), over 7 days in patients with COPD. Tiotropium was included as an open-label treatment arm. The primary efficacy endpoint was trough forced expiratory volume in 1 second (FEV1) on Day 8. Secondary efficacy endpoints included weighted mean FEV1 over 0–24 hours after morning dosing on Day 7, and serial FEV1 at each time point over 24 hours after morning dosing on Day 7. Safety and pharmacokinetics were also examined. Results One hundred and sixty-three patients (mean age 59.5 years, 52% female) were randomised. Based on the population dose–response model of trough FEV1 data, the geometric mean potency (ED50) of UMEC was 37 μg (95% confidence interval [CI]: 18, 57) with a predicted maximum intrinsic efficacy (Emax) at trough of 0.185 L (95% CI: 0.153, 0.218) after QD dosing. UMEC 125 μg QD demonstrated the greatest improvements in measure of lung function compared with doses of 62.5 μg and below. UMEC 125 μg QD exhibited more consistent increases in FEV1 from baseline across serial time points over 24 hours compared with other UMEC doses and tiotropium. Increases in FEV1 over 0–12 hours were similar to those observed over 12–24 hours after the second dose of UMEC was administered. UMEC was rapidly absorbed following inhaled dosing and eliminated from plasma. Adverse events, generally mild, were highest with UMEC 125 μg QD (18%) compared with placebo (8%), tiotropium (4%) and other UMEC doses (5–12%). Conclusions UMEC is a potent QD bronchodilator with geometric mean ED50 of 37 μg. A dose ordering over the range of UMEC 15.6–125 μg QD doses was observed, with UMEC 125 μg showing the greatest improvement in trough FEV1. Trial registration GlaxoSmithKline funded (clinicaltrials.gov NCT01372410; GlaxoSmithKline study number AC4115321).

Objective To evaluate the efficacy and tolerability of fluticasone propionate (FP) hydrofluoroalkane (HFA) in children age 1 to Study design Children were assigned (2:1) to receive FP HFA 88 μg (n = 239) or placebo HFA (n = 120) twice daily through a metered-dose inhaler with a valved holding chamber and attached facemask for 12 weeks. The primary efficacy measure was mean percent change from baseline to endpoint in 24-hour daily (composite of daytime and nighttime) asthma symptom scores. Results The FP-treated children had significantly greater ( P ≤ .05) reductions in 24-hour daily asthma symptom scores (−53.9% vs −44.1%) and nighttime symptom scores over the entire treatment period compared with the placebo group. Daytime asthma symptom scores and albuterol use were slightly more decreased with FP than with placebo; however, the differences were not statistically significant. Increases in the percentage of symptom-free days were comparable. The percentage of patients who experienced at least 1 adverse event was similar in the 2 groups. Baseline median urinary cortisol excretion values were comparable between the groups, and there was little change from baseline at endpoint. FP plasma concentrations demonstrated that systemic exposure was low. Conclusions FP HFA 88 μg twice daily was effective and well tolerated in pre–school-age children with asthma.