Population Dose-Response-Time Analysis of Itch Reduction and Patient-Reported Tolerability Supports Phase III Dose Selection for Linerixibat.

Increase in serum bile acids (BAs) in patients with primary biliary cholangitis (PBC) may play a causal role in cholestatic pruritus (itch). Linerixibat is a selective small molecule inhibitor of the ileal bile acid transporter, which blocks re-absorption of BAs in the gastrointestinal tract thereby lowering BAs in the systemic circulation and reducing itch. One consequence is excess BAs in the colon, leading to diarrhea and abdominal pain. GLIMMER (NCT02966834) was a placebo-controlled phase IIb dose-ranging trial of linerixibat once (q.d.) or twice daily (b.i.d.) in adults with moderate to severe pruritus and PBC. To determine the optimal dose for maximum itch reduction while minimizing diarrhea, a kinetic-pharmacodynamic (k-PD) model was developed using data from GLIMMER. The PD end point modeled was worst daily itch, derived from itch score reported by patients b.i.d. A proportional odds model was developed post hoc to indicate the probability of diarrhea occurrence, a patient-reported outcome (GI-5) recorded weekly. The final k-PD model successfully described the effects of linerixibat and placebo on itch. Model simulations were consistent with the observed dose-dependent increase in the average number of itch responders (patients with a ≥ 2-point improvement in itch). This was paralleled by a dose-dependent increase in the probability of higher diarrhea frequency scores. The b.i.d. dosing regimens led to a modest increase in the number of itch responders as compared with q.d. dosing. This quantitative framework highlights the trade-off between benefit and tolerability and supported the selection of 40 mg b.i.d. in the phase III GLISTEN trial (NCT04950127).

Breast Imaging Fellowship Training in the United States: A National Survey of Fellowship Program Directors.

OBJECTIVE: To provide an updated characterization of breast imaging fellowship programs in the United States to identify opportunities for improvement and standardization. METHODS: An anonymous survey was e-mailed to program directors of breast imaging fellowship programs listed on the Society of Breast Imaging website. The survey was open from April 23, 2021, through May 27, 2021. The survey was deemed exempt by the IRB. RESULTS: Forty-seven of 80 (59%) program directors responded, of which 36/47 (77%) represented programs dedicated 100% to breast imaging, and 11/47 (23%) represented programs dedicated 50%-75% to breast imaging. Common elements to most programs include tumor boards (47/47, 100%), journal clubs (39/47, 83%), case-based teaching sessions (35/47, 74%), didactic lectures (40/47, 85%), and participation in radiology-pathology conferences (29/47, 62%). Mammography Quality and Standards Act audit training (22/47, 47%), mammography quality control training (22/47, 47%), and formal communication training (19/47, 40%) were less common. Most programs provide exposure to wire (42/47, 89%) and wire-free localization procedures (45/47, 96%), but exposure to contrast-enhanced mammography (13/47, 28%) and molecular breast imaging (4/47, 9%) was limited. A small majority of programs (25/47, 53%) do not require weekday call; however, more (31/47, 66%) have weekend call responsibilities. Many programs (29/47, 62%) offer at least 3 weeks of elective time, which may be clinical or nonclinical. CONCLUSION: Breast imaging fellowship programs vary in curricula, modality exposure, and academic policies. The results of this survey can help guide further efforts to standardize and optimize fellowship training.

Impact of imaging nurse navigation on breast interventions: Direct and closed-loop patient communication and documentation.

OBJECTIVE: A breast imaging nurse navigator (NN) was established with the goals to enhance the patient experience after biopsy, improve care timeliness, accuracy, and coordination, facilitate direct communication to patients, and increase care retention within our system. Our aim was to determine the impact of NN on patient care time metrics, communication, documentation, compliance, and care retention at our institution after breast biopsy. METHODS: Retrospective review of a six-month period before (5/1/17-10/31/17) and after (5/1/19-10/31/19) establishment of a nurse navigator in our breast imaging department was performed, including 498 patients in the pre-navigation (pre-NN) group and 526 patients in the post-navigation (post-NN) group. Data was gathered from the electronic medical record and collected using REDCap. RESULTS: Biopsy pathology results were communicated directly to the patient more often post-NN (71%, 374/526) compared to pre-NN (4%, 21/498) (p < 0.0001), without change in overall time of result communication (p = 0.08). Due to factors outside of imaging, most care time metrics were longer post-NN, including days from biopsy to pathology report (p < 0.001), result communication to initiation of care (p < 0.001), and biopsy to surgery (p < 0.001). There was no difference and high compliance (p = 1) and care retention (p = 0.015) in both groups. There was improved documentation of pathology results, recommendations, and communication post-NN (0/526 vs 10/498, p = 0.001). CONCLUSION: Imaging nurse navigation added greatest value by communicating breast biopsy results and recommendations directly to patients and ensuring documentation. Compliance and retention were high in both groups. Factors outside of Radiology influenced time metrics, requiring further investigation of multidisciplinary collaboration.

Pharmacokinetic and pharmacokinetic/pharmacodynamic characterization of the dolutegravir/rilpivirine two-drug regimen in SWORD-1/-2 phase 3 studies.

AIM: SWORD-1 and SWORD-2 phase 3 studies concluded that switching virologically suppressed participants with HIV-1 from their current three- or four-drug antiretroviral regimen (CAR) to the two-drug regimen of once-daily dolutegravir (DTG, 50 mg) and rilpivirine (RPV, 25 mg) was safe, well tolerated and noninferior for maintaining HIV-1 suppression at week 48 and highly efficacious to week 148. A secondary objective was to characterize drug exposure and exposure-efficacy/safety relationships. METHODS: Adults with plasma HIV-1 RNA <50 copies/mL were randomized to switch to once-daily DTG + RPV on day 1 or to continue CAR for 52 weeks before switching. Trough plasma concentrations (C0) of DTG and RPV, the proportion of participants with HIV-1 RNA <50 copies/mL and adverse events to week 100 were summarized and subjected to exposure-response analyses in the overall population, in the subset of participants who switched from CAR containing enzyme-inducing drugs and by age category (≥50 and <50 years). The relationship between C0avg (individual average C0 across visits) and efficacy/safety was investigated. RESULTS: Although week 2 DTG and RPV C0 were lower in participants switching from enzyme-inducing antiretroviral drugs, C0 and C0avg stayed above in vitro antiviral protein binding-adjusted IC90 and to week 100 with viral suppression >89%. DTG or RPV C0avg showed no relationship with virologic failures or safety. Participants ≥50 years had similar C0avg and safety response to younger participants. CONCLUSION: No clinically relevant relationship between DTG or RPV exposures and virologic or safety response was observed, confirming the DTG + RPV switch for participants as a safe and effective treatment.

Comparative clinical pharmacology of mometasone furoate, fluticasone propionate and fluticasone furoate.

AIMS: To investigate the pharmacokinetics and effects on the hypothalamic-pituitary-adrenal (HPA) axis of mometasone furoate (MF), fluticasone propionate (FP) and fluticasone furoate (FF). METHODS: Study 1: Fourteen healthy participants received inhaled and intravenous MF (inhaled dose via Twisthaler) and FP (inhaled dose via Diskus), both given at 400 µg, using a randomised, single-dose, four-way crossover design. Study 2: Twenty-seven participants with mild to moderate asthma, who discontinued their corticosteroid medication for 5 days to obtain a baseline 24 h serum cortisol, received inhaled MF Twisthaler and FP Diskus, both given at 400 µg twice daily (BID), using a randomised, 14-day repeat dose, two-way crossover design. Study 3: Forty-four healthy participants were randomised to a double-blind, placebo-controlled, five-period crossover study where the following treatments were administered via the inhaled route for 7 days: FP Diskus (250, 500, 1000 µg BID), FF Diskus (100, 200, 400, 800, 1600 µg once daily [QD]) or placebo Diskus. In each study, 24-h serial blood samples were collected and assayed to assess concentrations of MF, 6ß-hydroxy mometasone, mometasone, FP, FF and cortisol. Pharmacokinetic and serum cortisol parameters were estimated as geometric means and 95% confidence intervals (CI). RESULTS: Study 1: For intravenous MF and FP, respectively: absolute bioavailability was 11.4% (95% CI: 7.5, 17.6) and 7.8% (6.3, 9.6); plasma clearance was 47 L/h (41, 52) and 60 L/h (52, 69); half-life was 7.4 h (6.9, 8.0) and 7.2 h (6.5, 8.0); and volume of distribution was 499 L (439, 567) and 623 L (557, 698). Inhalation of single dose MF or FP did not significantly affect serum cortisol (<10% reduction from baseline), whereas intravenous administration of MF or FP each changed serum cortisol by approximately -50% from baseline. Study 2: For MF and FP, respectively: area under the curve up to the last measurable concentration on Day 1 was 421 pg h/mL (270, 659) and 248 pg h/mL (154, 400), and on Day 14 was 1092 pg h/mL (939, 1269) and 591 pg h/mL (501, 696); absolute bioavailability was 12.8% (11.2, 14.2) and 8.9% (7.7, 10.2). On Day 14, 24-h serum cortisol change from baseline was -35% (-44%, -26%) and -18% (-28%, -5%) for MF and FP, respectively; the reduction was significantly greater for MF than FP (ratio for geometric adjusted mean serum cortisol concentration: 1.28 [1.04, 1.56]). Low plasma concentrations of 6ß-hydroxy mometasone were detected after intravenous dosing (Study 1) and after multiple inhaled dosing (Study 2); mometasone was not detected in any samples. Study 3: Inhaled FP and FF had similar systemic bioavailability estimates (12.0% [11.0, 13.2] and 15.0% [12.0, 17.3], respectively), but a differential effect on the HPA axis which was in agreement with the known 1.7-fold higher glucocorticoid receptor-binding affinity of FF versus FP. However, for FP 250 µg BID and FF 100, 200 and 400 µg QD, reduction in serum cortisol was not significantly different from placebo. For higher doses, FP 500 and 1000 µg BID, and FF 800 and 1600 µg QD, changes in serum cortisol concentration relative to placebo were -30%, -70%, -41% and -90%, respectively. Repeat inhaled dosing of FP 1000 µg/day (within the therapeutic dose range) resulted in comparable cortisol suppression to MF in the therapeutic range (30% reduction); whereas for FF this occurred at more than 3-fold above the therapeutic dose range (644 µg/day). CONCLUSIONS: Single inhaled and intravenous doses of MF and FP (400 µg) resulted in similar bioavailability and reductions in serum cortisol. Repeat dosing of inhaled MF and FP in the therapeutic range (800 µg/day) resulted in greater systemic exposure for MF, and a 35% reduction in serum cortisol that was 2-fold greater than for FP. The higher glucocorticoid receptor-binding affinity and bioavailability, lower clearance and the presence of active metabolites may contribute to the greater systemic exposure and effect on cortisol for MF. Repeat dosing of inhaled FP and FF resulted in similar systemic bioavailability but differed in terms of the dose required for comparable cortisol suppression to MF in the therapeutic range. Unlike FP and FF, MF has active metabolites that may contribute to its systemic effects, while device/formulation performance differences also exist between MF-containing products.

Characterization of True and False Positive Findings on Contrast-Enhanced Mammography.

RATIONALE AND OBJECTIVES: The purpose of this paper is to characterize true and false positive findings on contrast-enhanced mammography (CEM) and correlate enhancement pattern and method of detection with pathology outcomes. MATERIALS AND METHODS: This was an IRB-approved retrospective review of diagnostic CEM performed from December 2015 through December 2019 for which biopsy was recommended. Background parenchymal enhancement, tissue density, finding features, pathologic/clinical outcomes, and method of detection were captured. CEM includes low-energy images (LE), similar to standard 2D mammography, and recombined images (RI) that show enhancement. 'MG-detected' findings were identified on mammography or LE. 'RI-detected' findings were identified due to enhancement on RI. The positive predictive value (PPV2) was calculated on a per-case and a per-finding level. Comparisons were performed using Pearson chi-square and Fisher exact tests. RESULTS: One hundred sixty CEM cases with 220 findings were evaluated with a case PPV2 of 58.1%. 32.3% (71/220) of lesions were RI-detected.  The PPV2 of RI-detected enhancement was 40.8% with subanalysis revealing PPV2 of 22.2%, 32%, and 51.4% for foci, NME, and masses, respectively. The PPV2 of MG-detected enhancement was 73.5% with subanalysis revealing PPV2 of 50%, 54.1%, and 83.8% for foci, NME, and masses, respectively. There were 100 false positives findings, 42 of which were RI-detected. CONCLUSION: PPV2 of diagnostic CEM is within the range of other diagnostic breast imaging exams. However false positives remain a challenge, especially for RI-detected findings. Additional efforts to improve specificity of RI-detected findings are worthwhile.

Patient preferences regarding use of contrast-enhanced imaging for breast cancer screening.

RATIONALE AND OBJECTIVES: Our purpose is to understand patient preferences towards contrast-enhanced imaging such as CEM or MRI for breast cancer screening. METHODS AND MATERIALS: 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. RESULTS: 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 (p<0.001) and willing to pay more for MRI (p<0.001). If patients had prior CEM/MRI, there was less concern for an allergic reaction (p<0.001), 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). CONCLUSION: 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.

Cancer Conspicuity on Low-energy Images of Contrast-enhanced Mammography Compared With 2D Mammography.

OBJECTIVE: Low-energy (LE) images of contrast-enhanced mammography (CEM) have been shown to be noninferior to digital mammography. However, our experience is that LE images are superior to 2D mammography. Our purpose was to compare cancer appearance on LE to 2D images. METHODS: In this IRB-approved retrospective study, seven breast radiologists evaluated 40 biopsy-proven cancer cases on craniocaudal (CC) and mediolateral oblique (MLO) LE images and recent 2D images for cancer visibility, confidence in margins, and conspicuity of findings using a Likert scale. Objective measurements were performed using contrast-to-noise ratio (CNR) estimated from regions of interest placed on tumor and background parenchyma. Reader agreement was evaluated using Fleiss kappa. Per-reader comparisons were performed using Wilcoxon test and overall comparisons used three-way analysis of variance. RESULTS: Low-energy images showed improved performance for visibility (CC LE 4.0 vs 2D 3.5, P < 0.001 and MLO LE 3.7 vs 2D 3.5, P = 0.01), confidence in margins (CC LE 3.2 vs 2D 2.8, P < 0.001 and MLO LE 3.1 vs 2D 2.9, P < 0.008), and conspicuity compared to tissue density compared to 2D mammography (CC LE 3.6 vs 2D 3.2, P < 0.001 and MLO LE 3.5 vs 2D 3.2, P < 0.001). The average CNR was significantly higher for LE than for digital mammography (CC 2.1 vs 3.2, P < 0.001 and MLO 2.1 vs 3.4, P < 0.001). CONCLUSION: Our results suggest that cancers may be better visualized on the LE CEM images compared with the 2D digital mammogram.

Contrast-enhanced Mammography: A Guide to Setting Up a New Clinical Program.

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.

Injected Breast Materials: Review of Imaging Features and Characteristics.

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.

The Effect of Moderate- and High-Fat Meals on the Bioavailability of Dolutegravir/Rilpivirine Fixed-Dose Combination Tablet.

Dolutegravir 50 mg (DTG) and rilpivirine 25 mg (RPV) are a newly approved 2-drug regimen for the treatment of HIV in virally suppressed patients. A 2-part study evaluated the relative bioavailability and food effect of five experimental fixed-dose combination (FDC) tablet formulations of DTG/RPV. When given with a moderate- or high-fat meal, the absorption of both DTG and RPV was increased, resulting in higher exposures. As per product labelling, DTG/RPV FDC should be taken with a meal.

A randomized, double-blind, placebo-controlled, parallel-group study of once-daily inhaled fluticasone furoate on the hypothalamic-pituitary-adrenocortical axis of children with asthma.

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.

Imaging and management of fibroepithelial breast lesions on percutaneous core needle biopsy.

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.

Population Pharmacokinetic Analysis of Fluticasone Furoate/Umeclidinium Bromide/Vilanterol in Patients with Chronic Obstructive Pulmonary Disease.

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.

A Roadmap for a Successful Breast Imaging Fellowship.

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.

Comparison of Contrast-Enhanced Mammography With Conventional Digital Mammography in Breast Cancer Screening: A Pilot Study.

PURPOSE: To perform a pilot evaluation of contrast-enhanced mammography (CEM) for screening to determine whether it can improve accuracy and reader confidence in diagnosis. METHODS AND MATERIALS: 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. RESULTS: 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. SUMMARY: 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.

Bioequivalence of a Fixed-Dose Combination Tablet of the Complete Two-Drug Regimen of Dolutegravir and Rilpivirine for Treatment of HIV-1 Infection.

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.).

Population Pharmacokinetic Analysis of Fluticasone Furoate/Umeclidinium/Vilanterol via a Single Inhaler in Patients with COPD.

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).

Pharmacokinetic Comparison of a Unit Dose Dry Powder Inhaler with a Multidose Dry Powder Inhaler for Delivery of Fluticasone Furoate.

BACKGROUND: 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. AIM: This study compared the systemic exposure of fluticasone furoate after delivery from the UD-DPI with that from the ELLIPTA® inhaler. METHODS: This 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 [AUC0-6] and maximum plasma concentration [Cmax]. RESULTS: After single-dose administration of fluticasone furoate, systemic exposure was lower from all UD-DPI formulations versus the ELLIPTA inhaler in terms of both AUC0-6 [AUC0-6 geometric least squares mean (GLM) ratios confidence interval (90% CI) for: UD-DPI (400 µg 0.8% blend)/ELLIPTA: 0.61 (0.55-0.67) and Cmax GLM (90% CI) for: UD-DPI (400 µg 0.8% blend)/ELLIPTA: 0.56 (0.49-0.64)]. Systemic exposures were ∼10% lower for fluticasone furoate UD-DPI for the 0.8% blend versus the 0.6% blend [GLM ratio (90% CI); 0.90 (0.81-1.00) for AUC0-6 and 0.89 (0.77-1.01) for Cmax], and increasing doses of fluticasone furoate from the UD-DPI showed systemic exposures that were approximately dose proportional. All treatments were well tolerated. CONCLUSIONS: Fluticasone 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.