Bentracimab for Ticagrelor Reversal in Patients Undergoing Urgent Surgery.

BACKGROUND: Ticagrelor is a reversible oral P2Y12 platelet inhibitor used to treat patients with acute coronary syndromes, prior myocardial infarction, high-risk coronary artery disease, transient ischemic attack, or ischemic stroke. A healthy volunteer study showed that the intravenous monoclonal antibody bentracimab rapidly reverses ticagrelor, but the effect in patients was unknown. METHODS: In a prespecified interim analysis of a single-arm, prospective study, bentracimab was evaluated in ticagrelor-treated patients who required urgent surgery or had major hemorrhage. The extent of reversal was determined using the VerifyNow P2Y12 assay. Clinical hemostasis was assessed by central adjudication using validated criteria. Treatment-emergent safety events were evaluated. The trial is ongoing and will enroll approximately 200 patients with evaluable data. RESULTS: Of 150 enrolled patients, 142 required urgent surgery and 8 had major hemorrhage. For the end-point analysis, 129 patients had analyzable platelet data; 122 had data on adjudicated hemostasis. Bentracimab provided a rapid reversal of ticagrelor's antiplatelet effects within 5 to 10 minutes. The reversal was sustained for more than 24 hours, as measured with the VerifyNow P2Y12 and vasodilator-stimulated phosphoprotein phosphorylation assays (P<0.001, with both assays and in all subgroups). Adjudicated hemostasis was achieved for more than 90% of patients (P<0.001); approximately 5% of patients had thrombotic events. No allergic or infusion-related reactions were reported. CONCLUSIONS: Bentracimab provided immediate and sustained reversal of the antiplatelet effects of ticagrelor in patients undergoing surgical procedures. (Funded by PhaseBio Pharmaceuticals, Inc.; ClinicalTrials.gov number, NCT04286438.)

Efficacy of Reslizumab Treatment in Exacerbation-Prone Patients with Severe Eosinophilic Asthma.

BACKGROUND: Patients with severe eosinophilic asthma have increased risk of clinical asthma exacerbations (CAEs), impaired lung function, and lower quality of life (QoL) compared with patients with noneosinophilic asthma. The efficacy and safety of intravenous reslizumab have been demonstrated in 2 duplicate, randomized, double-blind, placebo-controlled, phase 3 studies. OBJECTIVE: We present findings from post hoc analyses of the subgroup of patients from the phase 3 studies with severe (Global Initiative for Asthma [GINA] Step 4 or 5) eosinophilic asthma who had ≥2 or ≥3 CAEs in the 12 months before screening. METHODS: Patients aged ≥12 years with severe eosinophilic asthma were randomized (1:1) to reslizumab 3.0 mg/kg or placebo every 4 weeks for 1 year. Outcomes assessed included CAEs, forced expiratory volume in 1 second (FEV1), and Asthma Control Questionnaire 6 (ACQ-6) and Asthma QoL Questionnaire (AQLQ) scores. RESULTS: Of 953 patients randomized, 318 (reslizumab: n = 156; placebo: n = 162) and 164 (reslizumab: n = 72; placebo: n = 92) were GINA 4/5 with ≥2 CAEs in the prior year and ≥3 CAEs in the prior year, respectively. Reslizumab significantly improved CAE rate, time to first CAE, and the proportion of patients who experienced ≥1 CAE versus placebo in both CAE subgroups. Improvements in FEV1, ACQ-6 and AQLQ scores, and systemic corticosteroid burden were also observed with reslizumab versus placebo after 52 weeks of treatment in both CAE subgroups. CONCLUSION: Reslizumab reduced CAE frequency and improved lung function, asthma control, and QoL versus placebo in patients with severe eosinophilic asthma with a high CAE rate before treatment.

In patients with severe asthma with eosinophilia in reslizumab clinical trials, high peripheral blood eosinophil levels are associated with low FEV1 reversibility.

BACKGROUND: A post hoc analysis of two randomized, placebo-controlled, Phase 3 trials of intravenous reslizumab, an anti-interleukin-5 (IL-5) biologic for severe eosinophilic asthma. METHODS: Relationships between baseline blood eosinophil levels (EOS), forced expiratory volume in 1 s (FEV1) reversibility to ß2-agonists and treatment outcomes were assessed. RESULTS: Mean baseline FEV1 reversibility was numerically lower among patients with high (≥ 400 cells/µL) versus low baseline EOS. Reslizumab produced clinically significant improvement in FEV1, exacerbation rates and patient-reported outcomes after 52 weeks, including in patients with high EOS and low FEV1 reversibility (≤ 14%) to ß2-agonists at baseline. CONCLUSIONS: Clinical trial eligibility criteria stipulating minimum FEV1 reversibility to ß2-agonists of ≥ 12% might exclude patients who would benefit from treatment with anti-IL-5 biologics.

Effect of fixed-dose subcutaneous reslizumab on asthma exacerbations in patients with severe uncontrolled asthma and corticosteroid sparing in patients with oral corticosteroid-dependent asthma: results from two phase 3, randomised, double-blind, placebo-controlled trials.

BACKGROUND: Reslizumab 3 mg/kg administered intravenously is approved for the treatment of severe eosinophilic asthma. We assessed the safety and efficacy of subcutaneous reslizumab 110 mg in two trials in patients with uncontrolled severe asthma and increased blood eosinophils. The aim was to establish whether subcutaneous reslizumab 110 mg can reduce exacerbation rates in these patients (study 1) or reduce maintenance oral corticosteroid dose in patients with corticosteroid-dependent asthma (study 2). METHODS: Both studies were randomised, double-blind, placebo-controlled, phase 3 studies. Entry criteria for study 1 were uncontrolled severe asthma, two or more asthma exacerbations in the previous year, a blood eosinophil count of 300 cells per µL or more (including no more than 30% patients with an eosinophil count <400 cells/µL), and at least a medium dose of inhaled corticosteroids with one or more additional asthma controllers. Patients in study 2 had severe asthma, a blood eosinophil count of 300 cells per µL or more, daily maintenance oral corticosteroid (prednisone 5-40 mg, or equivalent), and high-dose inhaled corticosteroids plus another controller. Patients were randomly assigned (1:1) to subcutaneous reslizumab (110 mg) or placebo once every 4 weeks for 52 weeks in study 1 and 24 weeks in study 2. Patients and investigators were masked to treatment assignment. Primary efficacy outcomes were frequency of exacerbations during 52 weeks in study 1 and categorised percentage reduction in daily oral corticosteroid dose from baseline to weeks 20-24 in study 2. Primary efficacy analyses were by intention to treat, and safety analyses included all patients who received at least one dose of study treatment. These studies are registered with ClinicalTrials.gov, NCT02452190 (study 1) and NCT02501629 (study 2). FINDINGS: Between Aug 12, 2015, and Jan 31, 2018, 468 patients in study 1 were randomly assigned to placebo (n=232) or subcutaneous reslizumab (n=236), and 177 in study 2 to placebo (n=89) or subcutaneous reslizumab (n=88). In study 1, we found no significant difference in the exacerbation rate between reslizumab and placebo in the intention-to-treat population (rate ratio 0·79, 95% CI 0·56-1·12; p=0·19). Subcutaneous reslizumab reduced exacerbation frequency compared with placebo in the subgroup of patients with blood eosinophil counts of 400 cells per µL or more (0·64, 95% CI 0·43-0·95). Greater reductions in annual exacerbation risk (p=0·0035) and longer time to first exacerbation were observed for patients with higher trough serum reslizumab concentrations. In study 2, we found no difference between placebo and fixed-dose subcutaneous reslizumab in categorised percentage reduction in daily oral corticosteroid dose (odds ratio for a lower category of oral corticosteroid use in the reslizumab group vs the placebo group, 1·23, 95% CI 0·70-2·16; p=0·47). The frequency of adverse events and serious adverse events with reslizumab were similar to those with placebo in both studies. INTERPRETATION: Fixed-dose (110 mg) subcutaneous reslizumab was not effective in reducing exacerbation frequency in patients with uncontrolled asthma and increased blood eosinophils (≥300 cells/µL), or in reducing the daily maintenance oral corticosteroid dose in patients with oral corticosteroid-dependent severe eosinophilic asthma. Higher exposures than those observed with 110 mg subcutaneous reslizumab are required to achieve maximal efficacy. FUNDING: Teva Branded Pharmaceutical Products R&D.

Efficacy of Intravenous Reslizumab in Oral Corticosteroid-Dependent Asthma.

BACKGROUND: Reslizumab displays efficacy in patients with inadequately controlled eosinophilic asthma; previous reports in oral corticosteroid-dependent asthma are limited. OBJECTIVE: To assess efficacy of reslizumab in oral corticosteroid-dependent patients and benefits on oral corticosteroid burden. METHODS: We report post hoc analyses of pooled data from duplicate, placebo-controlled phase 3 trials. Patients aged 12 to 75 years with inadequately controlled, moderate-to-severe asthma were randomized 1:1 to receive intravenous reslizumab 3.0 mg/kg or placebo every 4 weeks for 52 weeks, stratified by oral corticosteroid use at enrollment and by region. Assessments included efficacy and predictors of clinical asthma exacerbation response in oral corticosteroid-dependent patients, and systemic corticosteroids burden in the overall population. RESULTS: Patients were randomized to reslizumab (n = 477) or placebo (n = 476); 73 (15%) patients in each group were taking oral corticosteroids at baseline. Reslizumab was favored over placebo for all efficacy end points in oral corticosteroid-dependent patients, with numerically greater improvements in oral corticosteroid-dependent patients than the overall population. Having 2 or more versus 1 clinical asthma exacerbation in the previous 12 months was the strongest positive predictor of reduced exacerbation risk with reslizumab (risk reduction, 77.5% vs 15.2%; P ≤ .02). Significantly fewer new systemic corticosteroid prescriptions were issued per patient receiving reslizumab versus placebo (mean ± SD, 0.5 ± 1.07 vs 1.0 ± 1.52; P < .0001). Total and per-patient systemic corticosteroid burdens were lower: 121,135 versus 290,977 mg and 254 versus 611 mg/patient, respectively (both P < .0001). CONCLUSIONS: Oral corticosteroid-dependent patients benefited from reslizumab across asthma efficacy outcome measures. Reslizumab-treated patients required fewer new systemic corticosteroid prescriptions and had a lower systemic corticosteroid burden compared with placebo.

Relationship between handheld and clinic-based spirometry measurements in asthma patients receiving beclomethasone.

INTRODUCTION: Handheld spirometers for home use by patients allow longitudinal spirometry data to be collected daily and may overcome some of the limitations of in-clinic spirometry (long intervals between measurements, results can be affected by site-based coaching and patient's asthma status during a given visit). OBJECTIVES: To determine the relationship between spirometry values measured by clinic-based and handheld spirometers during a clinical trial. METHODS: A post hoc correlation analysis of data from a 6-week phase 3 study of beclomethasone dipropionate (BDP; delivered by breath-actuated inhaler: BAI) versus placebo in patients aged ≥12 years with persistent asthma. During the study, forced expiratory volume in 1 s (FEV1) was assessed by both office-based spirometry at Weeks 2, 4 and 6, and daily by handheld spirometer as a secondary study endpoint. RESULTS: There was a high correlation between FEV1 values measured at home and in-clinic (overall correlation coefficient = 0.8393, R = 0.81921, 0.85927, 0.85369 and 0.83734 for BAI 320 µg/day, BAI 640 µg/day, BDP metered dose inhaler 320 µg/day and placebo treatment groups, respectively), with the scatterplot showing an upward trend for all treatment groups. Nearly all patients achieved home FEV1 values close to clinic FEV1 values, with very few outliers. CONCLUSIONS: Clinic-based and handheld spirometry demonstrated comparable treatment effects relative to placebo, suggesting that home spirometry could be used to help patients monitor their asthma severity. Daily measurement of FEV1 provides more comprehensive data than can be achieved through clinic visits, and may lead to a new approach to clinical trial design.

Effect of Peanut Ball and Position Changes in Women Laboring With an Epidural.

OBJECTIVE: To examine the effect of a nurse-driven intervention using a peanut ball (PB) with position changes on length of labor and incidence of cesarean birth among women who receive epidural anesthesia. DESIGN: Quasiexperimental comparison group design. SETTING/LOCAL PROBLEM: A 407-bed, nonprofit, Magnet-designated, Baby-Friendly Hospital Initiative-designated hospital with 8 labor and delivery suites and an average of 100 births per month. PARTICIPANTS: A total of 343 participants were included, with 164 women in the PB group. INTERVENTION/MEASUREMENTS: The PB was placed after epidural administration; women were repositioned a minimum of every 1 to 2 hours, and the PB was removed at second stage of labor; duration was recorded. RESULTS: Overall, women in the PB group were 50% less likely to have cesarean birth. For women with cervical dilation of 4 cm or less, rates of vaginal birth were 61% with use of the peanut ball. A multivariate analysis of outcomes was used. A multiple linear regression model showed, after adjusting for other variables, that PB placement alone did not shorten labor length (p = .4684). However, a stratified analysis indicated that for women with cervical dilation of 4 cm or less, length of the first stage of labor was affected by parity (p = .0042) and frequency of position change (p < .001). For women with cervical dilation greater than 4 cm, length of the first stage of labor was influenced by frequency of position changes (p = .0130) and effacement (p = .0050). Length of the second state of labor was affected by the frequency of position change (p = .0416). CONCLUSION: The PB may be an effective intervention to reduce the incidence of cesarean birth. Changing position frequently was associated with reduced length of first and second stages of labor.

Intravenous Calcium-/Zinc-Diethylene Triamine Penta-Acetic Acid in Patients With Presumed Gadolinium Deposition Disease: A Preliminary Report on 25 Patients.

OBJECTIVES: The aim of this study was to report the use of intravenous calcium (Ca)-/zinc (Zn)-diethylene triamine penta-acetic acid (DTPA) for the treatment of 25 symptomatic patients diagnosed with gadolinium deposition disease (GDD). MATERIALS AND METHODS: Written informed consent was obtained. Twenty-five patients (18 women; mean age, 46.8 ± 15.3 years) with a diagnosis of GDD were included. All patients had received at least 1 administration of a gadolinium (Gd)-based contrast agent. Patients received 3 treatment sessions with Ca-/Zn-DTPA, 15 with treatments spaced 1 month apart, and 10 with treatments spaced 1 week apart. In all cases, every treatment consisted of an application of Ca-DTPA and Zn-DTPA separated by 24 hours. Measurements of 24-hour urine Gd content before dosing and on the first and second days of therapy were performed. Symptomatic improvement of patients was determined by use of a 10-point scale of patient symptoms. Serum electrolytes were quantified. RESULTS: Gadolinium content increased in the urine, with an overall mean of 30.3-fold increase in the monthly regimen (P < 0.001) and 12.9-fold in the weekly regimen (P < 0.001). Eleven patients experienced transient worsening of at least some of their symptoms, termed a "flare-up" phenomenon, in most of whom symptoms improved or receded. Overall, symptoms improved in 13 patients, unchanged in 10, and worse in 2. Significant clinical improvement was present for headache, brain fog, and bone pain for the monthly regimen and arm pain and leg pain for the weekly regimen. There were no significant changes in major serum electrolytes. CONCLUSIONS: Three courses of intravenous Ca-/Zn-DTPA therapy results in significantly increased urine content of Gd after treatment and moderate symptomatic improvement.

Randomized trial to assess the efficacy and safety of beclomethasone dipropionate breath-actuated inhaler in patients with asthma.

BACKGROUND: Breath-actuated inhalers (BAI) eliminate the need for the hand-breath coordination required with standard metered-dose inhalers (MDI). OBJECTIVE: To evaluate the efficacy and safety of beclomethasone dipropionate (BDP) administered via BAI. METHODS: This 6-week, phase III, double-blind study included patients aged ≥12 years with persistent asthma. During the single-blind run-in, patients discontinued asthma medications and received twice-daily placebo BAI or MDI. At randomization, BAI patients received BDP BAI 320 µg/day, BDP BAI 640 µg/day, or placebo BAI, and MDI patients received BDP MDI 320 µg/day or placebo MDI. Assessments included standardized baseline-adjusted trough morning forced expiratory volume in 1 second (FEV1) area under the effect curve from 0 to 6 weeks (AUEC[0-6 wk]) (obtained by clinic-based spirometry; the primary end point), morning peak expiratory flow (PEF), trough daily morning FEV1 (obtained by handheld spirometry), withdrawals, and tolerability. RESULTS: Of 425 patients randomized, most were white (81%) and female (61%). BDP BAI 320 and 640 µg/day significantly improved FEV1 AUEC(0-6 wk) versus placebo (p < 0.001). The BDP BAI treatment groups exhibited significantly improved morning PEF and daily morning FEV1 versus placebo (p < 0.001). Similar treatment effects were demonstrated for BDP MDI (p < 0.001). Fewer patients withdrew due to worsening asthma while taking BDP BAI 320 µg/day (n = 1), BDP BAI 640 µg/day (n = 0), and BDP MDI 320 µg/day (n = 1) versus placebo (n = 10). BDP BAI was well tolerated. CONCLUSION: BDP BAI demonstrated significant improvements in pulmonary function versus placebo, with results similar to BDP MDI. The safety profile of BDP BAI was comparable to BDP MDI, with no new safety signals.The study was registered on ClinicalTrials.gov (NCT02513160), www.clinicaltrials.gov.

Efficacy and safety of beclomethasone dipropionate breath-actuated or metered-dose inhaler in pediatric patients with asthma.

BACKGROUND: Breath-actuated inhalers (BAI) eliminate the need for hand-breath coordination and, therefore, simplify the delivery of inhaled medication. OBJECTIVE: To evaluate the efficacy and safety of beclomethasone dipropionate BAI and metered-dose inhaler (MDI) versus placebo in pediatric patients ages 4-11 years with persistent asthma. METHODS: In this double-blind, double-dummy, phase III study, 628 children with persistent asthma were randomly assigned (1:1:1:1:1) to twice-daily beclomethasone dipropionate (BAI 80 µg/day, BAI 160 µg/day, MDI 80 µg/day, or MDI 160 µg/day) or to placebo. Efficacy over 12 weeks was assessed by spirometry, peak expiratory flow (PEF) measurements and other clinical end points. The primary efficacy end point was the baseline-adjusted trough morning percent predicted forced expiratory volume in 1 second (PPFEV1) area under the effect curve from 0 to 12 weeks (AUEC[0-12 weeks]). RESULTS: PPFEV1 AUEC(0-12 weeks) showed numerical improvements from baseline in the BAI 80 µg/day and BAI 160 µg/day groups and MDI 80 µg/day and MDI 160 µg/day groups; however, these improvements were not significant versus placebo for any group after hierarchical testing was applied. Consistent improvements were noted in the active treatment groups versus placebo for the weekly average trough morning and evening PEFs, and with BAI 80 µg/day versus placebo for rescue albuterol/salbutamol use and the total daily asthma symptom score. Most patients indicated that the BAI device was easy or very easy to use. Adverse events were comparable across the groups; the incidence of oral candidiasis ranged from 0.8 to 3.2%. CONCLUSIONS: Although the primary efficacy end point was not demonstrated, consistent improvements in PEF and other clinical end points were observed with beclomethasone dipropionate BAI, particularly at the 80 µg/day dose. These clinical benefits, combined with the need for better symptom control in children with asthma, supported the development of beclomethasone dipropionate BAI.

Bioequivalence of Alendronate and Vitamin D3 in a Combination Tablet Versus Corresponding-Dose Individual Tablets in Healthy Taiwanese Volunteers, Determined Using a Novel Plasma Alendronate Assay.

OBJECTIVE: This study was designed to demonstrate that alendronate (ALN)/vitamin D3 combination tablets (ALN/D5600) are bioequivalent to corresponding doses of ALN and vitamin D3 as individual tablets in healthy Taiwanese volunteers. METHODS: In this open-label, randomized, 2-period, crossover study, 68 volunteers were randomized to a single ALN/D5600 combination tablet or corresponding doses of 70 mg ALN + 5600 IU vitamin D3 (2 × 2800 IU), followed by a 12-day washout period and administration of the alternate formulation. Plasma ALN levels were measured using a newly developed assay. Geometric mean ratios of ALN AUC0-last, AUC0-∞, and Cmax, and unadjusted vitamin D3 AUC0-80h and Cmax were compared and considered bioequivalent if the 90% CI was within 0.8 to 1.25. RESULTS: The geometric mean ratios were: AUC0-last, 1.084 (90% CI, 0.937-1.253); AUC0-∞, 1.081 (90% CI, 0.935-1.249); and Cmax, 1.112 (90% CI, 0.959-1.289) for ALN, and AUC0-80h 0.953 (90% CI, 0.827-1.098) and Cmax, 0.982 (90% CI, 0.854-1.130) for vitamin D3 unadjusted for endogenous levels. CONCLUSIONS: The combination tablet was considered bioequivalent to coadministration based on ALN AUC0-∞ and unadjusted vitamin D3 parameters. Slight differences for ALN AUC0-last and Cmax (upper 90% CIs outside the bounds) were not considered clinically significant. The combination tablet was well tolerated. No serious adverse experiences were reported. © 2015. The Authors. Published by Elsevier Inc. All rights reserved.

Small changes produce large gains in efficiency: a case study from Ross Memorial Hospital.

Healthcare is now more challenged to provide excellent care, while also increasing efficiency with more limited resources. The recent introduction of Ontario's funding reform challenges hospitals to increase the efficiency of specific procedures by providing funding based on patient volumes. The cataract surgery program at Ross Memorial Hospital, in Lindsay, Ontario, is an example of how a program designed a few years ago with a focus on patient care and efficiency managed to become substantially more efficient by introducing a series of small changes.

Quantifying monocyte infiltration in response to intradermal tetanus toxoid injection.

AIMS: To characterize monocyte response in a delayed-type hypersensitivity reaction to intradermal tetanus toxoid (TT) injection. MATERIALS & METHODS: Men with positive serum anti-tetanus titers were stratified by last TT vaccination. Subjects were administered three intradermal injections of TT and one saline control on the same side of the back. Skin biopsies were taken post-injection. After 2 weeks, the procedure was repeated on the contralateral side. RESULTS: Men who received TT booster vaccination 1 month before the study showed greater reproducibility and lower variability in monocyte responses than those who were not revaccinated. Monocyte concentration in subjects re-vaccinated within 1 month of study start appeared maximal at 48 h post-injection. CONCLUSION: This assay represents a novel approach that allows for quantification of dermal monocyte/macrophage influx. This clinical methodology has potential utility in the pharmacodynamic evaluation of therapies targeting inflammatory disorders, which involve monocyte tissue recruitment, like the delayed-type hypersensitivity response.

Single- and multiple-dose pharmacokinetics and tolerability of telcagepant, an oral calcitonin gene-related peptide receptor antagonist, in adults.

Telcagepant is a novel, orally active, and selective calcitonin gene-related peptide receptor antagonist being developed for acute treatment of migraine with and without aura. Three separate clinical studies were conducted to evaluate the pharmacokinetics and tolerability of telcagepant following single oral doses in healthy young and elderly men and women and multiple oral doses in men. Telcagepant was rapidly absorbed with a time to maximum concentration of approximately 1.5 hours. The terminal half-life was approximately 6 hours. A greater than dose-proportional increase was observed in the area under the plasma concentration versus time curve from zero to infinity. Following twice-daily dosing, with each dose separated by 2 hours, steady state was achieved in approximately 3 to 4 days with an accumulation ratio of approximately 2. There were no clinically meaningful pharmacokinetic differences when compared across age and gender. Telcagepant was generally well tolerated up to single doses of 1200 mg and multiple doses of 400 mg twice daily.

Inhibition of capsaicin-induced increase in dermal blood flow by the oral CGRP receptor antagonist, telcagepant (MK-0974).

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Calcitonin gene-related peptide (CGRP) was first described as a potent vasodilator. * CGRP is also increasingly recognized as a key player in the pathophysiology of migraine, and CGRP receptor antagonists potentially offer a new approach for treating migraine. * A novel pharmacodynamic assay to measure CGRP receptor antagonist activity non-invasively in humans has been developed, which involves measuring the increase in dermal blood flow induced by topical application of capsaicin on the forearm. WHAT THIS STUDY ADDS: * This study shows that the novel oral CGRP receptor antagonist, telcagepant, inhibits the increases in dermal blood flow induced by the topical application of capsaicin on the human forearm. * This experimental medicine model may have utility to assist in dose selection for the development of CGRP receptor antagonists. AIMS: To evaluate inhibition of capsaicin-induced increase in dermal blood flow (DBF) following telcagepant (MK-0974), a potent and selective orally bioavailable calcitonin gene-related peptide (CGRP) receptor antagonist being developed for the acute treatment of migraine. METHODS: A three-period crossover study in 12 healthy adult men. Each subject received a single oral dose of telcagepant 300 mg, telcagepant 800 mg or placebo at 0 h, followed 0.5 and 3.5 h later by two topical doses of 300 and 1000 microg capsaicin per 20 microl water-ethanol mixture. Capsaicin was applied at two sites on the volar surface of the subjects' left and right forearms. DBF was assessed by laser Doppler perfusion imaging immediately before ('baseline'), and 0.5 h after each capsaicin application at 1 and 4 h. Plasma samples to determine telcagepant concentrations were collected immediately after laser Doppler perfusion imaging. A pharmacodynamic model was developed to explore the relationship between plasma concentration and inhibition of capsaicin-induced increase in DBF. RESULTS: Geometric mean plasma concentrations after dosing with 300 mg and 800 mg telcagepant were 720 and 1146 nm, respectively, at 1 h, vs. 582 and 2548 nm, respectively, at 4 h. The pharmacodynamic model suggested that the EC(90) for telcagepant inhibition of capsaicin-induced increases in DBF was 909 nm. CONCLUSIONS: Telcagepant inhibits the increases in DBF induced by the topical application of capsaicin on the human forearm. This experimental medicine model may have utility to assist in dose selection for the development of CGRP receptor antagonists.

A thorough QTc study to assess the effect of sitagliptin, a DPP4 inhibitor, on ventricular repolarization in healthy subjects.

A randomized, double-blind, placebo-controlled, 4-period crossover study was performed with a single oral dose of sitagliptin (100 mg, 800 mg), moxifloxacin (400 mg), and placebo in order to provide a rigorous assessment of the effect of sitagliptin on ventricular repolarization based on the ICH E14 guidance. The clinical dose of sitagliptin 100 mg was not associated with an increase in QTc interval, corrected using the Fridericia correction (QTcf), at any time point. The supratherapeutic 800-mg dose of sitagliptin was generally well tolerated and was associated with minimal, clinically insignificant prolongation of the QTcf interval at concentrations approximately 11-fold higher than maximal concentrations following the 100-mg clinical dose. The PK/QTc model demonstrated a shallow relationship between the plasma concentration of sitagliptin and the placebo-subtracted QTcf change from baseline, with a 0.59-millisecond increase in QTc for every 1000-nM increment in sitagliptin plasma concentration. The sensitivity of the assay to detect modest increases in QTc interval was established with the active control moxifloxacin. In conclusion, at clinically relevant concentrations, sitagliptin is not associated with clinically meaningful QTcf prolongation.

Safety, pharmacokinetics, and pharmacodynamics of single doses of LXR-623, a novel liver X-receptor agonist, in healthy participants.

Liver X-receptor (LXR) agonists have been postulated to enhance reverse cholesterol transport (RCT), a process believed to shuttle cholesterol from the periphery back to the liver. Enhancing RCT via the upregulation of cholesterol transporters such as the adenosine triphosphate-binding cassettes ABCA1 and ABCG1 could therefore inhibit the progression of atherosclerosis. LXR-623 is a synthetic ligand for LXRs alpha and beta that has shown promise in animal models of atherosclerosis. The authors present results from a single ascending-dose study of the safety, pharmacokinetics, and pharmacodynamics of LXR-623 in healthy participants. LXR-623 was absorbed rapidly with peak concentrations (C(max)) achieved at approximately 2 hours. The C(max) and area under the concentration-time curve increased in a dose-proportional manner. The mean terminal disposition half-life was between 41 and 43 hours independently of dose. LXR activation resulted in a dose-dependent increase in ABCA1 and ABCG1 expression. The effect of LXR-623 concentration on ABCA1 and ABCG1 expression was further characterized via a population pharmacokinetic-pharmacodynamic analysis, yielding EC(50) estimates of 526 ng/mL and 729 ng/mL, respectively. Central nervous system-related adverse events were observed at the 2 top doses tested. The pharmacodynamic effects described here are the first demonstration of "target engagement" by an LXR agonist in humans.

Predicting tobacco sales in community pharmacies using population demographics and pharmacy type.

OBJECTIVE: To determine whether the population demographics of the location of pharmacies were associated with tobacco sales in pharmacies, when controlling for pharmacy type. DESIGN: Retrospective analysis. SETTING: Iowa. PARTICIPANTS: All retailers in Iowa that obtained tobacco licenses and all pharmacies registered with the Iowa Board of Pharmacy in 2003. MAIN OUTCOME MEASURE AND INTERVENTIONS: Percentage of pharmacies selling tobacco (examined by pharmacy type using chi-square analysis); median income and distribution of race/ethnicity in the county for pharmacies that did or did not sell tobacco (t tests); predictors of whether a pharmacy sold tobacco (logistic regression using the independent variables county-level demographic variables and pharmacy characteristics). RESULTS: County gender composition, race/ethnicity make-up, and income levels were different for tobacco-selling and -nonselling pharmacies. Logistic regression showed that whether a pharmacy sold tobacco was strongly dependent on the type of pharmacy; compared with independent pharmacies (of which only 5% sold tobacco products), chain pharmacies were 34 times more likely to sell tobacco products, mass merchandiser outlets were 47 times more likely to stock these goods, and grocery stores were 378 times more likely to do so. Pharmacies selling tobacco were more likely to be located in counties with significantly higher numbers of multiracial groups. CONCLUSION: The best predictor of whether an Iowa pharmacy sells tobacco products is type of pharmacy. In multivariable analyses, population demographics of the county in which pharmacies were located were generally not predictive of whether a pharmacy sold tobacco.

Pharmacokinetics of aprepitant after single and multiple oral doses in healthy volunteers.

Aprepitant is the first NK1 receptor antagonist approved for use with corticosteroids and 5HT3 receptor antagonists to prevent chemotherapy-induced nausea and vomiting (CINV). The effective dose to prevent CINV is a 125-mg capsule on day 1 followed by an 80-mg capsule on days 2 and 3. Study 1 evaluated the bioavailability of the capsules and estimated the effect of food. The mean (95% confidence interval [CI]) bioavailabilities of 125-mg and 80-mg final market composition (FMC) capsules, as assessed by simultaneous administration of stable isotope-labeled intravenous (i.v.) aprepitant (2 mg) and FMC capsules, were 0.59 (0.53, 0.65) and 0.67 (0.62, 0.73), respectively. The geometric mean (90% CI) area under the plasma concentration time curve (AUC) ratios (fed/fasted) were 1.2 (1.10, 1.30) and 1.09 (1.00, 1.18) for the 125-mg and 80-mg capsule, respectively, demonstrating that aprepitant can be administered independently of food. Study 2 defined the pharmacokinetics of aprepitant administered following the 3-day regimen recommended to prevent CINV (125 mg/80 mg/80 mg). Consistent daily plasma exposures of aprepitant were obtained following this regimen, which was generally well tolerated.

Effect of impaired renal function and haemodialysis on the pharmacokinetics of aprepitant.

BACKGROUND: The neurokinin NK(1)-receptor antagonist aprepitant has demonstrated efficacy in preventing highly emetogenic chemotherapy-induced nausea and vomiting. OBJECTIVE: The objective of the present study was to investigate the effects of impaired renal function on the pharmacokinetics and safety of aprepitant. SUBJECTS AND METHODS: A total of 32 patients and healthy subjects were evaluated in this open-label, two-part study. Pharmacokinetic parameters after a single oral dose of aprepitant 240 mg were measured in eight patients with end-stage renal disease (ESRD) requiring haemodialysis, eight patients with severe renal insufficiency (SRI [24-hour creatinine clearance <30 mL/min/1.73 m(2)]) and 16 healthy and age-, sex- and weight-matched subjects (controls). RESULTS: In ESRD patients, the area under the plasma concentration-time curve (AUC) from 0 to 48 hours (AUC(48)) for aprepitant was on average approximately 36% lower than that observed in control subjects (ratio [ESRD patients/healthy controls] of geometric means = 0.64), but the 90% confidence interval 0.52, 0.78 for the ratio of true mean AUC(48) fell within the predefined target interval of 0.5, 2.0. Also in ESRD patients, there was no statistically or clinically significant difference in unbound aprepitant AUC (which may be more clinically relevant than total aprepitant AUC) when compared with healthy control subjects. Aprepitant pharmacokinetic parameters in ESRD patients were clinically similar when haemodialysis was initiated at 4 hours or 48 hours after aprepitant administration. In SRI patients, the ratio (SRI patients/healthy controls) of aprepitant AUC from zero to infinity (AUC(infinity)) geometric mean value was 0.79 with a 90% confidence interval of 0.56, 1.10. On average, in SRI patients the principal aprepitant pharmacokinetic parameters (AUC(infinity), initial maximum plasma concentration [C(max)], time to initial C(max), and apparent elimination half-life) were not statistically different from those obtained in healthy control subjects. Aprepitant was generally well tolerated in both ESRD and SRI patients. CONCLUSION: The results of this study demonstrate that ESRD, haemodialysis and SRI have no clinically meaningful effect on aprepitant pharmacokinetics. Therefore, no dosage adjustment of aprepitant is warranted in SRI or ESRD patients.