Subcutaneous mepolizumab in children aged 6 to 11 years with severe eosinophilic asthma.

Objectives: There are no published reports for anti-interleukin-5 therapy in children <12 years with asthma. The primary objective of this study was to characterize the pharmacokinetics and pharmacodynamics of mepolizumab following subcutaneous (SC) administration in children 6 to 11 years-of-age with severe eosinophilic asthma.

Hypothesis: Mepolizumab SC pharmacokinetics and pharmacodynamics in children with severe eosinophilic asthma are comparable with adults.

Anti-inflammatory duration of action of fluticasone furoate/vilanterol trifenatate in asthma: a cross-over randomised controlled trial.

Background: Fluticasone furoate/Vilanterol trifenatate (FF/VI) is an inhaled corticosteroid/long-acting beta-agonist combination with a prolonged bronchodilator duration of action. We characterised the time-course of onset and offset of airway anti-inflammatory action of FF/VI, as assessed by fraction of exhaled nitric oxide (FeNO), and compared this to the bronchodilator duration of action.

Methods: A single-centre, randomised, double-blind, placebo-controlled, two-period, crossover study was undertaken in 28 steroid-naïve adults with asthma.

Randomised, double-blind, placebo-controlled, cross-over single dose study of the bronchodilator duration of action of combination fluticasone furoate/vilanterol inhaler in adult asthma.

Background: Fluticasone furoate (FF)/vilanterol (VI) is a once-daily maintenance treatment for asthma and chronic obstructive pulmonary disease. The duration of bronchodilation beyond 24 h has not been determined previously.

Methods: Adults aged 18-65 (n = 32), with asthma and reversibility to salbutamol (≥15% and ≥200 mL increase in forced expiratory volume in 1 s [FEV]) participated in a double-blind, placebo-controlled, crossover study.

The efficacy of fluticasone furoate administered in the morning or evening is comparable in patients with persistent asthma.

Background: The inhaled corticosteroid fluticasone furoate (FF) is efficacious as a once-daily treatment for the management of asthma. Asthma is associated with circadian changes, with worsening lung function at night. We compared the efficacy of once-daily FF in the morning or evening for the treatment of asthma.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Vilanterol, a Novel Inhaled Long-Acting β-Agonist, in Children Aged 5-11 Years with Persistent Asthma: A Randomized Trial.

This multi-center, randomized, double-blind, placebo-controlled, two-way crossover study was designed to characterize the safety, tolerability, pharmacokinetic, and pharmacodynamic profile of single and once-daily repeat doses of vilanterol 25 µg in children aged 5-11 years. Twenty-eight children with persistent asthma received a single inhaled dose of vilanterol 25 µg or placebo via the ELLIPTA™ dry powder inhaler (DPI) on Day 1, followed 7 days later by once-daily treatment for 7 days. Nine (33%) subjects reported adverse events (AEs) with vilanterol 25 µg and 6 (23%) with placebo.

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

Study Objective: To investigate the pharmacodynamic and pharmacokinetic profiles of fluticasone furoate (FF)/vilanterol (VI) - a fixed-dose combination of an inhaled corticosteroid (ICS) and a long-acting β2 -agonist for the treatment of asthma and chronic obstructive pulmonary disease - after single and repeat administration in healthy Chinese subjects.

Design: Double-blind, placebo-controlled, single-site, randomized, four-way crossover study.

Setting: The Clinical Pharmacological Research Centre at Peking Union Medical College Hospital [PUMCH]) in Beijing, China.

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

Purpose: To investigate the potential for systemic pharmacokinetic (PK) and pharmacodynamic (PD) interactions between inhaled fluticasone furoate (FF) and vilanterol (VI) when delivered simultaneously via the ELLIPTA™ dry powder inhaler (DPI).

Methods: Randomized, double-blind, placebo-controlled, crossover study. Healthy subjects (n = 16) received single doses of FF (800 mcg), VI (100 mcg), FF/VI (800/100 mcg), and placebo.

Tolerability of fluticasone furoate/vilanterol combination therapy in children aged 5 to 11 years with persistent asthma.

Background: Asthma is a chronic disease afflicting millions of children worldwide. Short-acting β2-agonist reliever medications and inhaled corticosteroid (ICS) maintenance therapies are effective treatments; however, many children remain uncontrolled with short-acting β2-agonist and ICS treatment, in which case guidelines recommend adding a long-acting β2-agonist.

Objective: We sought to investigate the safety profile, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of the long-acting β2-agonist vilanterol (VI) combined with the ICS fluticasone furoate (FF) administered via the ELLIPTA dry powder inhaler (GlaxoSmithKline, London, United Kingdom) in children aged 5 to 11 years with persistent asthma.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of fluticasone furoate, a novel inhaled corticosteroid, in children aged 5-11 years with persistent asthma: A randomized trial.

This multi-center, randomized, double-blind, placebo-controlled, two-way crossover study characterized the safety, tolerability, pharmacokinetics, and pharmacodynamics of fluticasone furoate (FF) in children (5-11 years) with persistent asthma. Twenty-seven children received inhaled FF 100 µg or placebo via the ELLIPTA™ dry powder inhaler once daily for 14 days, with a ≥7 day washout period. Adverse events (AEs) were reported by eight (31%) and four (16%) subjects during FF 100 µg and placebo treatment, respectively.

The efficacy of once-daily fluticasone furoate/vilanterol in asthma is comparable with morning or evening dosing.

Aim: To investigate the effect of time of day of dosing (morning or evening) on lung function following administration of fluticasone furoate (FF)/vilanterol (VI) 100/25 mcg.

Methods: Double-blind, placebo-controlled, randomised, three-way crossover study. Subjects with persistent asthma (N = 26) received FF/VI (morning or evening) or matching placebo once-daily for 14 (± 2 days) via dry powder inhaler (DPI).

Pharmacokinetics and pharmacodynamics of intravenous and inhaled fluticasone furoate in healthy Caucasian and East Asian subjects.

Aim: The aim of the study was to evaluate the pharmacokinetics (PK) of inhaled and intravenous (i.v.) fluticasone furoate (FF) in healthy Caucasian, Chinese, Japanese and Korean subjects.

A repeat-dose thorough QT study of inhaled fluticasone furoate/vilanterol combination in healthy subjects.

Aims: This study was designed as a thorough QT (TQT) study to evaluate the effects of fluticasone furoate (FF)/vilanterol (VI) in healthy subjects. Supportive data from a TQT study conducted with FF are also presented.

Methods: This was a randomized, placebo- and positive-controlled, double-dummy, double-blind, four-way crossover study, in which healthy subjects (n = 85) were randomized to 7 days of once-daily treatment of FF/VI (200/25 or 800/100 μg) or placebo or single-dose oral moxifloxacin (single-blind, 400 mg).

The safety, pharmacokinetics and pharmacodynamics of a combination of fluticasone furoate and vilanterol in healthy Japanese subjects.

Objective: To evaluate the safety, pharmacokinetics and pharmacodynamics of fluticasone furoate (FF) and vilanterol (VI) administered alone or in combination in three Phase I studies in healthy Japanese male subjects.

Materials: FF, VI and FF/VI inhalation powder in a novel dry powder inhaler (nDPI).

Methods: Study A: 48 subjects received the first dose on Day 1, followed by a 4-day washout and once-daily (OD) repeat doses of FF 200, 400 or 800 μg or placebo from Day 5 to Day 11 (7 days).

Vilanterol trifenatate, a novel inhaled long-acting beta2 adrenoceptor agonist, is well tolerated in healthy subjects and demonstrates prolonged bronchodilation in subjects with asthma and COPD.

Vilanterol (VI; GW642444M) is a novel inhaled long-acting β2-agonist with inherent 24 h activity in vitro in development as a combination with the inhaled corticosteroid fluticasone furoate for both COPD and asthma. These studies were conducted to determine the safety, tolerability, pharmacodynamics and pharmacokinetics of VI in healthy subjects and subjects with mild to moderate persistent asthma and moderate to severe COPD. Single doses of VI (25-100 μg) were given once daily to subjects with asthma and COPD and repeat doses once daily for 14 days to healthy subjects.

Influence of renal and hepatic impairment on the pharmacokinetic and pharmacodynamic properties and tolerability of fluticasone furoate and vilanterol in combination.

Background: Renal and hepatic disease may lead to alterations in drug absorption, distribution, and elimination, and, therefore, the potential effect of renal and hepatic impairment should be investigated in drugs under development.

Objective: To assess the effects of renal and hepatic impairment on the pharmacokinetic and pharmacodynamic properties and tolerability of fluticasone furoate/vilanterol (FF/VI) administered in combination.

Methods: Two open-label, parallel-group studies were conducted.

The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of inhaled fluticasone furoate and vilanterol trifenatate in healthy subjects.

Aim: To investigate the effects of the cytochrome P450 3A4 (CYP3A4) inhibitor ketoconazole on the pharmacokinetics (PK) and pharmacodynamics of fluticasone furoate (FF) and vilanterol trifenatate (VI).

Methods: Two double-blind, randomized, placebo-controlled, two-way crossover studies in healthy subjects. In study 1, subjects received single doses of ketoconazole (400 mg) or placebo on days 1-6, with a single dose of inhaled VI (25 μg) on day 5.

Metabolism and disposition of vilanterol, a long-acting β(2)-adrenoceptor agonist for inhalation use in humans.

The metabolism and disposition of vilanterol, a novel long-acting β(2)-adrenoceptor agonist (LABA) for inhalation use, was investigated after oral administration in humans. Single oral administrations of up to 500 μg of vilanterol were shown to be safe and well tolerated in two clinical studies in healthy men. In a human radiolabel study, six healthy men received a single oral dose of 200 μg of [(14)C]vilanterol (74 kBq).

Comparison of the efficacy of salmeterol/fluticasone propionate combination in Japanese and Caucasian asthmatics.

Introduction: The effect of ethnicity on the efficacy of salmeterol (S)+fluticasone propionate (FP) has not been examined in Japanese and Caucasian asthmatics. In this study, the efficacy of combination treatment with S and FP from a single inhaler (SFC) was compared with concurrent treatment with S and FP administration from separate inhalers (S+FP) in Japanese and Caucasian asthmatics.

Methods: This was a randomised, double-blind, crossover study in male and female Japanese (n=18) and Caucasian (n=17) asthmatics (50-100% predicted FEV(1); >35% reversibility in sGaw).

Comparison of the systemic pharmacodynamic effects and pharmacokinetics of salmeterol delivered by CFC propellant and non-CFC propellant metered dose inhalers in healthy subjects.

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.

Duration of effect of single-dose inhaled fluticasone propionate on AMP-induced bronchoconstriction.

Airway hyperresponsiveness induced by adenosine-5'-monophosphate (AMP) is regarded as a reliable model for allergic asthma and for the evaluation of anti-asthmatic drugs. Single-dose inhaled corticosteroids (ICS) are known to be protective in this model, but the duration of action of these drugs in this model has never been studied. The duration of ICS protection was determined by administration of single-dose fluticasone propionate (FP; 1,000 micrograms) up to 26 h before AMP challenge.

Pharmacokinetics of naratriptan in adolescent subjects with a history of migraine.

Naratriptan is a novel 5-HT1 agonist developed to treat acute migraine. The study objective was to characterize the pharmacokinetics of oral naratriptan in adolescent migraine patients outside a migraine attack. Subjects received a single 2.

Oxygen supply and oxygen demand in the isolated working rabbit heart perfused with asanguineous crystalloid solution.

Study Objective: It has been suggested that oxygenation of the isolated, crystalloid perfused, Langendorff rabbit heart is inadequate and that consequent hypoxia limits mechanical performance. The isolated working rabbit heart, which has a higher oxygen requirement than the Langendorff preparation, was used to investigate the relationships between the ability of the heart to perform external work, myocardial oxygen consumption, and tissue high energy phosphate content.

Design: Hearts from adult rabbits (1.

Transient hypothermic reperfusion and postischemic recovery in isolated rat heart.

The potential benefit of transient hypothermic reperfusion of the ischemic myocardium was investigated in isolated working rat hearts (n = 6/group) subjected to 25 min of global ischemia at 37 degrees C. Hearts were reperfused in the Langendorff mode at 5, 10, 20, 30, or 37 degrees C for 10 min plus 5 min at 37 degrees C before assessment of functional recovery (working mode). Compared with normothermic reperfusion (recovery of cardiac output = 42.

Protection of the immature heart. Temperature-dependent beneficial or detrimental effects of multidose crystalloid cardioplegia in the neonatal rabbit heart.

There are conflicting reports of the detrimental or beneficial effects of hypothermic cardioplegia in the immature heart. We therefore investigated the temperature-dependence of myocardial protection and the ability of single-dose and multidose infusions of cardioplegic solution to protect the immature heart during hypothermic ischemia. Isolated, working hearts (n = 6 per group) from neonatal rabbits (aged 7 to 10 days) were perfused aerobically (37.

Age-dependent changes in the tolerance of the rabbit heart to ischemia.

Many studies in several species have demonstrated an enhanced ischemic tolerance in the immature myocardium when compared with the adult. Little is known about the rate at which these changes occur. We have compared the extent of post-ischemic recovery using isolated working hearts from rabbits of various ages (7-90 days).