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. STUDY DESIGN: Multinational, nonrandomised, open-label (NCT02377427). PATIENT SELECTION: Children 6 to 11 years-of-age with severe eosinophilic asthma (blood eosinophil count ≥150 cells/µL at screening or ≥300 cells/µL <12 months of screening) and ≥2 exacerbations in the prior year. METHODOLOGY: Children received mepolizumab SC 40 mg (bodyweight <40 kg) or 100 mg (≥40 kg) every 4 weeks for 12 weeks. RESULTS: Thirty-six children received mepolizumab (40 mg, n = 26; 100 mg, n = 10). Mepolizumab exposures were higher and apparent clearance lower than predicted based on prior existing data. Derived mepolizumab exposures normalized to mean bodyweight for the 40 mg and 100 mg dose groups were 454 µg * day/mL and 675 µg * day/mL, respectively. At week 12, blood eosinophils were reduced by 89% and 83% from baseline to 42 and 55 cells/µL, respectively. Mepolizumab was well tolerated; no new safety signals were observed compared with previous adult/adolescent studies. CONCLUSION: In children 6 to 11 years-of-age with severe eosinophilic asthma, mepolizumab SC 40 or 100 mg provided bodyweight-adjusted drug exposure within twofold of target adult exposure as well as marked reductions to blood eosinophil counts similar to adults, and although not designed to evaluate efficacy outcomes, demonstrated a positive clinical profile.

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. Participants with an FEV1 ≥ 60% predicted, reversible airway disease, and FeNO > 40 ppb received FF/VI 100/25 mcg or placebo once daily for 14 days. FeNO and peak expiratory flow were measured twice-daily during treatment and during a 21-day washout period. FEV1 was measured for five days from treatment cessation. The primary outcome measure was FeNO change from baseline ratio for 21 days following treatment cessation. RESULTS: In the 27 subjects who completed the study, median (range) baseline FeNO was 87 ppb (42-212). FF/VI 100/25 mcg reduced FeNO by day 3, ratio FF/VI versus placebo 0.72 (95% confidence interval 0.61-0.86) with the maximum reduction occurring at day 14, 0.32 (0.27-0.37). Following cessation of treatment FeNO remained suppressed for 18 days, ratio on day 18 0.77 (0.59-1.00), whereas improvements in FEV1 and peak flow were maintained for 3 to 4 days post-treatment. CONCLUSIONS: The anti-inflammatory duration of action of FF/VI is consistent with the high glucocorticoid receptor affinity and long lung retention of fluticasone furoate. The anti-inflammatory effect of FF/VI was of greater duration than its bronchodilator effect in adults with mild asthma. Funding GlaxoSmithKline (201499). TRIAL REGISTRATION: Prospectively registered on ClinicalTrials.gov registry number NCT02712047 .

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 [FEV1]) participated in a double-blind, placebo-controlled, crossover study. Patients were admitted to a clinical trials unit for 72 h, and inhaled, in random order, placebo or FF/VI 100/25 mcg via ELLIPTA dry powder inhaler on two occasions 7-14 days apart. FEV1 was measured at baseline, 15 and 30 min, 1, 2, 4, 12, 24, 36, 48, 60, and 72 h. The differences in change in FEV1 from baseline between treatments and corresponding two-sided 95% confidence intervals (CI) were calculated at each time point. FINDINGS: FF/VI produced a rapid onset of bronchodilation (adjusted mean difference in change from baseline in FEV1 versus placebo at 15 min, 252 mL [95% CI 182-322]). Maximum bronchodilation was observed at 12 h (adjusted mean difference in the change from baseline in FEV1, 383 mL [95% CI 285-481]). Bronchodilation was maintained throughout the 72-h assessment period (adjusted mean difference in the change in FEV1 from baseline at 72 h, 108 mL (95% CI 15-200]). FF/VI was well tolerated and no serious side effects were reported. INTERPRETATION: A single dose of FF/VI 100/25 mcg showed evidence of a 72-h bronchodilator duration of action in adults with asthma.

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

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

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

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

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 ß2-agonist reliever medications and inhaled corticosteroid (ICS) maintenance therapies are effective treatments; however, many children remain uncontrolled with short-acting ß2-agonist and ICS treatment, in which case guidelines recommend adding a long-acting ß2-agonist. OBJECTIVE: We sought to investigate the safety profile, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of the long-acting ß2-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. METHODS: In this randomized, double-blind, repeated-dose, 2-way crossover study, data from 8- to 11-year-old children with asthma were reviewed before those from 5- to 7-year-old children with asthma. Patients received once-daily FF/VI, 100/25 µg, or FF, 100 µg, in the morning for 14 days, followed by a ≥7-day washout period before switching to the other treatment for 14 days; the study duration was ≤11 weeks. Primary end points were adverse events (AEs), clinical laboratory measurements, peak expiratory flow, maximum heart rate, blood pressure, and electrocardiographic parameters. Secondary end points comprised PK (AUC0-4, Cmax) and PD (serum potassium [0-4 hours], serum cortisol [0-12 hours], and glucose [0-4 hours]) parameters on day 14. RESULTS: Twenty-six children were randomized (58% boys; mean age, 8.1 years). No clinically significant changes in the primary end points were observed. Five patients reported 4 and 2 AEs with FF/VI and FF therapy, respectively. After FF/VI or FF treatment, the geometric mean ratios (90% CIs) for FF AUC0-4 (1.02 [0.86-1.22]) and FF Cmax (0.98 [0.65-1.48]) were similar. For serum glucose (0-4 hours) concentration, a difference of 0.50 mM (95% CI, 0.19-0.82 mM) was observed for FF/VI versus FF; no differences were observed for other PD parameters. No AEs were judged to be serious or treatment related. The PK profile of FF did not seem to be altered by VI and was not affected by age or sex. The significance of an increased serum glucose level is difficult to judge as measurements were taken from nonfasted patients. Results can be compared only with active treatment, and the ability to generalize is limited by the small number of patients in this single-center study. CONCLUSIONS: Once-daily repeated dosing of FF/VI, 100/25 µg, using the ELLIPTA dry powder inhaler was as well tolerated as FF, 100 µg, in this small, selected population of 5- to 11-year-old, mostly white/caucasian children 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. Headache was reported by three subjects during FF 100 µg treatment and by no subjects during placebo treatment, all other AEs were reported by only one subject on either treatment; there were no serious AEs. Following repeat dosing, the arithmetic mean (SD) FF Cmax was 26.71 pg/mL (9.16) at 31 minutes post-dose. Arithmetic mean (SD) FF AUC(0-t) was 121.44 pg h/mL (83.04). Arithmetic mean values for weighted mean (SD) serum cortisol (0-12 hours) on day 14 were 56.49 (16.51) and 67.57 (20.66) ng/mL for FF 100 µg and placebo, respectively. No clinically significant effect of FF on serum cortisol levels was observed. FF was well tolerated. Pharmacokinetic profiles were well defined and did not differ between age groups in the study population, and no clinically significant suppression of serum cortisol was observed.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Vilanterol, a Novel Inhaled Long-Acting ß-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. No serious or drug-related AEs were reported; 3 subjects experienced upper respiratory tract infection (URTI) with vilanterol 25 µg versus none with placebo. Similar pharmacokinetic profiles of vilanterol 25 µg were observed irrespective of age or gender. No clinically relevant changes in heart rate, Fridericia's correction (QTcF), maximum glucose or minimum potassium parameters were observed during treatment with vilanterol 25 µg compared with placebo treatment. Vilanterol was well-tolerated and no long-acting ß2-agonist (LABA)-mediated AEs were observed. The pharmacokinetic profile of vilanterol 25 µg suggests exposure is similar regardless of age or gender in a pediatric population aged 5-11 years.

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). In the supportive TQT study, subjects (n = 40) were randomized to single-dose inhaled FF (4000 µg), oral moxifloxacin (400 mg) or placebo. RESULTS: There was a lack of effect of FF/VI (200/25 µg) on QTcF (Fridericia's correction); all time-matched mean differences from baseline relative to placebo (0-24 h) were <5 ms, with upper 90% confidence intervals (CI) of <10 ms. At 800/100 µg, FF/VI had no significant clinical effect on QTcF except at 30 min postdose when the 90% CI was >10 ms [mean (90% CI), 9.6 ms (7.2, 12.0)]. No effect on QTci (individually corrected) was observed at either strength of FF/VI, with mean time-matched treatment differences <5 ms at all time points [upper 90% CIs <10 ms (0-24 h)]. Assay sensitivity was confirmed; moxifloxacin prolonged QTcF and QTci, with time-matched mean differences from baseline relative to placebo of >10 ms (1-8 h postdose). CONCLUSIONS: Repeat once-daily dosing of FF/VI (200/25 µg), which is the highest therapeutic strength used in phase III studies, is not associated with QTc prolongation in healthy subjects. Supratherapeutic strength FF/VI (800/100 µg) demonstrated a small transient effect on QTcF but not on QTci.

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. METHOD: This was an open label, randomized, two way crossover study in healthy Caucasian, Chinese, Japanese and Korean subjects (n = 20 per group). Inhaled FF (200 µg for 7 days, then 800 µg for 7 days from a dry powder inhaler [DPI]) was administered in one treatment period and i.v.FF (250 µg infusion) in the other. FF PK and serum cortisol (inhaled 200 µg only) were compared between the ethnic groups using analysis of variance. P450 CYP3A4 activity and safety were also assessed. RESULTS: Ethnic differences in i.v. FF PK were accounted for by body weight differences. CYP3A4 activity was similar across the groups. Higher FF systemic exposure was seen following inhaled dosing in Chinese, Japanese and Korean subjects compared with Caucasian subjects. Absolute bioavailability was greater (36%-55%) in all East Asian groups than for Caucasian subjects following inhaled FF 800 µg. Deconvolution analysis suggested inhaled FF resided in the lung of East Asian subjects longer than for Caucasians (time for 90% to be absorbed [t90]: 29.1-30.8 h vs. 21.4 h). In vitro simulation method predicted comparable delivered lung dose across ethnic groups. Serum cortisol weighted mean was similar between Caucasians and Chinese or Koreans, while in Japanese was on average 22% lower than in Caucasians. All FF treatments were safe and well tolerated. CONCLUSION: Modestly higher (<50%) FF systemic exposure seen in East Asian subjects following inhaled dosing was not associated with a clinically significant effect on serum cortisol, suggesting that a clinical dose adjustment in East Asian subjects is not required.

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). Weighted mean (0-24h) and pre-treatment FEV1 (morning and evening) were determined after the Day 14 evening dose, together with mean pre-treatment (morning and evening) peak expiratory flow (PEF) on Days 2-12. RESULTS: FF/VI 100/25 administered morning or evening produced clinically significant increases in weighted mean FEV1: the differences [95% confidence interval (CI)] from placebo were 377 mL [293, 462] and 422 mL [337, 507], respectively; the difference between morning and evening dosing was -44 mL [-125, 36]. Day 14 pre-treatment morning FEV1 differences [95% CI] from placebo were 403 mL [272, 533] and 496 mL [369, 624] after morning and evening dosing, respectively; the morning:evening treatment difference was -94 mL [-221, 34]. Pre-treatment evening FEV1 differences [95% CI] from placebo were 275 mL [169, 380] and 309 mL [205, 413] after morning and evening dosing, respectively; the morning:evening treatment difference was -34 mL [-138, 70]. FF/VI (morning or evening) produced rapid increases in PEF with the full effect apparent after the first dose and maintained throughout the 14-day treatment period. CONCLUSION: FF/VI 100/25 produces comparable improvements in lung function whether dosed in the morning or evening in subjects with persistent asthma.

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). Study B: 32 subjects received repeat doses of VI (12.5, 25 µg) OD for 7 days. Study C: 16 subjects received single doses of FF (800 µg), VI (50 µg), FF/VI (800/50 µg) and placebo. RESULTS: Overall, there were no safety concerns and no major differences were found in treatment-related adverse events when FF and VI were administered alone or in combination. Peak plasma concentration of FF and VI following repeat dosing was up to two times higher compared with the single dose. Individual pharmacokinetic parameters of FF and VI differed when co-administered but the differences from monotherapy were not clinically significant. Repeat dosing of FF affected weighted mean (0 - 24 hours) serum cortisol with FF 200, 400 and 800 µg resulting in respective reductions from placebo of 32%, 38% and 97%, respectively. Mean maximum heart rate (0 - 4 hours) was comparable between placebo, VI 12.5 and 25 µg over 7 days of dosing; for single dosing of FF/VI 800/50 and VI 50 µg, heart rate was comparable (70 and 73 bpm, respectively) and this was higher than FF 800 µg (66 bpm) or placebo (64 bpm), but the difference was not clinically significant. CONCLUSIONS: In healthy Japanese subjects, no safety concerns were found following repeat dosing of FF and VI or single dosing of FF, VI and FF/VI. Systemic exposure to FF and VI increased in a dose-dependent manner. Serum cortisol level was suppressed by 97% after 7 days repeat administration of FF at a dose of 800 µg. Heart rate with a single dose of VI 50 µg was higher than that of placebo, though not to a clinically significant extent.

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

The metabolism and disposition of vilanterol, a novel long-acting ß(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). Plasma, urine, and feces were collected up to 168 hours after the dose and were analyzed for vilanterol, metabolites, and radioactivity. At least 50% of the radioactive dose was orally absorbed. The primary route of excretion of drug-related material was via O-dealkylation to metabolites, which were mainly excreted in urine. Vilanterol represented a very small percentage (<0.5%) of the total drug-related material in plasma, indicative of extensive first-pass metabolism. Circulating metabolites resulted mainly from O-dealkylation and exhibited negligible pharmacologic activity. The therapeutic dose level for vilanterol is 25 µg by the inhalation route. At this low-dose level, the likelihood of pharmacologically inactive metabolites causing unexpected toxicity is negligible. In addition to providing an assessment of the disposition of vilanterol in human, this work highlights a number of complexities associated with determining human absorption, distribution, metabolism, and excretion (ADME) for inhaled molecules--mainly related to the low chemical doses and complications associated with the inhalation route of administration.

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. Pharmacodynamic and PK data were obtained up to 48 h following the VI dose. In study 2, subjects received once daily ketoconazole (400 mg) or placebo for 11 days, with FF/VI (200/25 µg) for the final 7 days. Pharmacodynamic and PK data were obtained up to 48 h following the day 11 dose. RESULTS: In study 1, there was no effect of co-administration of ketoconazole and VI on pharmacodynamic or PK parameters. In study 2, co-administration of ketoconazole and FF/VI had no effect on 0-4 h maximal heart rate or minimal blood potassium {treatment difference [90% confidence interval (CI)] -0.6 beats min(-1) (-5.8, 4.5) and 0.04 mmol l(-1) (-0.03, 0.11), respectively}, whilst there was a 27% decrease in 24 h weighted mean serum cortisol [treatment ratio (90% CI) 0.73 (0.62, 0.86)]. Co-administration of ketoconazole increased [percentage change (90% CI)] FF area under the curve (0-24) and maximal plasma concentration by 36% (16, 59) and 33% (12, 58), respectively, and VI area under the curve (0-t') and maximal plasma concentration by 65% (38, 97) and 22% (8, 38), respectively. CONCLUSION: Co-administration of FF/VI or VI with ketoconazole resulted in a less than twofold increase in systemic exposure to FF and VI. There was no increase in ß-agonist systemic pharmacodynamic effects, while serum cortisol was decreased by 27%. Co-administration of FF/VI with strong CYP3A4 inhibitors has the potential to increase systemic exposure to both fluticasone furoate and vilanterol, which could lead to an increase in the potential for adverse reactions.

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 ß2-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. Adverse events (AEs), vital signs, ECGs, pharmacodynamic endpoints, FEV(1) and VI plasma pharmacokinetics (AUC, Cmax and Tmax) were determined following dosing. VI (25-100 µg) was well tolerated. The incidence and severity of AEs were comparable to placebo. Following VI administration there were no clinically significant abnormalities in vital signs, 12-lead ECG, Holter ECG, blood glucose or potassium. There were no statistically significant effects on QTc of single and repeat VI doses up to 50 µg; some differences were seen following the 100 µg VI dose after single and repeat dose in healthy subjects and single dose in asthmatic subjects. All VI doses produced increases in FEV(1) from as early as 5 min after dosing which were maintained up to 24 h post-dose in subjects with asthma and COPD. In all subjects VI was rapidly absorbed (healthy subjects median Tmax at 5 min; asthma and COPD subjects median Tmax at 10 min) with systemic exposure increasing in an approximately dose proportional manner across the VI dose range. Marginal accumulation was seen on repeat dosing. Single doses of inhaled VI in subjects with asthma and COPD and repeat doses in healthy subjects were well tolerated with no clinically significant unwanted systemic effects. VI produced a rapid and prolonged bronchodilation over 24 h suggesting the potential for once daily administration.

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. Eligible study participants included adults with severe renal impairment (CrCl <30 mL/min) and those with mild, moderate, or severe hepatic impairment (by Child-Pugh classification). Patients were matched with healthy subjects. Participants received 7 days of inhaled FF/VI 200/25 or 100/12.5 µg (severe hepatic impairment only) once daily in the morning. Lack of effect was defined as an upper 90% confidence limit of the C(max) and AUC geometric mean impaired:healthy ratios (GMRs) of <2. RESULTS: Study participants included patients with severe renal impairment (n = 9) or with mild (n = 9), moderate (n = 9), or severe (n = 8) hepatic impairment, together with matched healthy subjects (n = 9 per study). Lack of effect of severe renal impairment was demonstrated with FF (GMRs [90% CI]: C(max), 0.96 [0.57-1.61]; AUC(0-24), 0.91 [0.60-1.38]) and VI (C(max), 0.70 [0.49-1.00]; AUC(0-24), 1.56 [1.27-1.92]). Day-7 dose-normalized FF AUC(0-24) was greater in the groups with mild, moderate, and severe hepatic impairment than in healthy subjects (GMRs [90% CI]: 1.34 [0.82-2.20], 1.83 [1.11-2.99], and 1.75 [1.05-2.91], respectively); lack of effect was not demonstrated. There was no effect of hepatic impairment on dose-normalized VI C(max) or AUC(0-24). Apart from reduced serum cortisol weighted mean (0-24 hour) in patients with moderate hepatic impairment (34% reduction [90% CI, 11%-51%] compared with healthy subjects), there was no evidence of a difference in heart rate, serum potassium, or 24-hour serum cortisol between patients with severe renal impairment of any hepatic impairment and healthy subjects. No safety concerns were identified in any of the groups with impairment or their matched healthy controls. CONCLUSIONS: Severe renal impairment had no apparent clinically relevant effects on the pharmacokinetic or pharmacodynamic properties or tolerability of FF/VI. Hepatic impairment had no apparent effect on VI systemic exposure but increased FF exposure. Fluticasone furoate was associated with reduced serum cortisol in patients with moderate hepatic impairment. These data suggest that caution should be exercised when prescribing FF/VI in patients with moderate or severe hepatic impairment due to a risk for unwanted systemic corticosteroid effects associated with increased FF systemic exposure. Clinicaltrials.gov identifiers: NCT01266941 and NCT01266980.

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. 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.