- Email: [email protected]
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
Pulmonary Pharmacology & Therapeutics 26 (2013) 256e264
Contents lists available at SciVerse ScienceDirect
Pulmonary Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/ypupt
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 Rodger Kempsford*, Virginia Norris, Sarah Siederer Respiratory & Immuno-Inflammation Medicine Development Centre, GlaxoSmithKline R&D, Stevenage, Hertfordshire SG1 2NY, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history: Received 17 May 2012 Received in revised form 30 November 2012 Accepted 2 December 2012
Vilanterol (VI; GW642444M) is a novel inhaled long-acting b2-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 (25e100 mg) 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, FEV1 and VI plasma pharmacokinetics (AUC, Cmax and Tmax) were determined following dosing. VI (25e100 mg) 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 mg; some differences were seen following the 100 mg VI dose after single and repeat dose in healthy subjects and single dose in asthmatic subjects. All VI doses produced increases in FEV1 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. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: Vilanterol b2-agonist COPD Asthma Pharmacokinetics Pharmacodynamics
1. Introduction International guidelines such as those issued by the Global Initiative for Asthma [1] advocate the use of inhaled long-acting b2agonists (LABAs) in combination with inhaled corticosteroids as maintenance therapy in asthma for subjects who remain symptomatic despite low doses of inhaled corticosteroids (ICS). In patients with severe-to-very severe COPD, combining a long-acting bronchodilator with an inhaled glucocorticosteroid can improve health status by reducing exacerbation frequency [2] and long-acting inhaled bronchodilators, including LABAs, are also * Corresponding author. Tel.: þ44 1438 76 6351. E-mail address: [email protected] (R. Kempsford). 1094-5539/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pupt.2012.12.001
recommended for symptomatic management of moderate-to-very severe COPD because they are more efficacious and convenient than short-acting bronchodilators [2]. Vilanterol trifenatate inhalation powder (VI; GW642444M) is an inhaled LABA with inherent 24 h activity in vitro which is in development for once-daily administration in combination with the inhaled corticosteroid fluticasone furoate for both COPD and asthma. The currently available LABAs such as salmeterol and formoterol require twice-daily administration although a once daily LABA, Indacaterol, has recently been launched for the treatment of COPD [3]. There is a significant opportunity therefore for a oncedaily inhaled medication that can help to improve patient compliance and overall disease management by providing sustained, 24-h bronchodilation.
R. Kempsford et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 256e264
Vilanterol is a selective long-acting b2-agonist that is equipotent with salmeterol at b2 adrenoceptors and is 1000 and 400 fold more selective for b2 than b1 and b3 adrenoceptors, respectively [4]. It has a faster onset of action than salmeterol in human bronchus and guinea pig trachea preparations [5]. In addition, it has been shown in isolated human airways to have a significantly longer duration of action compared to salmeterol, with a significant bronchodilator effect still observed at 22 h [6]. Vilanterol undergoes extensive firstpass metabolism in man [7], is metabolically labile and is rapidly broken down in human microsomes into products (GW630200 and GSK932009) with 100 fold less activity at the human b2 adrenoceptor [8]. This paper presents the results from four phase I studies that were conducted to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of repeat dosing in healthy subjects and single inhaled doses of VI in subjects with persistent asthma and COPD. These studies were pivotal in providing data for the design of the phase II dose-ranging studies. 2. Methods All subjects gave written informed consent prior to any study related procedures and the protocols were approved by the appropriate institutional review boards and conducted in accordance with good clinical practice guidelines and the Declaration of Helsinki. Vilanterol was administered once daily at doses of 25 mg, 50 mg and 100 mg via the DiskusÔ inhaler as a dry powder containing lactose and magnesium stearate 1% w/w as excipients. In study B2C111401 (study 4), VI was administered by a dry powder inhaler in development [9] and also a lower dose of VI of 6.25 mg was investigated. In all studies subjects were given instructions on the use of the inhaler and underwent a practice session before the first administration of study medication using demonstration inhalers containing placebo. In two studies (2 and 3), a further treatment arm was included with a single dose of the alphaphenylcinnamate salt of vilanterol (GW642444H). As this salt form was not developed further the results are not presented here. Study 1 (protocol number B2C108784) was a parallel group repeat dose study conducted in 36 healthy subjects (9 per arm). The study design details are shown in Table 1. Healthy male subjects and female subjects of non-child bearing potential aged between 18 and 55 years with FEV1 80% predicted and FEV1/FVC ratio 70%
257
who were non-smokers were included. After the screening visit, each subject was admitted to the Unit on Day 1 and remained resident until the morning of Day 2. Subjects returned to the Unit for two further in- house periods on the evening of Day 6 until the morning of Day 8 and from the evening of Day 13 to the morning of Day 15. On Days 3e6 and 9e13 the subjects returned to the Unit each morning to be dosed and remained on the Unit until at least 1 h post dose. A follow-up visit was scheduled for approximately 7 days after treatment. Study 2 (protocol number B2C106996) was a single dose crossover study conducted in 22 asthmatic subjects. The study design details are shown in Table 1. Subjects with a history of persistent asthma aged between 18 and 70 years with a prebronchodilator FEV1 60% predicted as defined in the GINA guidelines [1] who were non-smokers or had a smoking pack history of 10 pack years with reversible airway disease, defined as an increase in FEV1 of 12.0% over baseline and an absolute change of 200 mL within 30 min following a single 400 mg salbutamol dose were included. Subjects were also required to be taking ICS at a total daily dose of 200e500 mg of fluticasone propionate or equivalent which could be continued through the study. Subjects were required to remain free of oral or inhaled LABAs, tiotropium, oral leukotriene inhibitors, inhaled sodium cromoglycate and nedocromil sodium use for 1 week, ipratropium bromide for 48 h, and short acting inhaled b2 agonists for 6 h, prior to the screening visit. Short acting inhaled beta-2 agonists were also not allowed within 6 h prior to Day 1 of each treatment period. The screening visit took place within 28 days of the first dosing occasion. For each treatment period, the subject attended the Unit on Day 1 (or early morning Day 1) and remained resident on the Unit until after the 26 h assessments had been completed. There was a washout period of between 7 and 14 days between each dose. A follow-up visit was scheduled for approximately 7 days after treatment. Study 3 (protocol number B2C110165) was a single dose crossover study conducted in 20 COPD subjects. The study design details are shown in Table 1. Subjects aged between 40 and 75 years with a clinical history of COPD defined by the ATS/ERS [10] and a post-bronchodilator FEV1 40% and <80% of predicted normal and a post-bronchodilator FEV1/FVC ratio <0.7 were included. Subjects were required to be a smoker or an ex-smoker with a smoking history of at least 10 pack years. After the screening visit, each subject attended the research unit on Day 1 (or early
Table 1 Design of studies. Study number/centres
Subjects: enrolled/completed
Study design
Treatment details e dosage and route (number of subjects treated)
Duration of treatment
B2C108784 1 UK Study 1
Healthy subjects: 36/36
Single-centre, randomised, double-blind, placebo-controlled, parallel-group, ascending dose
14 days
B2C106996 3 UK Study 2
Persistent asthmatics: 22/20
Multi-centre, randomised, double-blind, placebo-controlled, dose-ascending, 4-way crossover
B2C110165 4 Germany Study 3
COPD: 20/18
Multi-centre, randomised, double-blind, placebo-controlled, dose-ascending, incomplete block crossover Each subject received 3 of the 4 possible treatments
B2C111401 2 Australia 1 New Zealand Study 4
Persistent asthmatics 24/23
Multi-centre, randomised double-blind, placebo-controlled incomplete block crossover Each subject received placebo for one treatment period and 2 of the 3 active treatments for the remaining treatment periods.
Inhaled dry powder (Diskus/Accuhaler): VI 25 mcg once daily (9) VI 50 mcg once daily (9) VI 100 mcg once daily (9) Placebo (9) Inhaled dry powder (Diskus/Accuhaler): VI 25 mcg (21) VI 50 mcg (19) VI 100 mcg (20) Placebo (21) Inhaled dry powder (Diskus/Accuhaler): VI 25 mcg (20) VI 50 mcg (19) VI 100 mcg (8) Placebo (19) Novel dry powder inhaler: VI 6.25 mcg (15) VI 25 mcg (15) VI 100 mcg (16) Placebo (24)
Single dose
Single dose
Single dose
258
R. Kempsford et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 256e264
morning Day 1) and remained resident on the unit until the 6 h assessments had been completed. Subjects came back on Day 2 for the 23 and 24 h post dosing assessments. Each dosing visit was followed by a washout period of 7e14 days and a follow-up visit was scheduled for approximately 7 days after treatment. Subjects were not allowed to have taken oral corticosteroids for 8 weeks prior to the study, ICS at a total daily dose of 1000 mg of fluticasone propionate or equivalent for 6 weeks and tiotropium for 2 weeks prior to the study and throughout the study period. Subjects were not allowed to take oral or inhaled LABAs, oral leukotriene inhibitors, theophyllines, inhaled sodium cromoglycate and nedocromil sodium use for 48 h prior to the screening visit and ipratropium bromide and short acting inhaled b2 agonists for 6 h prior to any clinic visit. Study 4 (protocol number B2C111401) was a single dose crossover study conducted in 24 asthmatic subjects. The study design details are shown in Table 1. The study design and the patients included were the same as for study 2. Single inhaled doses of VI (formulated in lactose and magnesium stearate) were given via a new dry powder inhaler. This formulation was the same as that subsequently administered in phase II and III studies. In this study the same doses of VI were also administered in a lactose only formulation. This formulation was not developed further and as the results were similar to those for the lactose/ magnesium stearate formulation, the data has not been included in this manuscript. 2.1. Primary endpoints In studies 1, 2 and 3 the primary endpoints were adverse events (AEs), laboratory safety tests (haematology, clinical chemistry and urinalysis), vital signs and 12-lead electrocardiography (ECG). In study 4 the primary endpoint was the mean change from baseline in trough FEV1 (mean of the FEV1 values obtained 23 and 24 h after dosing). 2.2. Outcome measurements 2.2.1. Safety Adverse events, laboratory safety tests, vital signs and 12-lead ECG were measured at all clinic visits. In all studies a serious adverse event was defined as an event which results in death, is life-threatening requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or requires intervention to prevent permanent impairment or damage. Clinical laboratory tests were analysed locally by the site for each study. In study 3, 24 h Holter monitoring was also measured. 2.2.2. Pharmacodynamic endpoints In addition to the blood potassium and blood glucose measurements performed as part of the standard laboratory safety assessments, both parameters were also monitored to assess the PD effects of VI. Whole blood samples (approximately 0.5 mL) were analysed for potassium and glucose using the i-STAT1 portable chemical analyser (Abbott Laboratories, USA). In study 1, samples were taken at pre-dose, 20, 45 min, 1, 2, 3 and 4 h on inpatient Days 1e2, 7e8 and 14e15 of the study. In studies 2, 3 and 4, samples were taken at time 0, 30 min, 1, 2, 3, 4 and 24 h post dose on days 1e2 of each treatment period. The following PD endpoints were derived; the maximum value and weighted mean QTc(F), supine heart rate (HR), glucose and blood potassium over 0e4 h.
2.2.3. Pharmacokinetic assessments Blood samples (approximately 3 mL) for the determination of VI plasma concentrations and the triphenyl acetate counter-ion (GI179710) and the metabolites GW630200 and GSK932009 were collected into tubes containing EDTA. Vilanterol was extracted from human plasma by protein precipitation using acetonitrile containing an isotopically labelled internal standard. Extracts were analysed by HPLC/MS/MS using a turboionspray interface and multiple reaction monitoring by DMPK, GlaxoSmithKline UK. The lower limit of quantification (LLQ) for VI was 30 pg/mL in studies 1, 2 and 3. Assay sensitivity was further improved (LLQ 10 pg/mL) in order to aid definition of the PK profile at the low clinical doses and this revised method was used to quantitate VI concentrations in study 4. Non-compartmental PK analysis was conducted by ICON Development Solutions (Ellicott City, MD, USA) (studies 1, 2 and 3) or by Clinical Pharmacology Modelling and Simulation, CPMS, GSK GlaxoSmithKline UK (study 4). In study 1, samples were taken pre-dose, time 0, 2, 5, 10, 15, 20, 30, 45 min, 1, 2, 4, 6, 8, 10, 12 and 24 h post-dose on inpatient Days 1e2, 7e8 and 14e15 of the study. In study 2, samples were taken at the same time as study 1 on days 1e2 of each treatment period. In study 3 samples were taken pre-dose, time 0, 2, 5, 10, 15, 20, 30 min and 1, 2, 4, 6, 8, 10 and 24 h post-dose on days 1e2 of each treatment period and in study 4 at 4, 10, 20, 30, 45 min and 1, 2, 3,4, 6, 8, 10 and 24 h post-dose on days 1e2 of each treatment period. Subjects for whom a PK sample was obtained and analysed were included in the PK populations. In all studies, PK analyses of plasma VI concentration-time data were conducted using noncompartmental Model 200 (for extravascular administration) of WinNonlin (Pharsight Corporation, Mountain View, CA). Values for the following pharmacokinetic parameters were estimated following single and repeat dosing of VI (as appropriate); the maximum observed plasma concentration (Cmax), the first time to reach Cmax (tmax) and the time of the last observed plasma concentration (tlast). Where possible, the terminal plasma elimination rate-constant (lz) was estimated from log-linear regression analysis of the terminal phase of the plasma concentration time profile. The area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC(0et)), from time zero to a common quantifiable concentration (AUC(0et’)), extrapolated to infinity (AUC(0eN)) and over the time of the dosing interval, as appropriate, were calculated by a combination of linear and logarithmic trapezoidal methods. 2.2.4. Efficacy Spirometry assessments were performed in accordance with ATS/ERS guidelines [11] and the highest of three manoeuvres was recorded at each assessment. In the two studies in asthmatic subjects, FEV1 was measured at pre-dose, time 0, 5, 20, 30 min, 1, 2, 4, 6, 8, 10, 12, 16, 22, 23, 24 and 25 h post dose on days 1e2 of each treatment period. In study 3 in COPD subjects, FEV1 was measured at pre-dose, time 0, 5, 20, 30 min, 1, 2, 4, 6 and 24 h post dose on days 1e2 of each treatment period. 2.3. Statistical analysis 2.3.1. Sample size calculation No formal sample size calculations were performed for studies 1, 2 and 3. The sample sizes were limited by safety considerations at this early stage in human exposure, but the sizes were considered adequate to provide preliminary information on dose-response. For study 4, the sample size of 24 was selected in order to have 90% power to detect a difference of 200 mL in the primary endpoint (mean change from baseline (pre-dose)) in trough FEV1 (mean of the FEV1 values obtained 23 and 24 h after dosing) FEV1 between VI and placebo.
R. Kempsford et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 256e264
2.3.2. Safety No formal statistical analysis was performed on safety data. 2.3.3. Pharmacodynamics In study 1 each PD endpoint was analysed using a repeated measures model with baseline, treatment, Day, baseline by Day and treatment by Day interactions as fixed effects. Baseline was defined as the mean of any pre-dose measurements. In studies 2, 3 and 4 each PD endpoint was analysed using a mixed-effects model with treatment, period, subject-level baseline, period-level baseline as fixed effects and subject as a random effect. 2.3.4. Pharmacokinetics Derived PK parameters were summarised by treatment. In study 1, additional statistical analysis of Cmax, AUC(0et) and AUC(0et’) was performed after a log transformation of the data from days 1, 7 and 14 to evaluate the accumulation ratio. The Cmax, AUC(0et) and AUC(0et’) on days 7 and 14 after repeat dosing were compared with values on Day 1 after single dosing in order to estimate the accumulation ratio for each treatment group. A statistical assessment of steady state was made for VI on AUC(0et) and Cmax on days 1e7 and on days 7e14. The dependent parameters were logarithmically transformed prior to analysis. A preliminary assessment of dose proportionality was performed for VI on Cmax using the power model. However, dose proportionality was not assessed for AUC as there was insufficient data at 25 mg. The dependent parameter (Cmax) was logarithmically transformed prior to analysis. Where VI was not detected due to assay limitations, Cmax was imputed as ½ the lower limit of quantification (LLQ) (10 or 30 pg/ mL) and summary statistics generated for this imputation method. 2.3.5. Efficacy In study 2, data were analysed across serial timepoints (up to 25 h) using a repeated measures model. Mean FEV1 (over 23 and 24 h) was analysed using a mixed model. In studies 3 and 4, mean change from baseline in FEV1 obtained at trough (mean of 23 and 24 h) after dosing was statistically analysed using mixed-effects ANOVA modelling.
3. Results 3.1. Study population All subjects who received at least one dose of study treatment were included in the subject population. The baseline characteristics of the subjects in the four studies are summarised in Table 2.
259
3.2. Safety and tolerability In study 1, VI administered for 14 days was well tolerated in healthy subjects. A total of 37 all-causality AEs were reported during the study with a similar total incidence after VI and placebo with no evidence of a VI dose-related increase in AE incidence. The most frequently reported AEs reported by more than one subject are shown in Table 3. Only one potential b2 agonist-related AE was reported (muscle twitching after the 100 mg dose) and there were no reports of tremor or palpitations. There were no serious AEs or withdrawals and there were no clinical laboratory, vital sign or 12lead abnormalities of clinical significance or falls in FEV1 immediately after dosing. In study 2, single doses of VI (25e100 mg) were well tolerated in subjects with persistent asthma. A total of 30 all-causality AEs were reported during the study. The only AE reported by more than one subject across all treatment groups was headache (Table 3). There were no reports of tremor or palpitations and no clinically significant abnormalities in vital signs, 12-lead ECG, or Holter ECG. There were no SAEs reported but two patients were withdrawn prematurely; one patient experienced asymptomatic ventricular tachycardia (recorded in the Holter ECG) 24 h after receiving placebo and a further patient experienced an increased HR 6e12 h after receiving 25 mg VI. The increase in HR had a temporal relationship with pyrexia and the development of an upper respiratory tract infection and was considered by the Investigator to be unrelated to the study drug. In study 3, VI (25e100 mg) administered as single doses was well tolerated in subjects with COPD. A total of 5 all-causality AEs were reported during the study (Table 3). There were no AEs at the 100 mg VI dose. There were no reports of tremor or palpitations and there were no laboratory safety tests, vital signs or ECG (12-lead or 24 h Holter ECG) findings of clinical significance. There were no serious AEs or AEs that led to withdrawal. Two subjects were however withdrawn, one because they had known (clinically stable) intermittent atrial fibrillation (seen during period 1) so it was not possible to evaluate cardiovascular endpoints and the other subject was lost to follow-up. In study 4, single doses of VI (6.25e100 mg) were well tolerated in subjects with asthma. A total of 29 all-causality AEs were reported during the study. The most frequently reported AE was headache which was reported with a similar incidence following placebo and all doses of VI (Table 3). There were no reports of tremor or palpitations and no clinically significant abnormalities in vital signs, 12-lead ECG, or Holter ECG. There were no serious AEs or withdrawals due to AEs. One subject was withdrawn prematurely as the staff could not successfully obtain a blood sample.
Table 2 Demographic characteristics of subjects in each study.
Subjects randomised, N Subjects completed, N Mean age (range) Males, n (%) Mean body mass index, kg/m2 (range) Race, Caucasian, n (%) Mean FEV1 % predicted (range) Mean FEV1 % reversibility (range)
Study 1a
Study 2
Study 3
Study 4
Healthy subjects
Asthma subjects
COPD subjects
Asthma subjects
Placebo
VI 25 mcg
VI 50 mcg
VI 100 mcg
Total
Total
Total
9 9 28.1 (20e46) 9 (100) 24.9 (20.5e28.3)
9 9 26.7 (19e45) 8 (89) 23.5 (20.6e27. 9) 6 (67) ND ND
9 9 27.3 (23e32) 9 (100) 24.9 (19.3e28.4) 7 (78) ND ND
9 9 29.1 (21e53) 9 (100) 24.6 (21.7e29.2)
22 20 36.9 (21e60) 22 (100) 25.1 (19.3e29.7)
20 18 62.3 (48e75) 17 (85) 26.6 (19.2e32.9)
24 23 35.5 (18e66) 18 (75) 25.0 (19.4e29.8)
9 (100) ND ND
20 (91) 78.6 (60.2e104.3) 18.5 (11.7e34.1)
20 (100) 50.3 (27.3e76.9) ND
22 (92) 80.3 (63.9e109.9) 20.7 (12.3e40.0)
9 (100) ND ND
ND: not determined. a Study 1 was a parallel group study; all other studies were crossover studies.
260
R. Kempsford et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 256e264
Table 3 Adverse events experienced by 1 subject in any study. Study 1
Headache Throat irritation Nasopharyngitis URTI Nausea Vomiting Dysgeusia Influenza LRTI Rhinorrhoea Eczema Cough Chest discomfort Epistaxis Dizziness Urinary tract infection Ventricular extrasystoles Application site rash Constipation Hot flush Muscle twitching Diarrhoea Dyspepsia Apthous stomatitis Pharyngo-laryngeal pain Musculoskeletal pain Ear pain Abdominal pain Upper airway secretion Nasal congestion Vision blurred
Study 2
Study 3
Study 4
Plac
VI 25
VI 50
VI 100
Plac
VI 25
VI 50
VI 100
Plac
VI 25
VI 50
VI 100
Plac
VI 6.25
VI 25
VI 100
5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0
2 2 1 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1
0 1 0 2 1 1 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 1 0 1 1 1 1 0 0 0 0
0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 0 0 0 0 0 0 0 0 0 0
3 0 1 0 0 0 0 0 0 0 0 1 1 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0
4 0 0 0 1 0 0 0 0 0 0 1 0 0 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0
1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
3 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0
1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
4 0 2 0 2 1 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
3 0 0 0 0 0 0 1 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
6 0 1 0 2 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
3.3. PD derived endpoints 3.3.1. Heart rate In healthy subjects, following single doses of VI, the maximum heart rates were higher than after placebo, more notably after the 100 mg dose where the mean difference was 15 bpm (Table 4). Following single doses in subjects with asthma or COPD the increases in HR were less than in healthy subjects with no
statistically significant effects at VI doses of 6.25, 25 or 50 mg while small but statistically significant increases in maximum HR (<6 bpm) compared with placebo were seen at the 100 mg VI dose in studies 2 and 4 (Table 4). Results for repeat dosing with VI in healthy subjects (study 1) are also shown in Table 4. There were no statistically significant effects on maximum heart rate (Day 14; 0e4 h) at VI doses of 25, 50 or 100 mg: adjusted mean differences from placebo were all <3 bpm.
Table 4 Statistical analysis for derived pharmacodynamic endpoints (0e4 h). Parameter
Maximum HR (bpm)
Minimum potassium (mmol/L) Maximum glucose (mmol/L) Maximum QTc(F) (ms)
Comparison (test-reference)
6.25 mcg-placebo 25 mcg-placebo 50 mcg-placebo 100 mcg-placebo 6.25 mcg-placebo 25 mcg-placebo 50 mcg-placebo 100 mcg-placebo 6.25 mcg-placebo 25 mcg-placebo 50 mcg-placebo 100 mcg-placebo 6.25 mcg-placebo 25 mcg-placebo 50 mcg-placebo 100 mcg-placebo
Study 1a
Study 1a
Study 2
Study 3
Study 4
Healthy subject single dose
Healthy subject repeat dose
Asthma subjects single dose
COPD subjects single dose
Asthma subjects single dose
Difference in adjusted means (95% CI)
Difference in adjusted means (95% CI)
Difference in adjusted means (95% CI)
Difference in adjusted means (95% CI)
Difference in adjusted means (95% CI)
NA 9.46 (2.50, 16.43) 4.45 (2.52, 11.43) 14.85 (7.98, 21.73) NA 0.06 (0.18, 0.07) 0.11 (0.23, 0.02) 0.03 (0.16, 0.10) NA 0.15 (0.07, 0.37) 0.19 (0.04, 0.42) 0.66 (0.44, 0.89) NA 3.04 (3.92, 10.00) 5.77 (1.15, 12.69) 9.54 (2.65, 16.44)
NA 1.52 (7.60, 4.55) 2.94 (9.02, 3.14) 2.39 (3.60, 8.39) NA 0.02 (0.15, 0.11) 0.01 (0.13, 0.12) 0.00 (0.13, 0.13) NA 0.12 (0.17, 0.41) 0.05 (0.25, 0.35) 0.41 (0.12,0.70) NA 5.82 (1.93, 13.57) 4.47 (3.24, 12.18) 9.08 (1.40, 16.76)
NA 3.2 (7.2, 0.8) 2.1 (1.6, 5.8) 5.1 (1.3, 8.9) NA 0.1 (0.1, 0.2) 0.1 (0.3, 0.1) 0.0 (0.2, 0.2) NA 0.0 (0.3, 0.2) 0.3 (0.0, 0.5) 0.1 (0.2, 0.3) NA 2.3 (3.0, 7.6) 4.3 (0.5, 9.0) 9.8 (4.8, 14.7)
NA 2.07 (2.01, 6.14) 1.75 (5.68, 2.18) 0.11 (5.86, 5.63) NA 0.01 (0.11, 0.13) 0.05 (0.16, 0.06) 0.05 (0.11, 0.22) NA 0.13 (1.01, 0.75) 0.08 (0.91, 0.75) 0.25 (1.07, 1.57) NA 3.61 (11.68, 4.46) 2.79 (10.48, 4.90) 2.94 (13.97, 8.10)
0.39 (2.84, 3.61) 1.74 (1.45, 4.93) NA 5.91 (2.81, 9.01) 0.03 (0.07, 0.12) 0.03 (0.12, 0.07) NA 0.13 (0.22, 0.03) 0.02 (0.16, 0.12) 0.06 (0.08, 0.19) NA 0.23 (0.10, 0.37) 3.86 (8.56, 0.85) 0.63 (5.31, 4.05) NA 0.68 (3.91, 5.27)
NA ¼ not applicable. a Study 1 was a parallel group study; all other studies were crossover studies.
R. Kempsford et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 256e264
3.3.2. Blood potassium Following single doses there were no clinically significant effects on minimum blood potassium (0e4 h); all mean differences from placebo were less than 0.13 mmol/L (Table 4). In study 4 the minimum potassium was however statistically significantly lower than placebo for VI 100 mg. Following repeat dose VI in healthy subjects (study 1) for the minimum potassium (0e4 h; Day 14) the adjusted mean differences from placebo were all 0.02 mmol/L and the 95% CIs included zero.
261
data for healthy subjects is given in Fig. 1. There was some evidence of accumulation of VI (30%) on repeat dosing with steady-state achieved by Day 7 (Table 6). Vilanterol was rapidly absorbed into the plasma of subjects with asthma (studies 2 and 4). The rate of absorption appeared to be independent of the dose (25e100 mg or 6.25 mge100 mg) and device (Diskus vs new dry powder inhaler) with median tmax achieved 10 min post-dose in both studies (Table 5). In subjects with COPD, median tmax was achieved 10 min post-dose following the 25 and 50 mg doses. The absorption appeared slower following the 100 mg dose (median tmax 25 min) (Table 5) although caution should be taken since there were only eight subjects in the PK parameter population for the 100 mg dose group compared with 20 for the 25 mg dose group and 19 for the 50 mg dose group in this study. Plasma VI concentrations rapidly declined from peak in subjects with asthma and COPD. At the lowest dose to produce bronchodilation (25 mg), systemic exposure was generally non-quantifiable (<30 pg/mL) beyond 1 h post dose (Table 5, Figs. 2 and 3). Following higher doses (50 and 100 mg) plasma VI concentrations were generally below the LLQ of 30 pg/mL beyond 4-6 h postinhalation following administration via Diskus and below the LLQ of 10 pg/mL beyond 10 h post-inhalation after 100 mg via new dry powder inhaler. Approximately dose proportional increases in systemic exposure were observed as the VI dose was escalated from 25 to 100 mg (Table 5, Figs. 2 and 3). Systemic exposure to the triphenyl acetate counter-ion was low and the GW642444 metabolites, GW630200 and GSK932009, were below the limits of quantification at all doses.
3.3.3. Blood glucose Following single doses there were no clinically significant effects on blood glucose; where statistically significant differences from placebo were seen these were <1 mmol/L (Table 4). In study 4, the maximum and weighted mean glucose were statistically significantly greater than placebo for VI 100 mg but no differences from placebo were seen for the 6.25 mg or 25 mg VI doses. Following repeat dose VI in healthy subjects (study 1) there were no effects on Day 14 blood glucose except with 100 mg VI (adjusted mean difference in 0e4 h maximum glucose 0.41 mmol/L [95% CI:0.12, 0.70]) which was not considered to be clinically significant (Table 4). 3.3.4. QTc(F) Following single doses there were no statistically significant effects on QTcF of VI doses up to 50 mg (Table 4). Similarly there were no statistically significant effects on QTcF of repeat VI doses up to 50 mg in healthy subjects. At the 100 mg VI dose there were statistically significant differences in QTcF from placebo (mean differences <10 ms) after single and repeat dose in healthy subjects and after single dose in asthma subjects (study 2). However, there was no statistically significant difference in QTcF from placebo after single dose 100 mg VI in COPD subjects or in asthma subjects in study 4 (mean differences <1 ms; Table 4).
3.5. Efficacy 3.5.1. FEV1 In asthma and COPD subjects, in studies 2 and 3, VI produced increases in FEV1 from as early as 5 min after dosing (Table 7). There were statistically significant increases in FEV1 at all time points from 5 min to 25 h post-dose for all doses of VI (25, 50 and 100 mg compared with placebo (Figs. 4 and 5)). Mean FEV1 (difference from baseline) 23e24 h after dosing was at least 200 mL greater than placebo for all doses, indicating 24 h duration of action after a single dose. In study 4 in asthma subjects, the primary endpoint was change from baseline in trough FEV1. All doses except for 6.25 mg gave
3.4. PK derived endpoints Vilanterol was rapidly absorbed into the plasma of healthy subjects (median tmax at 5e10 min) with approximate dose proportional increases in Cmax across the dose range (Table 5). The results of the statistical analysis of Cmax using the power model was 1.02 (90% CI 0.889, 1.15). Vilanterol plasma concentration/time
Table 5 Summary of PK parameters. Study number
Dose
Day
N
AUC (0et) (pg.h/mL)a
AUC (0e1) (pg.h/mL)a
Cmax (pg/mL)
Tmax (h)b
Tlast (h)b
Study 1 (healthy subjects)
25 mcg
1 7 14 1 7 14 1 7 14 1 1 1 1 1 1 1 1 1
9 9 9 9 9 9 9 9 9 21 19 20 20 19 8 15 15 16
52 105 80.0 160 385 274 734 1040 913 70.5 143.3 440.7 56.5 222 573 5.51 76.9 734.1
e 103 (11.6) 99.0 (8.76) 168 (29.0) 204 (22.2) 174 (29.2) 369 (26.2) 364 (23.5) 357 (16.6) 64.9 (70.5) 104.9 (26.4) 208.7 (56.0) 58.0 (25.4) 106 (44.5) 196 (23.9) ND 64.7 (39.7) 317.7 (43.9)
193 248 246 452 567 509 929 932 932 95.4 204.8 344.6 78.2 151 260 23.1 89.7 417.6
0.08 0.17 0.08 0.08 0.08 0.10 0.17 0.08 0.08 0.17 0.17 0.17 0.18 0.20 0.43 0.17 0.17 0.17
0.50 (0.35, 0.77) 1.02 (0.73, 2.00) 0.75 (0.50, 2.00) 1.00 (0.75, 2.00) 4.00 (2.00, 8.00) 4.00 (0.75, 8.00) 8.00 (4.00, 23.83) 12.00 (4.00, 23.83) 10.00 (6.00, 24.00) 1.0 (0.2, 4.1) 2.00 (0.7, 4.1) 4.05 (0.8, 24.2) 0.98 (0.15, 2.07) 3.98 (0.33, 10.00) 5.98 (2.00, 10.00) 0.38 (0.1e0.8) 3.00 (0.5e6.1) 24.1 (6.0e24.1)
50 mcg
100 mcg
Study 2 (asthma)
Study 3 (COPD)
Study 4 (asthma)
25 mcg 50 mcg 100 mcg 25 mcg 50 mcg 100 mcg 6.25 mcg 25 mcg 100 mcg
(31.2) (26.6) (32.8) (29.5) (32.5) (56.0) (37.2) (47.0) (25.7) (72.8) (51.3) (127.4) (86.2) (96.5) (45.3) (70.2) (69.3) (69.0)
N represents the number of subjects in the pharmacokinetic concentration population. a Geometric mean (CV%). b Median (range).
(26.4) (20.9) (15.3) (32.8) (25.8) (44.0) (30.4) (28.3) (17.9) (114.0) (43.1) (78.9) (43.9) (53.1) (22.2) (61.3) (50.5) (50.6)
(0.08, 0.22) (0.08,0.17) (0.07, 0.17) (0.08, 0.25) (0.08, 0.17) (0.08, 0.18) (0.08, 0.22) (0.08, 0.17) (0.08, 0.18) (0.1, 1.0) (0.1, 0.3) (0.1, 1.1) (0.03, 2.00) (0.08, 1.00) (0.15, 1.03) (0.1e0.8) (0.1, 0.6) (0.1e0.6)
262
R. Kempsford et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 256e264
Fig. 1. Median vilanterol plasma concentrations following repeat dose administration of 25, 50 and 100 mcg VI. Day 1 data (n ¼ 9/group) (study 1).
Fig. 2. Median vilanterol plasma concentrations following single dose (25, 50 and 100 mcg) in asthma patients (study 2).
statistically significantly greater trough FEV1 change from baseline, compared to placebo. For the 25 mg and 100 mg doses these estimated mean differences were greater than 200 mL. Vilanterol produced a rapid onset of bronchodilation with increased FEV1 maintained over the 0e26 h post-dose period at all dose levels (Fig. 6).
studies in asthmatics [13] and subjects with COPD [14], where the incidence of events potentially indicative of a LABA-class effect were less than 3% in any treatment group indicating that VI is well tolerated at doses up to 50 mg. In asthma and COPD patients there were statistically significant increases in FEV1 at all time points from 5 min to 24 h post-dose for VI 25 mg, 50 mg and 100 mg, compared with placebo. There were no statistically significant increases in FEV1 compared with placebo after the lower VI dose of 6.25 mg in subjects with asthma suggesting that this could be considered a no-effect dose. In asthmatic patients the mean difference from baseline in FEV1 23e24 h after dosing was at least 240 mL greater than placebo for all doses, indicating a 24 h duration of action after a single dose. This improvement is greater than the average minimal patient perceivable improvement of 230 mL for FEV1 [15]. In COPD patients the mean difference from baseline in trough FEV1 23e24 h after dosing was at least 190 mL greater than placebo for all doses, which represents a clinically relevant treatment difference in COPD patients as it is greater than 100 mL [16]. Although the dosee response relationship analysis of mean FEV1 over 23 and 24 h was suggestive of a dose response, albeit of small magnitude, overlapping confidence intervals and a lack of any clear increment in FEV1 response with increasing dose suggests that all doses of VI were residing near to the top of the efficacy doseeresponse curve. Direct comparisons between treatments were not considered to be appropriate as these small studies were not powered for this. Of interest is that in subsequent phase IIb studies in asthma and COPD
4. Discussion Vilanterol is an inhaled LABA with inherent 24 h activity confirmed in many experimental models [6]. It is therefore being developed as a once-daily clinical treatment for asthma and COPD in combination with fluticasone furoate, a novel ICS also active for 24 h [12]. These four early phase studies were performed to evaluate the safety and tolerability and the pharmacokinetics and pharmacodynamics of repeat dosing of VI in healthy subjects and single inhaled doses of VI in subjects with persistent asthma and COPD. Data from these studies were pivotal in providing data for the phase II dose-ranging studies. In all the studies VI was administered as a dry powder with lactose and magnesium stearate. In three of the studies VI was administered via the DiskusÒ inhaler while in the other study (study 4) VI was administered via a Dry Powder Inhaler which is currently in development [9]. The range of VI doses examined (up to 100 mg for 14 days) included and exceeded the 50 mg dose evaluated in combination with FF in phase II dose-ranging studies [13,14]. Vilanterol was generally well tolerated by all subjects following single doses and repeat dosing for 14 days. The overall incidence of AEs was low compared with placebo and the incidence of AEs potentially indicative of LABA-class effects such as tremor, muscle twitching and palpitations was also low in these studies. These data are in agreement with the results of the 28-day dose-ranging VI
Table 6 Summary of vilanterol accumulation following repeat dosing for 14 days. Comparison
Ratio adjusted means (90% CI for ratio) AUCa
Cmax 25 mcg Day 7: Day1 50 mcg Day 7: Day 1 100 mcg Day 7: Day 1 25 mcg Day 14: Day1 50 mcg Day 14: Day 1 100 mcg Day 14: Day 1
1.29 1.25 1.00 1.27 1.13 1.00
(1.10, (1.07, (0.86, (1.09, (0.96, (0.86,
1.51) 1.47) 1.17) 1.49) 1.32) 1.17)
ND 1.20 1.07 ND 0.98 1.01
(1.06, 1.35) (0.95, 1.20) (0.86, 1.11) (0.9, 1.13)
ND: not determined (AUC too limited to assess accumulation). a AUC(0et0 ) (to common time-point) to account for LLQ censoring.
Fig. 3. Median vilanterol plasma concentrations following single dose (25, 50 and 100 mcg) in COPD patients (study 3).
R. Kempsford et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 256e264
263
Table 7 Statistical analysis of FEV1 (mL; difference from placebo) at 5 min and 23e24 h following single dose VI (25e100 mcg) in asthmatic and COPD patients. Comparison
Time post Study 2 e asthma Study 3 e COPD dose Difference in adjusted Difference in adjusted means (95% CI) means (95% CI)
25 mcg vs. placebo 50 mcg vs. placebo 100 mcg vs. placebo 25 mcg vs. placebo 50 mcg vs. placebo 100 mcg vs. placebo
5 min 5 min 5 min 23e24 h 23e24 h 23e24 h
225 203 276 273 242 321
(127, (112, (183, (178, (156, (233,
324) 293) 368) 369) 328) 410)
69 85 133 190 206 210
(8, 146) (5, 165) (25, 241) (88, 292) (100, 312) (67, 354)
the VI 25 mcg dose was shown to be optimal and that a higher dose of 50 mcg was not associated with significantly greater efficacy [13,14]. A single dose of VI administered in asthma subjects also produced a rapid, dose-dependent clinically significant bronchodilation that was maintained over the 24 h post-dose period. A clinically significant effect of VI on trough FEV1, defined as greater than 200 mL versus placebo was seen with the 25 mg and 100 mg dose of VI. The once-daily duration of action on lung function has also been demonstrated in other studies performed in asthma and COPD patients. Results from a repeat-dose study in asthmatic subjects demonstrated that once-daily treatment with VI provided bronchodilation out to 24 h, supporting once-daily dosing [13]. Similarly, in a 28-day dose-ranging clinical efficacy study in COPD, a 24-h sustained bronchodilatory effect superior to placebo was also confirmed, as shown by analysis of serial FEV1 [14]. LABA-class related systemic pharmacodynamic effects on blood glucose, blood potassium, heart rate and QTcF were monitored in all the studies. No particularly marked effects were seen on any of these parameters with no consistent doseeresponse relationships over the 6.25e100 mg VI dose range. In addition there was no evidence of increased pharmacodynamic effects with repeat dosing. Some pharmacodynamic effects were seen, particularly at the highest VI dose (100 mg), although these were not consistently produced across all the studies and populations. For example, small (<10 ms) differences from placebo in mean maximum QTcF seen after the supratherapeutic dose of 100 mg VI were seen in healthy subjects (study 1 [parallel group]; single and repeat dose) and in
Fig. 4. Mean FEV1 profile (0e24 h) following single dose VI (25, 50 and 100 mcg) and placebo in asthma patients (study 2).
Fig. 5. Mean FEV1 profile (0e24 h) following single dose VI (25, 50 and 100 mcg) and placebo in COPD patients (study 3).
subjects with asthma (study 2) were not replicated in subjects with COPD (study 3) or in other subjects with asthma (study 4). The difference between the populations was particularly evident in the subjects with COPD where no statistically significant pharmacodynamic effects were seen after any dose of VI including 100 mg. The limited size of the studies reported and the variability in the data should be considered when assessing this data. The studies were not powered or designed to definitely make conclusions about QTc. In addition in small studies clinical significance is judged at the individual level by protocol stopping criteria and no subject met the criteria for QTc. In phase IIb studies of four weeks duration VI doses up to 50 mg were not associated with significant systemic pharmacodynamic effects in subjects with either asthma or COPD [13,14]. At the proposed therapeutic dose of VI (25 mcg) it has been demonstrated that there was a lack of effect on the QTc interval as measured by either QTcF or QTci. At a four-fold multiple of the VI therapeutic dose (100 mcg) there was a small, predictable and transient effect on QTcF but not on QTci during the first hour after dosing [17]. The pharmacokinetics of VI following doses of 25, 50 and 100 mg once-daily for 14 days in healthy subjects were characterised by rapid absorption in healthy subjects and subjects with asthma and
Fig. 6. Mean FEV1 profile (0e24 h) following single dose VI (6.25, 25 and 100 mcg) and placebo in asthma patients (study 4).
264
R. Kempsford et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 256e264
COPD. The rate of absorption appeared independent of the inhaler type. Plasma concentrations of VI declined rapidly over the first 1e2 h post-dose. At the lowest dose to produce bronchodilation (25 mg), systemic exposure was generally non-quantifiable (<30 pg/mL) beyond 1 h post dose and following 50 and 100 mg, plasma VI concentrations were generally non-quantifiable beyond 4e6 h post-inhalation. Approximate dose-proportional increases in systemic exposure over the dose range 25e100 mg VI were demonstrated in both healthy subjects and asthmatic and COPD subjects. The Cmax following dosing with VI in asthmatic and COPD subjects was approximately 2-fold lower than that in healthy subjects. This is likely to account for the lesser and limited systemic pharmacodynamic effects seen in the patient groups at the higher VI doses compared with healthy subjects. Overall, there appeared to be a marginal amount of VI accumulation (<30%) in plasma following repeat dosing in healthy subjects. There was evidence for Cmax accumulation over the first 7 days of dosing following 25 mg and 50 mg VI, but no further accumulation beyond Day 7. By Day 14 there was no evidence for accumulation compared with Day 1 or for a difference between Cmax on days 7 and 14. These results suggest a marginal amount of accumulation in VI on repeat once-daily administration with steady-state conditions achieved by Day 7 of dosing. In conclusion, repeat dosing with inhaled VI (25e100 mcg) once daily for 14 days was well tolerated in healthy subjects and was not associated with any clinically significant unwanted systemic effects. Vilanterol was rapidly absorbed and showed approximately dose proportional pharmacokinetics and marginal accumulation on repeat dosing. Single doses of inhaled VI were well tolerated in patients with mild to moderate persistent asthma or moderate to severe COPD with no clinically significant unwanted systemic effects. Vilanterol produces a rapid and prolonged bronchodilation over 24 h suggesting the potential for once-daily administration in asthma and COPD. Conflict of interest None as all authors are employees of GSK, the sponsoring company. Acknowledgements The following studies funded by GSK have been incorporated into this manuscript: Protocol number B2C108784 (clinicaltrials.gov NCT00469040); protocol number B2C106996 (clinicaltrials.gov NCT00463697); protocol number B2C110165 (clinicaltrials.gov NCT00519376); protocol number B2C111401 (clinicaltrials.gov NCT00702910). All listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. All the authors are employees of GSK. The authors wish to acknowledge Nick Bird for statistical review of this manuscript.
The authors wish to acknowledge Diana Jones of Cambrian Clinical Associates Ltd for development of manuscript first draft, editorial suggestions to draft versions of this paper, assembling tables and figures, collating author comments and referencing. This assistance was funded by GSK.
References [1] Global Initiative for Asthma (GINA), National Heart Lung and Blood Institute, National Institutes of Health. GINA report. Global strategy for asthma management and prevention. Bethesda: National Institutes of Health; 2006. [2] Global Initiative for Obstructive Lung Disease (GOLD), National Heart Lung and Blood Institute, National Institutes of Health. GOLD report. Global strategy for diagnosis, management and prevention of COPD. Bethesda: National Institutes of Health; 2009. [3] Jones PW, Barnes N, Vogelmeier C, Lawrence D, Kramer B. Efficacy of indacaterol in the treatment of patients with COPD. Prim Care Respir J 2011;20: 380e8. [4] Slack R, Barrett V, Ford A, Knowles K. In vitro pharmacological characterisation of the b2-adrenoceptor binding kinetics of [3H]vilanterol, a novel long acting b2-agonist. Br J Pharmacol 2011;9(3):P008. [5] Morrison V, Sturton G, Barrett V, Ford A, Knowles A. Pharmacological characterisation of GW642444, a long-acting b2-agonist (LABA) with rapid onset and long duration, on isolated large and small human airways. Am J Respir Crit Care Med 2010;181:A4453. [6] Barrett V, Emmons A, Ford A, Knowles R. In vitro pharmacological characterization of GW64244, a novel long-acting b2-agonist (LABA) using human recombinant b1/2/3 adrenoceptor cAMP assays. Am J Respir Crit Care Med 2010;181:A4451. [7] Harrell A, Siederer S, Bal J, Kempsford R. Vilanterol, a novel inhaled longacting b2 adrenoceptor agonist (LABA), demonstrates extensive first pass clearance to metabolites with negligible pharmacological activity in man. Eur Respir J 2011;38(Suppl. 55):137s. [8] Ford A, Hughes S, Smith C, Somers G, Ranshaw L. The therapeutic index (TI) of vilanterol trifenatate. Eur Respir J 2010;36(Suppl. 54):208s. [9] Prime D, De Backer W, Hamilton M, Cahn A, Preece A, Kelleher D, et al. Comparison of inhalation profiles through a novel dry powder inhaler (nDPI) and lung function measurements for healthy subjects, asthma and chronic obstructive pulmonary disease (COPD) patients. Am J Respir Crit Care Med 2012;185. [10] Celli BR, MacNee W. ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004;23:932e46. [11] Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J 2005;26(2):319e38. [12] van den Berge M, Luijk B, Bareille P, Dallow N, Postma DS, Lammers J-WJ. Prolonged protection of the new inhaled corticosteroid fluticasone furoate against AMP hyperresponsiveness in patients with asthma. Allergy 2010; 65(12):1531e5. [13] Lötvall J, Bateman ED, Bleecker ER, Busse W, Woodcock A, Follows R, et al. Dose-related efficacy of vilanterol trifenatate (VI), a long-acting beta2 agonist (LABA) with inherent 24-hour activity, in patients with persistent asthma. Eur Respir J 2010;36(Suppl. 54):1013s. [14] Hanania NA, Feldman G, Zachgo W, Shim JJ, Crim C, Sanford L, et al. Safety of vilanterol trifenatate (VI) in a COPD dose-ranging study. Chest 2012;142: 119e27. [15] Santanello NC, Zhang J, Seidenberg B, Reiss TF, Barber BL. What are minimal important changes for asthma measures in a clinical trial? Eur Respir J 1999; 14:23e7. [16] Donohue JF. Minimal clinically important differences in COPD lung function. COPD. COPD 2005;2:111e24. [17] Kempsford R, Allen A, Kelly K, Saggu P, Crim C. A repeat dose, double-blind, placebo-controlled, thorough Qt/Qtc study to assess the cardiac safety of fluticasone furoate (FF) and vilanterol (VI) administered, 2012 of fluticasone furoate (FF) and vilanterol (VI) administered in combination. Am J Respir Crit Care Med 2012;185:A2841.
Contents lists available at SciVerse ScienceDirect
Pulmonary Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/ypupt
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 Rodger Kempsford*, Virginia Norris, Sarah Siederer Respiratory & Immuno-Inflammation Medicine Development Centre, GlaxoSmithKline R&D, Stevenage, Hertfordshire SG1 2NY, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history: Received 17 May 2012 Received in revised form 30 November 2012 Accepted 2 December 2012
Vilanterol (VI; GW642444M) is a novel inhaled long-acting b2-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 (25e100 mg) 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, FEV1 and VI plasma pharmacokinetics (AUC, Cmax and Tmax) were determined following dosing. VI (25e100 mg) 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 mg; some differences were seen following the 100 mg VI dose after single and repeat dose in healthy subjects and single dose in asthmatic subjects. All VI doses produced increases in FEV1 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. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: Vilanterol b2-agonist COPD Asthma Pharmacokinetics Pharmacodynamics
1. Introduction International guidelines such as those issued by the Global Initiative for Asthma [1] advocate the use of inhaled long-acting b2agonists (LABAs) in combination with inhaled corticosteroids as maintenance therapy in asthma for subjects who remain symptomatic despite low doses of inhaled corticosteroids (ICS). In patients with severe-to-very severe COPD, combining a long-acting bronchodilator with an inhaled glucocorticosteroid can improve health status by reducing exacerbation frequency [2] and long-acting inhaled bronchodilators, including LABAs, are also * Corresponding author. Tel.: þ44 1438 76 6351. E-mail address: [email protected] (R. Kempsford). 1094-5539/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pupt.2012.12.001
recommended for symptomatic management of moderate-to-very severe COPD because they are more efficacious and convenient than short-acting bronchodilators [2]. Vilanterol trifenatate inhalation powder (VI; GW642444M) is an inhaled LABA with inherent 24 h activity in vitro which is in development for once-daily administration in combination with the inhaled corticosteroid fluticasone furoate for both COPD and asthma. The currently available LABAs such as salmeterol and formoterol require twice-daily administration although a once daily LABA, Indacaterol, has recently been launched for the treatment of COPD [3]. There is a significant opportunity therefore for a oncedaily inhaled medication that can help to improve patient compliance and overall disease management by providing sustained, 24-h bronchodilation.
R. Kempsford et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 256e264
Vilanterol is a selective long-acting b2-agonist that is equipotent with salmeterol at b2 adrenoceptors and is 1000 and 400 fold more selective for b2 than b1 and b3 adrenoceptors, respectively [4]. It has a faster onset of action than salmeterol in human bronchus and guinea pig trachea preparations [5]. In addition, it has been shown in isolated human airways to have a significantly longer duration of action compared to salmeterol, with a significant bronchodilator effect still observed at 22 h [6]. Vilanterol undergoes extensive firstpass metabolism in man [7], is metabolically labile and is rapidly broken down in human microsomes into products (GW630200 and GSK932009) with 100 fold less activity at the human b2 adrenoceptor [8]. This paper presents the results from four phase I studies that were conducted to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of repeat dosing in healthy subjects and single inhaled doses of VI in subjects with persistent asthma and COPD. These studies were pivotal in providing data for the design of the phase II dose-ranging studies. 2. Methods All subjects gave written informed consent prior to any study related procedures and the protocols were approved by the appropriate institutional review boards and conducted in accordance with good clinical practice guidelines and the Declaration of Helsinki. Vilanterol was administered once daily at doses of 25 mg, 50 mg and 100 mg via the DiskusÔ inhaler as a dry powder containing lactose and magnesium stearate 1% w/w as excipients. In study B2C111401 (study 4), VI was administered by a dry powder inhaler in development [9] and also a lower dose of VI of 6.25 mg was investigated. In all studies subjects were given instructions on the use of the inhaler and underwent a practice session before the first administration of study medication using demonstration inhalers containing placebo. In two studies (2 and 3), a further treatment arm was included with a single dose of the alphaphenylcinnamate salt of vilanterol (GW642444H). As this salt form was not developed further the results are not presented here. Study 1 (protocol number B2C108784) was a parallel group repeat dose study conducted in 36 healthy subjects (9 per arm). The study design details are shown in Table 1. Healthy male subjects and female subjects of non-child bearing potential aged between 18 and 55 years with FEV1 80% predicted and FEV1/FVC ratio 70%
257
who were non-smokers were included. After the screening visit, each subject was admitted to the Unit on Day 1 and remained resident until the morning of Day 2. Subjects returned to the Unit for two further in- house periods on the evening of Day 6 until the morning of Day 8 and from the evening of Day 13 to the morning of Day 15. On Days 3e6 and 9e13 the subjects returned to the Unit each morning to be dosed and remained on the Unit until at least 1 h post dose. A follow-up visit was scheduled for approximately 7 days after treatment. Study 2 (protocol number B2C106996) was a single dose crossover study conducted in 22 asthmatic subjects. The study design details are shown in Table 1. Subjects with a history of persistent asthma aged between 18 and 70 years with a prebronchodilator FEV1 60% predicted as defined in the GINA guidelines [1] who were non-smokers or had a smoking pack history of 10 pack years with reversible airway disease, defined as an increase in FEV1 of 12.0% over baseline and an absolute change of 200 mL within 30 min following a single 400 mg salbutamol dose were included. Subjects were also required to be taking ICS at a total daily dose of 200e500 mg of fluticasone propionate or equivalent which could be continued through the study. Subjects were required to remain free of oral or inhaled LABAs, tiotropium, oral leukotriene inhibitors, inhaled sodium cromoglycate and nedocromil sodium use for 1 week, ipratropium bromide for 48 h, and short acting inhaled b2 agonists for 6 h, prior to the screening visit. Short acting inhaled beta-2 agonists were also not allowed within 6 h prior to Day 1 of each treatment period. The screening visit took place within 28 days of the first dosing occasion. For each treatment period, the subject attended the Unit on Day 1 (or early morning Day 1) and remained resident on the Unit until after the 26 h assessments had been completed. There was a washout period of between 7 and 14 days between each dose. A follow-up visit was scheduled for approximately 7 days after treatment. Study 3 (protocol number B2C110165) was a single dose crossover study conducted in 20 COPD subjects. The study design details are shown in Table 1. Subjects aged between 40 and 75 years with a clinical history of COPD defined by the ATS/ERS [10] and a post-bronchodilator FEV1 40% and <80% of predicted normal and a post-bronchodilator FEV1/FVC ratio <0.7 were included. Subjects were required to be a smoker or an ex-smoker with a smoking history of at least 10 pack years. After the screening visit, each subject attended the research unit on Day 1 (or early
Table 1 Design of studies. Study number/centres
Subjects: enrolled/completed
Study design
Treatment details e dosage and route (number of subjects treated)
Duration of treatment
B2C108784 1 UK Study 1
Healthy subjects: 36/36
Single-centre, randomised, double-blind, placebo-controlled, parallel-group, ascending dose
14 days
B2C106996 3 UK Study 2
Persistent asthmatics: 22/20
Multi-centre, randomised, double-blind, placebo-controlled, dose-ascending, 4-way crossover
B2C110165 4 Germany Study 3
COPD: 20/18
Multi-centre, randomised, double-blind, placebo-controlled, dose-ascending, incomplete block crossover Each subject received 3 of the 4 possible treatments
B2C111401 2 Australia 1 New Zealand Study 4
Persistent asthmatics 24/23
Multi-centre, randomised double-blind, placebo-controlled incomplete block crossover Each subject received placebo for one treatment period and 2 of the 3 active treatments for the remaining treatment periods.
Inhaled dry powder (Diskus/Accuhaler): VI 25 mcg once daily (9) VI 50 mcg once daily (9) VI 100 mcg once daily (9) Placebo (9) Inhaled dry powder (Diskus/Accuhaler): VI 25 mcg (21) VI 50 mcg (19) VI 100 mcg (20) Placebo (21) Inhaled dry powder (Diskus/Accuhaler): VI 25 mcg (20) VI 50 mcg (19) VI 100 mcg (8) Placebo (19) Novel dry powder inhaler: VI 6.25 mcg (15) VI 25 mcg (15) VI 100 mcg (16) Placebo (24)
Single dose
Single dose
Single dose
258
R. Kempsford et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 256e264
morning Day 1) and remained resident on the unit until the 6 h assessments had been completed. Subjects came back on Day 2 for the 23 and 24 h post dosing assessments. Each dosing visit was followed by a washout period of 7e14 days and a follow-up visit was scheduled for approximately 7 days after treatment. Subjects were not allowed to have taken oral corticosteroids for 8 weeks prior to the study, ICS at a total daily dose of 1000 mg of fluticasone propionate or equivalent for 6 weeks and tiotropium for 2 weeks prior to the study and throughout the study period. Subjects were not allowed to take oral or inhaled LABAs, oral leukotriene inhibitors, theophyllines, inhaled sodium cromoglycate and nedocromil sodium use for 48 h prior to the screening visit and ipratropium bromide and short acting inhaled b2 agonists for 6 h prior to any clinic visit. Study 4 (protocol number B2C111401) was a single dose crossover study conducted in 24 asthmatic subjects. The study design details are shown in Table 1. The study design and the patients included were the same as for study 2. Single inhaled doses of VI (formulated in lactose and magnesium stearate) were given via a new dry powder inhaler. This formulation was the same as that subsequently administered in phase II and III studies. In this study the same doses of VI were also administered in a lactose only formulation. This formulation was not developed further and as the results were similar to those for the lactose/ magnesium stearate formulation, the data has not been included in this manuscript. 2.1. Primary endpoints In studies 1, 2 and 3 the primary endpoints were adverse events (AEs), laboratory safety tests (haematology, clinical chemistry and urinalysis), vital signs and 12-lead electrocardiography (ECG). In study 4 the primary endpoint was the mean change from baseline in trough FEV1 (mean of the FEV1 values obtained 23 and 24 h after dosing). 2.2. Outcome measurements 2.2.1. Safety Adverse events, laboratory safety tests, vital signs and 12-lead ECG were measured at all clinic visits. In all studies a serious adverse event was defined as an event which results in death, is life-threatening requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or requires intervention to prevent permanent impairment or damage. Clinical laboratory tests were analysed locally by the site for each study. In study 3, 24 h Holter monitoring was also measured. 2.2.2. Pharmacodynamic endpoints In addition to the blood potassium and blood glucose measurements performed as part of the standard laboratory safety assessments, both parameters were also monitored to assess the PD effects of VI. Whole blood samples (approximately 0.5 mL) were analysed for potassium and glucose using the i-STAT1 portable chemical analyser (Abbott Laboratories, USA). In study 1, samples were taken at pre-dose, 20, 45 min, 1, 2, 3 and 4 h on inpatient Days 1e2, 7e8 and 14e15 of the study. In studies 2, 3 and 4, samples were taken at time 0, 30 min, 1, 2, 3, 4 and 24 h post dose on days 1e2 of each treatment period. The following PD endpoints were derived; the maximum value and weighted mean QTc(F), supine heart rate (HR), glucose and blood potassium over 0e4 h.
2.2.3. Pharmacokinetic assessments Blood samples (approximately 3 mL) for the determination of VI plasma concentrations and the triphenyl acetate counter-ion (GI179710) and the metabolites GW630200 and GSK932009 were collected into tubes containing EDTA. Vilanterol was extracted from human plasma by protein precipitation using acetonitrile containing an isotopically labelled internal standard. Extracts were analysed by HPLC/MS/MS using a turboionspray interface and multiple reaction monitoring by DMPK, GlaxoSmithKline UK. The lower limit of quantification (LLQ) for VI was 30 pg/mL in studies 1, 2 and 3. Assay sensitivity was further improved (LLQ 10 pg/mL) in order to aid definition of the PK profile at the low clinical doses and this revised method was used to quantitate VI concentrations in study 4. Non-compartmental PK analysis was conducted by ICON Development Solutions (Ellicott City, MD, USA) (studies 1, 2 and 3) or by Clinical Pharmacology Modelling and Simulation, CPMS, GSK GlaxoSmithKline UK (study 4). In study 1, samples were taken pre-dose, time 0, 2, 5, 10, 15, 20, 30, 45 min, 1, 2, 4, 6, 8, 10, 12 and 24 h post-dose on inpatient Days 1e2, 7e8 and 14e15 of the study. In study 2, samples were taken at the same time as study 1 on days 1e2 of each treatment period. In study 3 samples were taken pre-dose, time 0, 2, 5, 10, 15, 20, 30 min and 1, 2, 4, 6, 8, 10 and 24 h post-dose on days 1e2 of each treatment period and in study 4 at 4, 10, 20, 30, 45 min and 1, 2, 3,4, 6, 8, 10 and 24 h post-dose on days 1e2 of each treatment period. Subjects for whom a PK sample was obtained and analysed were included in the PK populations. In all studies, PK analyses of plasma VI concentration-time data were conducted using noncompartmental Model 200 (for extravascular administration) of WinNonlin (Pharsight Corporation, Mountain View, CA). Values for the following pharmacokinetic parameters were estimated following single and repeat dosing of VI (as appropriate); the maximum observed plasma concentration (Cmax), the first time to reach Cmax (tmax) and the time of the last observed plasma concentration (tlast). Where possible, the terminal plasma elimination rate-constant (lz) was estimated from log-linear regression analysis of the terminal phase of the plasma concentration time profile. The area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC(0et)), from time zero to a common quantifiable concentration (AUC(0et’)), extrapolated to infinity (AUC(0eN)) and over the time of the dosing interval, as appropriate, were calculated by a combination of linear and logarithmic trapezoidal methods. 2.2.4. Efficacy Spirometry assessments were performed in accordance with ATS/ERS guidelines [11] and the highest of three manoeuvres was recorded at each assessment. In the two studies in asthmatic subjects, FEV1 was measured at pre-dose, time 0, 5, 20, 30 min, 1, 2, 4, 6, 8, 10, 12, 16, 22, 23, 24 and 25 h post dose on days 1e2 of each treatment period. In study 3 in COPD subjects, FEV1 was measured at pre-dose, time 0, 5, 20, 30 min, 1, 2, 4, 6 and 24 h post dose on days 1e2 of each treatment period. 2.3. Statistical analysis 2.3.1. Sample size calculation No formal sample size calculations were performed for studies 1, 2 and 3. The sample sizes were limited by safety considerations at this early stage in human exposure, but the sizes were considered adequate to provide preliminary information on dose-response. For study 4, the sample size of 24 was selected in order to have 90% power to detect a difference of 200 mL in the primary endpoint (mean change from baseline (pre-dose)) in trough FEV1 (mean of the FEV1 values obtained 23 and 24 h after dosing) FEV1 between VI and placebo.
R. Kempsford et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 256e264
2.3.2. Safety No formal statistical analysis was performed on safety data. 2.3.3. Pharmacodynamics In study 1 each PD endpoint was analysed using a repeated measures model with baseline, treatment, Day, baseline by Day and treatment by Day interactions as fixed effects. Baseline was defined as the mean of any pre-dose measurements. In studies 2, 3 and 4 each PD endpoint was analysed using a mixed-effects model with treatment, period, subject-level baseline, period-level baseline as fixed effects and subject as a random effect. 2.3.4. Pharmacokinetics Derived PK parameters were summarised by treatment. In study 1, additional statistical analysis of Cmax, AUC(0et) and AUC(0et’) was performed after a log transformation of the data from days 1, 7 and 14 to evaluate the accumulation ratio. The Cmax, AUC(0et) and AUC(0et’) on days 7 and 14 after repeat dosing were compared with values on Day 1 after single dosing in order to estimate the accumulation ratio for each treatment group. A statistical assessment of steady state was made for VI on AUC(0et) and Cmax on days 1e7 and on days 7e14. The dependent parameters were logarithmically transformed prior to analysis. A preliminary assessment of dose proportionality was performed for VI on Cmax using the power model. However, dose proportionality was not assessed for AUC as there was insufficient data at 25 mg. The dependent parameter (Cmax) was logarithmically transformed prior to analysis. Where VI was not detected due to assay limitations, Cmax was imputed as ½ the lower limit of quantification (LLQ) (10 or 30 pg/ mL) and summary statistics generated for this imputation method. 2.3.5. Efficacy In study 2, data were analysed across serial timepoints (up to 25 h) using a repeated measures model. Mean FEV1 (over 23 and 24 h) was analysed using a mixed model. In studies 3 and 4, mean change from baseline in FEV1 obtained at trough (mean of 23 and 24 h) after dosing was statistically analysed using mixed-effects ANOVA modelling.
3. Results 3.1. Study population All subjects who received at least one dose of study treatment were included in the subject population. The baseline characteristics of the subjects in the four studies are summarised in Table 2.
259
3.2. Safety and tolerability In study 1, VI administered for 14 days was well tolerated in healthy subjects. A total of 37 all-causality AEs were reported during the study with a similar total incidence after VI and placebo with no evidence of a VI dose-related increase in AE incidence. The most frequently reported AEs reported by more than one subject are shown in Table 3. Only one potential b2 agonist-related AE was reported (muscle twitching after the 100 mg dose) and there were no reports of tremor or palpitations. There were no serious AEs or withdrawals and there were no clinical laboratory, vital sign or 12lead abnormalities of clinical significance or falls in FEV1 immediately after dosing. In study 2, single doses of VI (25e100 mg) were well tolerated in subjects with persistent asthma. A total of 30 all-causality AEs were reported during the study. The only AE reported by more than one subject across all treatment groups was headache (Table 3). There were no reports of tremor or palpitations and no clinically significant abnormalities in vital signs, 12-lead ECG, or Holter ECG. There were no SAEs reported but two patients were withdrawn prematurely; one patient experienced asymptomatic ventricular tachycardia (recorded in the Holter ECG) 24 h after receiving placebo and a further patient experienced an increased HR 6e12 h after receiving 25 mg VI. The increase in HR had a temporal relationship with pyrexia and the development of an upper respiratory tract infection and was considered by the Investigator to be unrelated to the study drug. In study 3, VI (25e100 mg) administered as single doses was well tolerated in subjects with COPD. A total of 5 all-causality AEs were reported during the study (Table 3). There were no AEs at the 100 mg VI dose. There were no reports of tremor or palpitations and there were no laboratory safety tests, vital signs or ECG (12-lead or 24 h Holter ECG) findings of clinical significance. There were no serious AEs or AEs that led to withdrawal. Two subjects were however withdrawn, one because they had known (clinically stable) intermittent atrial fibrillation (seen during period 1) so it was not possible to evaluate cardiovascular endpoints and the other subject was lost to follow-up. In study 4, single doses of VI (6.25e100 mg) were well tolerated in subjects with asthma. A total of 29 all-causality AEs were reported during the study. The most frequently reported AE was headache which was reported with a similar incidence following placebo and all doses of VI (Table 3). There were no reports of tremor or palpitations and no clinically significant abnormalities in vital signs, 12-lead ECG, or Holter ECG. There were no serious AEs or withdrawals due to AEs. One subject was withdrawn prematurely as the staff could not successfully obtain a blood sample.
Table 2 Demographic characteristics of subjects in each study.
Subjects randomised, N Subjects completed, N Mean age (range) Males, n (%) Mean body mass index, kg/m2 (range) Race, Caucasian, n (%) Mean FEV1 % predicted (range) Mean FEV1 % reversibility (range)
Study 1a
Study 2
Study 3
Study 4
Healthy subjects
Asthma subjects
COPD subjects
Asthma subjects
Placebo
VI 25 mcg
VI 50 mcg
VI 100 mcg
Total
Total
Total
9 9 28.1 (20e46) 9 (100) 24.9 (20.5e28.3)
9 9 26.7 (19e45) 8 (89) 23.5 (20.6e27. 9) 6 (67) ND ND
9 9 27.3 (23e32) 9 (100) 24.9 (19.3e28.4) 7 (78) ND ND
9 9 29.1 (21e53) 9 (100) 24.6 (21.7e29.2)
22 20 36.9 (21e60) 22 (100) 25.1 (19.3e29.7)
20 18 62.3 (48e75) 17 (85) 26.6 (19.2e32.9)
24 23 35.5 (18e66) 18 (75) 25.0 (19.4e29.8)
9 (100) ND ND
20 (91) 78.6 (60.2e104.3) 18.5 (11.7e34.1)
20 (100) 50.3 (27.3e76.9) ND
22 (92) 80.3 (63.9e109.9) 20.7 (12.3e40.0)
9 (100) ND ND
ND: not determined. a Study 1 was a parallel group study; all other studies were crossover studies.
260
R. Kempsford et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 256e264
Table 3 Adverse events experienced by 1 subject in any study. Study 1
Headache Throat irritation Nasopharyngitis URTI Nausea Vomiting Dysgeusia Influenza LRTI Rhinorrhoea Eczema Cough Chest discomfort Epistaxis Dizziness Urinary tract infection Ventricular extrasystoles Application site rash Constipation Hot flush Muscle twitching Diarrhoea Dyspepsia Apthous stomatitis Pharyngo-laryngeal pain Musculoskeletal pain Ear pain Abdominal pain Upper airway secretion Nasal congestion Vision blurred
Study 2
Study 3
Study 4
Plac
VI 25
VI 50
VI 100
Plac
VI 25
VI 50
VI 100
Plac
VI 25
VI 50
VI 100
Plac
VI 6.25
VI 25
VI 100
5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0
2 2 1 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1
0 1 0 2 1 1 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 1 0 1 1 1 1 0 0 0 0
0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 0 0 0 0 0 0 0 0 0 0
3 0 1 0 0 0 0 0 0 0 0 1 1 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0
4 0 0 0 1 0 0 0 0 0 0 1 0 0 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0
1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
3 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0
1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
4 0 2 0 2 1 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
3 0 0 0 0 0 0 1 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
6 0 1 0 2 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
3.3. PD derived endpoints 3.3.1. Heart rate In healthy subjects, following single doses of VI, the maximum heart rates were higher than after placebo, more notably after the 100 mg dose where the mean difference was 15 bpm (Table 4). Following single doses in subjects with asthma or COPD the increases in HR were less than in healthy subjects with no
statistically significant effects at VI doses of 6.25, 25 or 50 mg while small but statistically significant increases in maximum HR (<6 bpm) compared with placebo were seen at the 100 mg VI dose in studies 2 and 4 (Table 4). Results for repeat dosing with VI in healthy subjects (study 1) are also shown in Table 4. There were no statistically significant effects on maximum heart rate (Day 14; 0e4 h) at VI doses of 25, 50 or 100 mg: adjusted mean differences from placebo were all <3 bpm.
Table 4 Statistical analysis for derived pharmacodynamic endpoints (0e4 h). Parameter
Maximum HR (bpm)
Minimum potassium (mmol/L) Maximum glucose (mmol/L) Maximum QTc(F) (ms)
Comparison (test-reference)
6.25 mcg-placebo 25 mcg-placebo 50 mcg-placebo 100 mcg-placebo 6.25 mcg-placebo 25 mcg-placebo 50 mcg-placebo 100 mcg-placebo 6.25 mcg-placebo 25 mcg-placebo 50 mcg-placebo 100 mcg-placebo 6.25 mcg-placebo 25 mcg-placebo 50 mcg-placebo 100 mcg-placebo
Study 1a
Study 1a
Study 2
Study 3
Study 4
Healthy subject single dose
Healthy subject repeat dose
Asthma subjects single dose
COPD subjects single dose
Asthma subjects single dose
Difference in adjusted means (95% CI)
Difference in adjusted means (95% CI)
Difference in adjusted means (95% CI)
Difference in adjusted means (95% CI)
Difference in adjusted means (95% CI)
NA 9.46 (2.50, 16.43) 4.45 (2.52, 11.43) 14.85 (7.98, 21.73) NA 0.06 (0.18, 0.07) 0.11 (0.23, 0.02) 0.03 (0.16, 0.10) NA 0.15 (0.07, 0.37) 0.19 (0.04, 0.42) 0.66 (0.44, 0.89) NA 3.04 (3.92, 10.00) 5.77 (1.15, 12.69) 9.54 (2.65, 16.44)
NA 1.52 (7.60, 4.55) 2.94 (9.02, 3.14) 2.39 (3.60, 8.39) NA 0.02 (0.15, 0.11) 0.01 (0.13, 0.12) 0.00 (0.13, 0.13) NA 0.12 (0.17, 0.41) 0.05 (0.25, 0.35) 0.41 (0.12,0.70) NA 5.82 (1.93, 13.57) 4.47 (3.24, 12.18) 9.08 (1.40, 16.76)
NA 3.2 (7.2, 0.8) 2.1 (1.6, 5.8) 5.1 (1.3, 8.9) NA 0.1 (0.1, 0.2) 0.1 (0.3, 0.1) 0.0 (0.2, 0.2) NA 0.0 (0.3, 0.2) 0.3 (0.0, 0.5) 0.1 (0.2, 0.3) NA 2.3 (3.0, 7.6) 4.3 (0.5, 9.0) 9.8 (4.8, 14.7)
NA 2.07 (2.01, 6.14) 1.75 (5.68, 2.18) 0.11 (5.86, 5.63) NA 0.01 (0.11, 0.13) 0.05 (0.16, 0.06) 0.05 (0.11, 0.22) NA 0.13 (1.01, 0.75) 0.08 (0.91, 0.75) 0.25 (1.07, 1.57) NA 3.61 (11.68, 4.46) 2.79 (10.48, 4.90) 2.94 (13.97, 8.10)
0.39 (2.84, 3.61) 1.74 (1.45, 4.93) NA 5.91 (2.81, 9.01) 0.03 (0.07, 0.12) 0.03 (0.12, 0.07) NA 0.13 (0.22, 0.03) 0.02 (0.16, 0.12) 0.06 (0.08, 0.19) NA 0.23 (0.10, 0.37) 3.86 (8.56, 0.85) 0.63 (5.31, 4.05) NA 0.68 (3.91, 5.27)
NA ¼ not applicable. a Study 1 was a parallel group study; all other studies were crossover studies.
R. Kempsford et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 256e264
3.3.2. Blood potassium Following single doses there were no clinically significant effects on minimum blood potassium (0e4 h); all mean differences from placebo were less than 0.13 mmol/L (Table 4). In study 4 the minimum potassium was however statistically significantly lower than placebo for VI 100 mg. Following repeat dose VI in healthy subjects (study 1) for the minimum potassium (0e4 h; Day 14) the adjusted mean differences from placebo were all 0.02 mmol/L and the 95% CIs included zero.
261
data for healthy subjects is given in Fig. 1. There was some evidence of accumulation of VI (30%) on repeat dosing with steady-state achieved by Day 7 (Table 6). Vilanterol was rapidly absorbed into the plasma of subjects with asthma (studies 2 and 4). The rate of absorption appeared to be independent of the dose (25e100 mg or 6.25 mge100 mg) and device (Diskus vs new dry powder inhaler) with median tmax achieved 10 min post-dose in both studies (Table 5). In subjects with COPD, median tmax was achieved 10 min post-dose following the 25 and 50 mg doses. The absorption appeared slower following the 100 mg dose (median tmax 25 min) (Table 5) although caution should be taken since there were only eight subjects in the PK parameter population for the 100 mg dose group compared with 20 for the 25 mg dose group and 19 for the 50 mg dose group in this study. Plasma VI concentrations rapidly declined from peak in subjects with asthma and COPD. At the lowest dose to produce bronchodilation (25 mg), systemic exposure was generally non-quantifiable (<30 pg/mL) beyond 1 h post dose (Table 5, Figs. 2 and 3). Following higher doses (50 and 100 mg) plasma VI concentrations were generally below the LLQ of 30 pg/mL beyond 4-6 h postinhalation following administration via Diskus and below the LLQ of 10 pg/mL beyond 10 h post-inhalation after 100 mg via new dry powder inhaler. Approximately dose proportional increases in systemic exposure were observed as the VI dose was escalated from 25 to 100 mg (Table 5, Figs. 2 and 3). Systemic exposure to the triphenyl acetate counter-ion was low and the GW642444 metabolites, GW630200 and GSK932009, were below the limits of quantification at all doses.
3.3.3. Blood glucose Following single doses there were no clinically significant effects on blood glucose; where statistically significant differences from placebo were seen these were <1 mmol/L (Table 4). In study 4, the maximum and weighted mean glucose were statistically significantly greater than placebo for VI 100 mg but no differences from placebo were seen for the 6.25 mg or 25 mg VI doses. Following repeat dose VI in healthy subjects (study 1) there were no effects on Day 14 blood glucose except with 100 mg VI (adjusted mean difference in 0e4 h maximum glucose 0.41 mmol/L [95% CI:0.12, 0.70]) which was not considered to be clinically significant (Table 4). 3.3.4. QTc(F) Following single doses there were no statistically significant effects on QTcF of VI doses up to 50 mg (Table 4). Similarly there were no statistically significant effects on QTcF of repeat VI doses up to 50 mg in healthy subjects. At the 100 mg VI dose there were statistically significant differences in QTcF from placebo (mean differences <10 ms) after single and repeat dose in healthy subjects and after single dose in asthma subjects (study 2). However, there was no statistically significant difference in QTcF from placebo after single dose 100 mg VI in COPD subjects or in asthma subjects in study 4 (mean differences <1 ms; Table 4).
3.5. Efficacy 3.5.1. FEV1 In asthma and COPD subjects, in studies 2 and 3, VI produced increases in FEV1 from as early as 5 min after dosing (Table 7). There were statistically significant increases in FEV1 at all time points from 5 min to 25 h post-dose for all doses of VI (25, 50 and 100 mg compared with placebo (Figs. 4 and 5)). Mean FEV1 (difference from baseline) 23e24 h after dosing was at least 200 mL greater than placebo for all doses, indicating 24 h duration of action after a single dose. In study 4 in asthma subjects, the primary endpoint was change from baseline in trough FEV1. All doses except for 6.25 mg gave
3.4. PK derived endpoints Vilanterol was rapidly absorbed into the plasma of healthy subjects (median tmax at 5e10 min) with approximate dose proportional increases in Cmax across the dose range (Table 5). The results of the statistical analysis of Cmax using the power model was 1.02 (90% CI 0.889, 1.15). Vilanterol plasma concentration/time
Table 5 Summary of PK parameters. Study number
Dose
Day
N
AUC (0et) (pg.h/mL)a
AUC (0e1) (pg.h/mL)a
Cmax (pg/mL)
Tmax (h)b
Tlast (h)b
Study 1 (healthy subjects)
25 mcg
1 7 14 1 7 14 1 7 14 1 1 1 1 1 1 1 1 1
9 9 9 9 9 9 9 9 9 21 19 20 20 19 8 15 15 16
52 105 80.0 160 385 274 734 1040 913 70.5 143.3 440.7 56.5 222 573 5.51 76.9 734.1
e 103 (11.6) 99.0 (8.76) 168 (29.0) 204 (22.2) 174 (29.2) 369 (26.2) 364 (23.5) 357 (16.6) 64.9 (70.5) 104.9 (26.4) 208.7 (56.0) 58.0 (25.4) 106 (44.5) 196 (23.9) ND 64.7 (39.7) 317.7 (43.9)
193 248 246 452 567 509 929 932 932 95.4 204.8 344.6 78.2 151 260 23.1 89.7 417.6
0.08 0.17 0.08 0.08 0.08 0.10 0.17 0.08 0.08 0.17 0.17 0.17 0.18 0.20 0.43 0.17 0.17 0.17
0.50 (0.35, 0.77) 1.02 (0.73, 2.00) 0.75 (0.50, 2.00) 1.00 (0.75, 2.00) 4.00 (2.00, 8.00) 4.00 (0.75, 8.00) 8.00 (4.00, 23.83) 12.00 (4.00, 23.83) 10.00 (6.00, 24.00) 1.0 (0.2, 4.1) 2.00 (0.7, 4.1) 4.05 (0.8, 24.2) 0.98 (0.15, 2.07) 3.98 (0.33, 10.00) 5.98 (2.00, 10.00) 0.38 (0.1e0.8) 3.00 (0.5e6.1) 24.1 (6.0e24.1)
50 mcg
100 mcg
Study 2 (asthma)
Study 3 (COPD)
Study 4 (asthma)
25 mcg 50 mcg 100 mcg 25 mcg 50 mcg 100 mcg 6.25 mcg 25 mcg 100 mcg
(31.2) (26.6) (32.8) (29.5) (32.5) (56.0) (37.2) (47.0) (25.7) (72.8) (51.3) (127.4) (86.2) (96.5) (45.3) (70.2) (69.3) (69.0)
N represents the number of subjects in the pharmacokinetic concentration population. a Geometric mean (CV%). b Median (range).
(26.4) (20.9) (15.3) (32.8) (25.8) (44.0) (30.4) (28.3) (17.9) (114.0) (43.1) (78.9) (43.9) (53.1) (22.2) (61.3) (50.5) (50.6)
(0.08, 0.22) (0.08,0.17) (0.07, 0.17) (0.08, 0.25) (0.08, 0.17) (0.08, 0.18) (0.08, 0.22) (0.08, 0.17) (0.08, 0.18) (0.1, 1.0) (0.1, 0.3) (0.1, 1.1) (0.03, 2.00) (0.08, 1.00) (0.15, 1.03) (0.1e0.8) (0.1, 0.6) (0.1e0.6)
262
R. Kempsford et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 256e264
Fig. 1. Median vilanterol plasma concentrations following repeat dose administration of 25, 50 and 100 mcg VI. Day 1 data (n ¼ 9/group) (study 1).
Fig. 2. Median vilanterol plasma concentrations following single dose (25, 50 and 100 mcg) in asthma patients (study 2).
statistically significantly greater trough FEV1 change from baseline, compared to placebo. For the 25 mg and 100 mg doses these estimated mean differences were greater than 200 mL. Vilanterol produced a rapid onset of bronchodilation with increased FEV1 maintained over the 0e26 h post-dose period at all dose levels (Fig. 6).
studies in asthmatics [13] and subjects with COPD [14], where the incidence of events potentially indicative of a LABA-class effect were less than 3% in any treatment group indicating that VI is well tolerated at doses up to 50 mg. In asthma and COPD patients there were statistically significant increases in FEV1 at all time points from 5 min to 24 h post-dose for VI 25 mg, 50 mg and 100 mg, compared with placebo. There were no statistically significant increases in FEV1 compared with placebo after the lower VI dose of 6.25 mg in subjects with asthma suggesting that this could be considered a no-effect dose. In asthmatic patients the mean difference from baseline in FEV1 23e24 h after dosing was at least 240 mL greater than placebo for all doses, indicating a 24 h duration of action after a single dose. This improvement is greater than the average minimal patient perceivable improvement of 230 mL for FEV1 [15]. In COPD patients the mean difference from baseline in trough FEV1 23e24 h after dosing was at least 190 mL greater than placebo for all doses, which represents a clinically relevant treatment difference in COPD patients as it is greater than 100 mL [16]. Although the dosee response relationship analysis of mean FEV1 over 23 and 24 h was suggestive of a dose response, albeit of small magnitude, overlapping confidence intervals and a lack of any clear increment in FEV1 response with increasing dose suggests that all doses of VI were residing near to the top of the efficacy doseeresponse curve. Direct comparisons between treatments were not considered to be appropriate as these small studies were not powered for this. Of interest is that in subsequent phase IIb studies in asthma and COPD
4. Discussion Vilanterol is an inhaled LABA with inherent 24 h activity confirmed in many experimental models [6]. It is therefore being developed as a once-daily clinical treatment for asthma and COPD in combination with fluticasone furoate, a novel ICS also active for 24 h [12]. These four early phase studies were performed to evaluate the safety and tolerability and the pharmacokinetics and pharmacodynamics of repeat dosing of VI in healthy subjects and single inhaled doses of VI in subjects with persistent asthma and COPD. Data from these studies were pivotal in providing data for the phase II dose-ranging studies. In all the studies VI was administered as a dry powder with lactose and magnesium stearate. In three of the studies VI was administered via the DiskusÒ inhaler while in the other study (study 4) VI was administered via a Dry Powder Inhaler which is currently in development [9]. The range of VI doses examined (up to 100 mg for 14 days) included and exceeded the 50 mg dose evaluated in combination with FF in phase II dose-ranging studies [13,14]. Vilanterol was generally well tolerated by all subjects following single doses and repeat dosing for 14 days. The overall incidence of AEs was low compared with placebo and the incidence of AEs potentially indicative of LABA-class effects such as tremor, muscle twitching and palpitations was also low in these studies. These data are in agreement with the results of the 28-day dose-ranging VI
Table 6 Summary of vilanterol accumulation following repeat dosing for 14 days. Comparison
Ratio adjusted means (90% CI for ratio) AUCa
Cmax 25 mcg Day 7: Day1 50 mcg Day 7: Day 1 100 mcg Day 7: Day 1 25 mcg Day 14: Day1 50 mcg Day 14: Day 1 100 mcg Day 14: Day 1
1.29 1.25 1.00 1.27 1.13 1.00
(1.10, (1.07, (0.86, (1.09, (0.96, (0.86,
1.51) 1.47) 1.17) 1.49) 1.32) 1.17)
ND 1.20 1.07 ND 0.98 1.01
(1.06, 1.35) (0.95, 1.20) (0.86, 1.11) (0.9, 1.13)
ND: not determined (AUC too limited to assess accumulation). a AUC(0et0 ) (to common time-point) to account for LLQ censoring.
Fig. 3. Median vilanterol plasma concentrations following single dose (25, 50 and 100 mcg) in COPD patients (study 3).
R. Kempsford et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 256e264
263
Table 7 Statistical analysis of FEV1 (mL; difference from placebo) at 5 min and 23e24 h following single dose VI (25e100 mcg) in asthmatic and COPD patients. Comparison
Time post Study 2 e asthma Study 3 e COPD dose Difference in adjusted Difference in adjusted means (95% CI) means (95% CI)
25 mcg vs. placebo 50 mcg vs. placebo 100 mcg vs. placebo 25 mcg vs. placebo 50 mcg vs. placebo 100 mcg vs. placebo
5 min 5 min 5 min 23e24 h 23e24 h 23e24 h
225 203 276 273 242 321
(127, (112, (183, (178, (156, (233,
324) 293) 368) 369) 328) 410)
69 85 133 190 206 210
(8, 146) (5, 165) (25, 241) (88, 292) (100, 312) (67, 354)
the VI 25 mcg dose was shown to be optimal and that a higher dose of 50 mcg was not associated with significantly greater efficacy [13,14]. A single dose of VI administered in asthma subjects also produced a rapid, dose-dependent clinically significant bronchodilation that was maintained over the 24 h post-dose period. A clinically significant effect of VI on trough FEV1, defined as greater than 200 mL versus placebo was seen with the 25 mg and 100 mg dose of VI. The once-daily duration of action on lung function has also been demonstrated in other studies performed in asthma and COPD patients. Results from a repeat-dose study in asthmatic subjects demonstrated that once-daily treatment with VI provided bronchodilation out to 24 h, supporting once-daily dosing [13]. Similarly, in a 28-day dose-ranging clinical efficacy study in COPD, a 24-h sustained bronchodilatory effect superior to placebo was also confirmed, as shown by analysis of serial FEV1 [14]. LABA-class related systemic pharmacodynamic effects on blood glucose, blood potassium, heart rate and QTcF were monitored in all the studies. No particularly marked effects were seen on any of these parameters with no consistent doseeresponse relationships over the 6.25e100 mg VI dose range. In addition there was no evidence of increased pharmacodynamic effects with repeat dosing. Some pharmacodynamic effects were seen, particularly at the highest VI dose (100 mg), although these were not consistently produced across all the studies and populations. For example, small (<10 ms) differences from placebo in mean maximum QTcF seen after the supratherapeutic dose of 100 mg VI were seen in healthy subjects (study 1 [parallel group]; single and repeat dose) and in
Fig. 4. Mean FEV1 profile (0e24 h) following single dose VI (25, 50 and 100 mcg) and placebo in asthma patients (study 2).
Fig. 5. Mean FEV1 profile (0e24 h) following single dose VI (25, 50 and 100 mcg) and placebo in COPD patients (study 3).
subjects with asthma (study 2) were not replicated in subjects with COPD (study 3) or in other subjects with asthma (study 4). The difference between the populations was particularly evident in the subjects with COPD where no statistically significant pharmacodynamic effects were seen after any dose of VI including 100 mg. The limited size of the studies reported and the variability in the data should be considered when assessing this data. The studies were not powered or designed to definitely make conclusions about QTc. In addition in small studies clinical significance is judged at the individual level by protocol stopping criteria and no subject met the criteria for QTc. In phase IIb studies of four weeks duration VI doses up to 50 mg were not associated with significant systemic pharmacodynamic effects in subjects with either asthma or COPD [13,14]. At the proposed therapeutic dose of VI (25 mcg) it has been demonstrated that there was a lack of effect on the QTc interval as measured by either QTcF or QTci. At a four-fold multiple of the VI therapeutic dose (100 mcg) there was a small, predictable and transient effect on QTcF but not on QTci during the first hour after dosing [17]. The pharmacokinetics of VI following doses of 25, 50 and 100 mg once-daily for 14 days in healthy subjects were characterised by rapid absorption in healthy subjects and subjects with asthma and
Fig. 6. Mean FEV1 profile (0e24 h) following single dose VI (6.25, 25 and 100 mcg) and placebo in asthma patients (study 4).
264
R. Kempsford et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 256e264
COPD. The rate of absorption appeared independent of the inhaler type. Plasma concentrations of VI declined rapidly over the first 1e2 h post-dose. At the lowest dose to produce bronchodilation (25 mg), systemic exposure was generally non-quantifiable (<30 pg/mL) beyond 1 h post dose and following 50 and 100 mg, plasma VI concentrations were generally non-quantifiable beyond 4e6 h post-inhalation. Approximate dose-proportional increases in systemic exposure over the dose range 25e100 mg VI were demonstrated in both healthy subjects and asthmatic and COPD subjects. The Cmax following dosing with VI in asthmatic and COPD subjects was approximately 2-fold lower than that in healthy subjects. This is likely to account for the lesser and limited systemic pharmacodynamic effects seen in the patient groups at the higher VI doses compared with healthy subjects. Overall, there appeared to be a marginal amount of VI accumulation (<30%) in plasma following repeat dosing in healthy subjects. There was evidence for Cmax accumulation over the first 7 days of dosing following 25 mg and 50 mg VI, but no further accumulation beyond Day 7. By Day 14 there was no evidence for accumulation compared with Day 1 or for a difference between Cmax on days 7 and 14. These results suggest a marginal amount of accumulation in VI on repeat once-daily administration with steady-state conditions achieved by Day 7 of dosing. In conclusion, repeat dosing with inhaled VI (25e100 mcg) once daily for 14 days was well tolerated in healthy subjects and was not associated with any clinically significant unwanted systemic effects. Vilanterol was rapidly absorbed and showed approximately dose proportional pharmacokinetics and marginal accumulation on repeat dosing. Single doses of inhaled VI were well tolerated in patients with mild to moderate persistent asthma or moderate to severe COPD with no clinically significant unwanted systemic effects. Vilanterol produces a rapid and prolonged bronchodilation over 24 h suggesting the potential for once-daily administration in asthma and COPD. Conflict of interest None as all authors are employees of GSK, the sponsoring company. Acknowledgements The following studies funded by GSK have been incorporated into this manuscript: Protocol number B2C108784 (clinicaltrials.gov NCT00469040); protocol number B2C106996 (clinicaltrials.gov NCT00463697); protocol number B2C110165 (clinicaltrials.gov NCT00519376); protocol number B2C111401 (clinicaltrials.gov NCT00702910). All listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. All the authors are employees of GSK. The authors wish to acknowledge Nick Bird for statistical review of this manuscript.
The authors wish to acknowledge Diana Jones of Cambrian Clinical Associates Ltd for development of manuscript first draft, editorial suggestions to draft versions of this paper, assembling tables and figures, collating author comments and referencing. This assistance was funded by GSK.
References [1] Global Initiative for Asthma (GINA), National Heart Lung and Blood Institute, National Institutes of Health. GINA report. Global strategy for asthma management and prevention. Bethesda: National Institutes of Health; 2006. [2] Global Initiative for Obstructive Lung Disease (GOLD), National Heart Lung and Blood Institute, National Institutes of Health. GOLD report. Global strategy for diagnosis, management and prevention of COPD. Bethesda: National Institutes of Health; 2009. [3] Jones PW, Barnes N, Vogelmeier C, Lawrence D, Kramer B. Efficacy of indacaterol in the treatment of patients with COPD. Prim Care Respir J 2011;20: 380e8. [4] Slack R, Barrett V, Ford A, Knowles K. In vitro pharmacological characterisation of the b2-adrenoceptor binding kinetics of [3H]vilanterol, a novel long acting b2-agonist. Br J Pharmacol 2011;9(3):P008. [5] Morrison V, Sturton G, Barrett V, Ford A, Knowles A. Pharmacological characterisation of GW642444, a long-acting b2-agonist (LABA) with rapid onset and long duration, on isolated large and small human airways. Am J Respir Crit Care Med 2010;181:A4453. [6] Barrett V, Emmons A, Ford A, Knowles R. In vitro pharmacological characterization of GW64244, a novel long-acting b2-agonist (LABA) using human recombinant b1/2/3 adrenoceptor cAMP assays. Am J Respir Crit Care Med 2010;181:A4451. [7] Harrell A, Siederer S, Bal J, Kempsford R. Vilanterol, a novel inhaled longacting b2 adrenoceptor agonist (LABA), demonstrates extensive first pass clearance to metabolites with negligible pharmacological activity in man. Eur Respir J 2011;38(Suppl. 55):137s. [8] Ford A, Hughes S, Smith C, Somers G, Ranshaw L. The therapeutic index (TI) of vilanterol trifenatate. Eur Respir J 2010;36(Suppl. 54):208s. [9] Prime D, De Backer W, Hamilton M, Cahn A, Preece A, Kelleher D, et al. Comparison of inhalation profiles through a novel dry powder inhaler (nDPI) and lung function measurements for healthy subjects, asthma and chronic obstructive pulmonary disease (COPD) patients. Am J Respir Crit Care Med 2012;185. [10] Celli BR, MacNee W. ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004;23:932e46. [11] Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J 2005;26(2):319e38. [12] van den Berge M, Luijk B, Bareille P, Dallow N, Postma DS, Lammers J-WJ. Prolonged protection of the new inhaled corticosteroid fluticasone furoate against AMP hyperresponsiveness in patients with asthma. Allergy 2010; 65(12):1531e5. [13] Lötvall J, Bateman ED, Bleecker ER, Busse W, Woodcock A, Follows R, et al. Dose-related efficacy of vilanterol trifenatate (VI), a long-acting beta2 agonist (LABA) with inherent 24-hour activity, in patients with persistent asthma. Eur Respir J 2010;36(Suppl. 54):1013s. [14] Hanania NA, Feldman G, Zachgo W, Shim JJ, Crim C, Sanford L, et al. Safety of vilanterol trifenatate (VI) in a COPD dose-ranging study. Chest 2012;142: 119e27. [15] Santanello NC, Zhang J, Seidenberg B, Reiss TF, Barber BL. What are minimal important changes for asthma measures in a clinical trial? Eur Respir J 1999; 14:23e7. [16] Donohue JF. Minimal clinically important differences in COPD lung function. COPD. COPD 2005;2:111e24. [17] Kempsford R, Allen A, Kelly K, Saggu P, Crim C. A repeat dose, double-blind, placebo-controlled, thorough Qt/Qtc study to assess the cardiac safety of fluticasone furoate (FF) and vilanterol (VI) administered, 2012 of fluticasone furoate (FF) and vilanterol (VI) administered in combination. Am J Respir Crit Care Med 2012;185:A2841.