Pharmacokinetics of fluticasone propionate and salmeterol delivered as a combination dry powder via a capsule-based inhaler and a multi-dose inhaler

Pulmonary Pharmacology & Therapeutics 29 (2014) 66e73

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Pharmacokinetics of fluticasone propionate and salmeterol delivered as a combination dry powder via a capsule-based inhaler and a multi-dose inhaler Rashmi Mehta a, *, Peter T. Daley-Yates b, Kevin Jenkins b, Joseph Bianco c, Anastasia Stylianou d, Margaret D. Louey a, Robert H. Chan b a

GlaxoSmithKline, Research Triangle Park, NC, USA GlaxoSmithKline, Stockley Park, Uxbridge, UK GlaxoSmithKline, Melbourne, Victoria, Australia d GlaxoSmithKline, Stevenage, UK b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 12 March 2014 Received in revised form 25 June 2014 Accepted 6 July 2014 Available online 14 July 2014

Aim: To compare salmeterol (SALM) and fluticasone propionate (FP) systemic exposure following inhaled salmeterol/fluticasone propionate combination (SFC) from a unit-dose capsule-based inhaler (Rotacaps®/Rotahaler®) and a multi-dose dry powder inhaler (Diskus®) in healthy volunteers. Methods: An open-label, randomised, repeat-dose, cross-over, adaptive design study (n ¼ 36 in each part) evaluated SFC 50/250 mg and SFC 50/100 mg in Rotacaps used with two types of Rotahaler inhalers (airflow resistance similar to (S) and lower than (L) Diskus) versus the Diskus. Primary endpoints were area under the concentration-time curve over the dosing interval [AUC0et] and maximum plasma concentration [Cmax]. Results: SFC 50/250 mg Rotacaps/Rotahaler (S) showed 1.2e1.9-fold greater FP and SALM systemic exposure compared with Diskus. FP and SALM systemic exposure were comparable to DISKUS following SFC 50/250 mg Rotacaps/Rotahaler (L) (90% CI of ratio of Rotahaler to DISKUS within 0.8e1.25) for salmeterol (AUC0et and Cmax) and FP (AUC0et). Following SFC 50/100 mg Rotacaps/Rotahaler (L), FP and SALM systemic exposures were 1.2e1.4 fold higher in terms of FP (AUC0et and Cmax) and salmeterol (Cmax) compared with Diskus. SFC at both doses and via both inhalers was well tolerated. Conclusions: SFC 50/250 mg Rotacaps/Rotahaler (L) showed comparable systemic exposure to Diskus in terms of FP AUC and SALM AUC and Cmax. These results merit further progression of SFC 50/250 mg Rotacaps/Rotahaler (L) to phase 3 clinical evaluation in asthma and COPD patients. The lack of pharmacokinetic comparability between the inhalers for SFC 50/100 mg requires further evaluation. © 2014 Elsevier Ltd. All rights reserved.

Keywords: Fluticasone propionate Salmeterol Dry powder inhaler Rotacaps Rotahaler Diskus

1. Introduction Asthma and chronic obstructive pulmonary disease (COPD) are chronic, inflammatory diseases of the lung which are associated with significant morbidity, and social and economic burdens [1e5]. It has been estimated that asthma is responsible for the loss of 15 million disability-adjusted life years (DALY) annually [3], and poor asthma control has been shown to be associated with worse healthrelated quality of life, and increased numbers of doctor visits and hospitalisations [6,7]. By 2030 COPD is expected to be the seventh

* Corresponding author. E-mail address: [email protected] (R. Mehta). http://dx.doi.org/10.1016/j.pupt.2014.07.001 1094-5539/© 2014 Elsevier Ltd. All rights reserved.

leading cause of DALYs lost worldwide [5], and COPD exacerbations are responsible for the greatest proportion of the total COPD healthcare system burden [2]. The prevalence of asthma is predicted to increase in developing countries due to the adoption of western lifestyles and increased urbanization [1,3]. The prevalence of COPD is also predicted to increase worldwide due to the continued effects of tobacco and because many more people are expected to live into the COPD age range (usually  40 years), particularly in developing countries [5]. Despite clear asthma and COPD management goals designed to control symptoms and prevent future risk of exacerbations [1,2], many patients with asthma are poorly controlled [1,8,9], and COPD remains under-diagnosed and suboptimally treated [2,10].

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Inhaled combination therapy with a corticosteroid and a longacting beta2-agonist (ICS/LABA) is a recommended maintenance therapy for asthmatic patients when clinical control is not achieved with ICS alone, and for COPD patients at high risk of exacerbations [1,2]. Salmeterol (SALM) and fluticasone propionate (FP) combination products (SFC), administered via the metered dose inhaler (MDI) and multi-dose powder inhaler (Diskus®), are approved treatments for asthma and COPD [1,2]. In developing countries, there is a need for inhaled asthma and COPD therapies to be both affordable and accessible [11,12]. Health care provision is often less sophisticated and proportionally more patients are expected to pay out of pocket for their treatment. In some of these countries for patients on low incomes the high up-front acquisition cost of a multi-dose inhaler such as Diskus, designed to provide a month's treatment, may not be affordable. Given the Rotacap/Rotahaler system is a single unit dose inhaler and already established for delivering inhaled salbutamol, adapting SFC to this system as an alternative treatment option seems reasonable. This will allow more patients the ability to purchase the ICS/LABA combination in a lower number of dose units than Diskus but on a more frequent basis in quantities sufficient to provide twice daily treatment chronically. This better access is expected to result in improved control of their chronic respiratory disease. A comparative bioavailability study of SFC 50/250 mg Diskus and SFC 50/250 mg (SFC 50/250) delivered via Rotacaps/Rotahaler (S, which has similar airflow resistance to Diskus) in subjects with asthma and COPD, demonstrated no major differences in in vitro aerodynamic particle size profiles or systemic pharmacodynamic endpoints, but failed to show pharmacokinetic bioequivalence in terms of FP and SALM systemic exposure, highlighting a requirement for further refinement of the Rotacaps/Rotahaler performance [13]. As a next step in device refinement and pharmacokinetic performance evaluation, the current study compared the pharmacokinetic parameters of SFC 50/250 delivered from the Rotacaps/ Rotahaler (S) and (L, lower airflow resistance relative to Diskus), and the Diskus in healthy volunteers. The pharmacokinetic parameters of the Rotacaps/Rotahaler product were also investigated at a lower dose, SFC 50/100 mg (SFC 50/100). 2. Materials and methods 2.1. Study design An open-label, randomised, cross-over, within-subject replicate treatment, adaptive study design was used to compare the systemic exposure of SALM and FP following delivery of SFC 50/250 and SFC 50/100 via Rotacaps/Rotahaler and Diskus in healthy volunteers (GlaxoSmithKline Protocol ASR116409; NCT: 01540708). The study was conducted at a single site, the GSK Medicines Research Unit, Randwick, Australia. Two types of Rotahaler inhalers were investigated: one with airflow resistance similar to the Diskus (S) and one with lower airflow resistance relative to the Diskus (L). A detailed description of the Rotahaler and Diskus inhalers has been reported previously [13]. The Rotahaler version used in that particular study was the same as the version (S) used in the current study i.e. had similar airflow resistance to the Diskus (S). The Rotahaler (S) and Rotahaler (L) differ in design which results in differences in airflow resistance from typically  2.7 kPa and 0.7 kPa respectively, compared with 2.6 kPa for the Diskus, when tested at 60 L/min. The Rotacaps 50/250 and 50/100 consist of a powder blend, containing 50 mg micronized salmeterol (as xinafoate) and 250 or 100 mg micronized fluticasone propionate with lactose monohydrate, encapsulated within a hard gelatin capsule. For each treatment, subjects were dosed twice daily for 3 days and once on the fourth day in the morning. The first dose on Day 1

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was administered at the site and the next four doses were selfadministered at home. Subjects were then admitted to the investigation unit on the evening of the third day when they were administered the sixth dose, followed by the seventh dose on the subsequent morning (Day 4). They remained in the unit on Day 4 for 12 h post-dose pharmacokinetic sampling. A minimum of a three-day wash-out separated each treatment arm. All subjects underwent training on how to use the Rotahaler device and their technique was checked when doses were administered in the clinic. 2.1.1. SFC 50/250 This consisted of a four-treatment cross-over design with each subject receiving the following treatments in replicate: SFC 50/250 via the Diskus; SFC 50/250 via the Rotahaler (S); SFC 50/250 via low resistance Rotahaler using one single inhalation per dose (L1); SFC 50/250 via low resistance Rotahaler, using multiple inhalations per dose until no powder remained (L2). 2.1.2. SFC 50/100 This comprised an a priori two treatment, cross-over, replicate study design. Each subject received SFC 50/100 via the Diskus and SFC 50/100 via low resistance Rotahaler using one single inhalation (L1). In order to have measurable plasma concentrations (that exceeded the lower level of quantification of the bioanalytical methods for FP and SALM), subjects were asked to inhale two doses of their treatment (i.e. 100 mg SALM and 200 mg FP) throughout all treatment periods. 2.2. Subjects Male or female subjects aged 18e65 years with a body mass index of 18e35 kg/m2 and who were judged to be healthy by the investigator (based on medical history, physical examination, laboratory tests and cardiac monitoring) were eligible for inclusion. Key exclusion criteria included a current diagnosis or history of asthma, COPD or liver disease. Other than paracetamol which was permitted at doses of 2 g/day, subjects were asked to refrain from taking any prescription or non-prescription drugs within 7 days (or 14 days if the drug was a potential enzyme inducer) or five halflives (whichever was longer) before the first dose of study medication until completion of the follow-up visit, unless, in the opinion of the Investigator and Sponsor, the medication would not interfere with the study. All subjects gave written informed consent to participation prior to any study procedures and the study was approved by the Bellberry Human Research Ethics Committee, Dulwich SA, Australia 5065. 2.3. Pharmacokinetic assessments On Day 4 of each treatment period, serial 6 mL blood samples were collected pre-morning dose and at 5, 10, 30 min and 1, 2, 4, 8, 10 and 12 h post-dose into ethylenediaminetetraacetic acid (EDTA) tubes. The blood samples were centrifuged at 1500  g for 10 min at 4  C, and the resulting plasma was divided into two aliquots, one for FP and one for SALM analysis, and stored at 20  C. Plasma samples were analysed using a validated analytical method based on solid phase extraction, then high performance liquid chromatography (HPLC)/tandem mass spectrometry analysis. Both assays used Sciex API 5000 instrumentation in positive mode with TurboIonspray. The assay for FP used D3-FP internal standard (transitions 501/313 and 504/313), and the assay for salmeterol used the D3-Salmeterol internal standard (transitions 416/232 and 419/235). The lower limit of

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quantification for FP was 3 pg/mL using a 500 mL aliquot of EDTA plasma and for SALM 1 pg/mL using a 250 mL aliquot of EDTA plasma. The following pharmacokinetic parameters were determined from the plasma concentration-time data for subjects in each active treatment for FP and SALM: maximum plasma concentration (Cmax), time at which Cmax was observed (tmax), area under the concentration-time curve from time zero (pre-dose) to tau where tau is the dosing interval (AUC0et). The co-primary endpoints were FP AUC0et and Cmax, and SALM AUC0et and Cmax on the last day of each study treatment period (Day 4).

2.4. Safety For the SFC 50/250 dose, vital signs (heart rate, blood pressure, and 12-lead electrocardiograph [ECG] measurements) were measured at the randomisation visit (Day 1) pre-morning dose and post-dose (within 30 min). For the SFC 50/100 dose, vital signs were measured pre-dose, and at 10 min, 30 min and 60 min post-dose on Day 1, Day 3 (evening) and Day 4. In both parts of the study, routine haematology, biochemistry and urinalysis tests were performed at screening and follow-up visits. Adverse events were monitored throughout each treatment period and during follow-up (7e10 days post-last dose).

Fig. 1. a: Disposition of subjects receiving SFC 50/250 mg from the Rotahaler and Diskus A: SFC 50/250 mg via Diskus, B: SFC 50/250 mg via Rotahaler (S; airflow resistance similar to Diskus), C: SFC 50/250 mg via Rotahaler (L1; lower airflow resistance relative to Diskus using one single inhalation), D: Rotahaler (L2; lower airflow resistance relative to Diskus using multiple inhalations until no powder remained) Figure 1b: Disposition of subjects receiving SFC 50/100 mg from the Rotahaler and Diskus E: SFC 50/100 mg via Diskus; F: SFC 50/ 100 mg via Rotahaler (L1).

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2.5. Statistical analysis Based on calculations from a previous study [13], it was estimated that a sample size of 32 subjects had approximately 90% power to demonstrate pharmacokinetic bioequivalence for both the compounds with an eight period cross-over study design with two replicates for each of the four arms. Thirty six patients were planned for each part of the study to allow for withdrawals. Following loge-transformation, AUC(0et) and Cmax of FP and SALM were analysed separately using a mixed effects model with fixed effect terms for period and treatment. Subject was treated as a random effect in the model. Point estimates and their associated 90% confidence intervals were constructed for all treatment comparisons. The point estimates and their associated 90% confidence intervals were back-transformed to provide point estimates and 90% confidence intervals for the ratio, Rotahaler/Diskus. If the 90% confidence interval for the ratio of SFC Rotahaler geometric mean to SFC Diskus geometric mean for AUC(0et) and Cmax fell entirely within the range 0.8e1.25 then the two inhaler products should be considered to have pharmacokinetic bioequivalence. Two treatments were defined as comparable in terms of systemic exposure if equivalence was demonstrated at least for FP AUC(0et) and SALM Cmax. The tmax of FP and SALM was analysed separately using Wilcoxon's signed rank test. 3. Results 3.1. SFC 50/250 3.1.1. Subjects Thirty six subjects were randomized to treatment and 32 subjects completed the study (Fig. 1a). Three subjects withdrew consent and one subject was withdrawn due to an adverse event of dental caries. There were no reported errors in inhaler technique for any subjects. The mean age of subjects was 31 years, 67% were male and 67% were Caucasian (Table 1). 3.1.2. Pharmacokinetic assessments 3.1.2.1. Fluticasone propionate. Following repeat-dose administration, FP was rapidly absorbed with a median tmax of approximately 0.8 h for the Diskus and 0.2e0.3 h for the Rotacaps/Rotahalers (S, L1

Table 1 Demographic characteristics of study subjects.

Age, (yrs), mean (range) Sex, n (%) Female Male Body mass index, (kg/cm2), mean (range) Height, (cm), mean (range) Weight, (kg), mean (range) Ethnicity, n (%) Hispanic or Latino Not Hispanic or Latino Race, n (%) WhiteeWhite/Caucasian/European heritage Mixed race Asian e Central/South Asian Heritage White e mixed race Asian e East Asian heritage Asian e Japanese heritage African American/African heritage

SFC 50/250 mg

SFC 50/100 mg

n ¼ 36

n ¼ 32

30.5 (18e55)

30.6 (18e52)

12 (33) 24 (67) 24.42 (18.1e31.4)

15 (47) 17 (53) 24.56 (19.3e33.3)

174.4 (157e195) 171.8 (160e183) 75.0 (48.1e119.5) 72.6 (55.0e102.0) 1 (3) 35 (97)

4 (13) 28 (88)

24 (67)

22 (69)

9 (25) 2 (6) 1 (3) 0 0 0

2 1 2 3 1 1

(6) (3) (6) (9) (3) (3)

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and L2) (Table 2). Compared with delivery of SFC 50/250 from the Diskus, delivery from the Rotahaler (S) resulted in higher systemic exposure of FP in terms of AUC0et (1.40 fold higher) and Cmax (1.85 fold higher) (Fig. 2a; Table 2). FP systemic exposure following Rotahaler (L), irrespective of number of inhalations per Rotacap dose (i.e. L1 and L2), was comparable to Diskus in terms of AUC0et (90% interval for the ratio of GMRs fell within 0.8e1.25) but resulted in higher systemic exposure for Cmax (approximately 1.5 fold higher) (Fig. 2a; Table 2). 3.1.2.2. Salmeterol. SALM was rapidly absorbed with a median tmax of 0.08 h following repeat dosing with all treatments (Table 2). Compared with the Diskus, SALM systemic exposure following the Rotahaler (S) was higher in terms of AUC0et (1.20 fold) and Cmax (1.52 fold) (Fig. 2b; Table 2). SALM systemic exposure following Rotahaler (L), irrespective of number of inhalations per Rotacap dose, was comparable to Diskus in terms of AUC0et and Cmax (90% interval for the ratios of GMRs fell within 0.8e1.25) (Fig. 2b; Table 2). 3.2. SFC 50/100 In this part of the study, FP and SALM systemic exposures were compared following SFC 50/100 delivered via the Diskus and the Rotahaler (L1). The Rotahaler (L1) was selected due to the comparable systemic exposures of FP and SALM between these devices demonstrated following delivery of SFC 50/250. 3.2.1. Subjects Thirty two subjects were randomized to treatment; 31 subjects completed the study and one subject withdrew consent (Fig. 1b). The mean age of subjects was 31 years, 53% were male and 69% were Caucasian (Table 1). 3.2.2. Pharmacokinetic assessments 3.2.2.1. Fluticasone propionate. Following repeat-dose administration FP was rapidly absorbed with a median tmax of approximately 0.1 h from the Diskus and the Rotahaler (Table 2). FP systemic exposure following Rotahaler (L1) was higher compared to that following Diskus in terms of AUC0et and Cmax (1.16 and 1.35 fold higher respectively) (Fig. 3a; Table 2). 3.2.2.2. Salmeterol. After repeat dosing, SALM was rapidly absorbed with a median tmax of 0.08 h for both treatments (Table 2). SALM systemic exposure following Rotahaler (L1) was comparable to that following Diskus in terms of AUC0et but 1.24 times higher in terms of Cmax (Fig. 3b; Table 2). 3.3. Safety There were no observable differences in the proportion of subjects reporting adverse events (AEs) following delivery of SFC by Diskus and the Rotahaler (S or L) following both doses of SFC. The percentage of subjects reporting AEs was consistently lower for the second administration of all treatments compared with the first administration. Headache was the most frequently reported AE, reported by 53% and 50% of subjects following SFC 50/250 and SFC 50/100 respectively. There were no reports of serious AEs. The AE of dental caries resulting in subject withdrawal was considered not related to treatment by the investigator and was not assessed. During the study, no subjects had a clinically significant clinical laboratory, vital signs or ECG result on any treatments delivered by the Diskus or the Rotahaler (S or L).

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Table 2 Summary of plasma fluticasone propionate and salmeterol pharmacokinetic parameters. Treatment SFC 50/250 mg Fluticasone propionate SFC 50/250 mg Diskus SFC 50/250 mg Rotahaler SFC 50/250 mg Rotahaler SFC 50/250 mg Rotahaler Salmeterol SFC 50/250 mg Diskus SFC 50/250 mg Rotahaler SFC 50/250 mg Rotahaler SFC 50/250 mg Rotahaler SFC 50/100 mg Fluticasone propionate SFC 50/100 mg Diskus SFC 50/100 mg Rotahaler Salmeterol SFC 50/100 mg Diskus SFC 50/100 mg Rotahaler

AUC(0et) (pg h/mL)

AUC(0et) ratio of Rotahaler/Diskus (90% CI)a

Cmax (pg/mL)

Cmax ratio of Rotahaler/Diskus (90% CI)a

tmax (h)

(S) (L1) (L2)

476.1 668.2 508.1 541.9

(25.7) (24.6) (24.4) (24.9)

N/A 1.40 (1.33, 1.47) 1.07 (1.00, 1.14) 1.13 (1.06, 1.21)

70.20 129.93 106.27 109.82

(27.1) (29.4) (30.4) (34.7)

N/A 1.85 (1.71, 1.99) 1.51 (1.40, 1.63) 1.55 (1.43, 1.69)

0.765 0.170 0.290 0.290

(0.17, (0.08, (0.08, (0.08,

(S) (L1) (L2)

225.4 270.9 233.2 244.6

(40.9) (39.8) (44.4) (43.0)

N/A 1.20 (1.14, 1.26) 1.02 (0.96, 1.08) 1.09 (1.03, 1.15)

112.97 171.74 118.33 125.08

(32.5) (31.1) (34.5) (39.1)

N/A 1.52 (1.40, 1.64) 1.05 (0.97, 1.14) 1.11 (1.02, 1.21)

0.080 0.08 0.080 0.080

(0.04, 0.54) (0.08, 0.08) (0.08,0.29) (0.08, 0.10)

(L1)

424.5 (20.5) 494.6 (21.0)

N/A 1.16 (1.07, 1.26)

98.41 (25.6) 132.90 (23.4)

N/A 1.35 (1.17, 1.55)

0.100 (0.04, 1.00) 0.108 (0.08, 1.50)

(L1)

522.0 (39.6) 597.7 (41.2)

N/A 1.14 (1.09, 1.20)

284.4 (23.8) 356.6 (25.6)

N/A 1.24 (1.12, 1.38)

0.080 (0.04, 0.09) 0.080 (0.08, 0.13)

3.00) 2.00) 1.09) 1.25)

Data presented as geometric mean (% coefficient of variation [CV]) except tmax, presented as median (range). SFC: Salmeterol/fluticasone propionate combination; Diskus: Multi-dose dry powder inhaler; Rotahaler (S): capsule-based powder inhaler, airflow resistance similar to Diskus; Rotahaler (L1): capsule-based powder inhaler, lower airflow resistance relative to Diskus (one inhalation); Rotahaler (L2): capsule-based powder inhaler, lower airflow resistance relative to Diskus (multiple inhalations until no powder remains); AUC(0et): area under the concentration-time curve from time zero to tau where tau is the dosing interval; AUC(0et): area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration; Cmax, maximum plasma concentration; t½: terminal half-life; tmax: time to maximum plasma concentration; N/A: not applicable. a The two treatments were defined as comparable if the ratio of SFC Rotahaler geometric mean to SFC Diskus geometric mean was 0.80 and 1.25.

4. Discussion This study was conducted as a follow-up to a comparison of the Rotahaler and Diskus in subjects with asthma and COPD [13]. The aim was to further investigate variables in the SFC Rotahaler product performance by comparing its pharmacokinetic characteristics with the SFC Diskus in healthy subjects. Compared with delivery of SFC 50/250 from the Diskus, delivery from the Rotahaler (S) resulted in higher systemic exposure of both FP and SALM in terms of AUC0et and Cmax. Delivery of SFC 50/250 from Rotahaler (L1 and L2) was comparable (90% CI of ratio within 0.8e1.25) for the pharmacokinetics of SALM in terms of AUC0et and Cmax, and for the pharmacokinetics of FP in terms of AUC0et. As FP Cmax was higher following the Rotahaler (L1 and L2) compared with Diskus, bioequivalence was not achieved for this parameter. However, geometric mean ratios and 90% CI for SALM AUC0et, SALM Cmax and FP AUC0et indicated that delivery of SFC 50/250 using the lower resistance Rotahaler (L) was biocomparable to Diskus. This biocomparability was independent of the number of inhalations used per Rotacap dose (single or multiple inhalations), which further validates this finding. The systemic bioequivalence demonstrated for SFC 50/250 Rotahaler (L) for both AUC0et and Cmax of SALM provide reassurance of the systemic safety with chronic treatment given the well established safety profile of SFC 50/250 Diskus. Similarly, the comparability of AUC for FP for the two inhalers provides reassurance in terms of ICS systemic safety. It is well established that sustained high levels of corticosteroids, including high doses of ICS, have the potential to induce dose dependent systemic effects such as cortisol suppression [14]. These effects are related to total systemic exposure to corticosteroid (AUC) [15,16], whereas the influence of Cmax on ICS systemic corticosteroid effects is less well documented. However, since the systemic absorption of FP is derived almost entirely from the inhaled portion, since FP has

negligible oral absorption [17], a difference in Cmax may reflect a different pattern of regional lung deposition. Other authors have also noted that changes in regional (central vs. more peripheral) lung deposition of inhaled drugs can be detected by PK studies (specifically, Cmax values) when the relative contributions of ciliary removal of the centrally deposited fraction of dose and its absorption rate from the lung are impacted by a different lung deposition pattern [18]. The potential impact of this on clinical efficacy requires further evaluation in a clinical study with patients. The current study identified no safety concerns with respect to incidence of adverse events, vital signs or routine laboratory parameters, for the Rotacaps/Rotahaler (S and L) and Diskus devices. These safety results are similar to those demonstrated in a study comparing the systemic exposure of SFC 50/250 administered from the Rotahaler (S) and Diskus in subjects with asthma and COPD [13]. The pharmacokinetics results; the higher plasma exposures of FP and SALM following delivery of SFC 50/ 250 in healthy subjects via the Rotahaler (S) compared with those from the Diskus are also consistent with those demonstrated in the comparative bioavailability study in subjects with asthma and COPD [13]. The reproducibility of the two studies with the S device provides reassurance of the validity of the results. Given the design and handling differences, the Rotahaler is not considered to be an interchangeable device with Diskus. Therefore in addition to the pharmacokinetic comparability established in this study, there is a need to provide evidence that Rotahaler (L) is also comparable to Diskus in terms of safety and efficacy in a larger clinical study in a relevant patient population. Based on the results with SFC 50/250, the Rotahaler (L) was used for the SFC 50/100 dose comparative study. Following administration of SFC 50/100 from the Rotahaler (L) compared with Diskus, plasma exposures of FP (AUC0et and Cmax) and SALM (Cmax) were higher from the Rotahaler (L). Although the upper

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Fig. 2. Plasma concentration versus time data for a) FP and b) SALM, following delivery of SFC 50/250 mg from the Rotahaler and Diskus in healthy volunteers.

limit of the CI for some of the PK parameters narrowly missed the comparability limits, in vitro investigations have shown that further refinement of the Rotahaler/Rotacap system for SFC at this low dose is possible to achieve a closer match to the Diskus. Therefore further clinical studies to evaluate this dose are planned or ongoing. The recruitment of healthy volunteers instead of patients is a limitation of this study given that the systemic exposure for inhaled drugs is generally higher in healthy volunteers compared to patients [19]. This study included the same Rotacaps/Rotahaler (S) product as in a previous patient study. As the systemic exposure ratios for FP and SALM of Rotahaler(S) vs. Diskus were similar in both studies, it provides a bridge and reassurance that Rotahaler (L) of SFC 50/250 is likely to be comparable if the study is repeated in patients. In the SFC50/100 dose part of the study, subjects were required to receive two doses of their treatment (i.e. 100 mg SALM and

200 mg FP) in order to have quantifiable plasma concentrations of FP and SALM (greater than the lower level of quantification of the bioanalytical methods). These conditions are less likely to reflect the “real life” clinical situation and is another limitation of this study. In summary, the results of this study indicated that, in healthy volunteers, administration of SFC 50/250 mg Rotacaps/Rotahaler (L) was well tolerated and showed comparable systemic exposure to Diskus in terms of FP AUC and SALM AUC and Cmax. Using these data together with the demonstration of similar tolerability in subjects with asthma and COPD [13], the clinical development of Rotahaler (L) merits the progression towards further evaluation in phase 3 safety and efficacy studies in the target asthma and COPD patient populations. The lack of comparability in FP and SALM systemic exposure between the Rotahaler (L) and Diskus following delivery of SFC 50/100 requires further investigation.

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Fig. 3. Plasma concentration versus time data for a) FP and b) SALM, following delivery of SFC 50/100 mg from the Rotahaler (L1) and Diskus in healthy volunteers.

Disclosure statement This study was funded by GSK (Protocol ASR116409; NCT: 01540708). All authors are employees of GSK; there are no other conflicts of interest to declare.

Acknowledgements The authors would like to thank Paul Thomas, GSK Medicines Research Unit, Randwick, Australia, for his role as principal investigator and for providing medical oversight during the conduct of this clinical trial, and Kylie Riddell, GSK Medicines Research Unit, Randwick, Australia, for providing operational as well as editorial support. Authors would also like to acknowledge editorial support in the form of draft manuscript development, collating of author comments and copyediting which was provided by Kate Hollingworth of Continuous Improvement Ltd. This support was funded by GSK.

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