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Pharmacokinetics of indacaterol and mometasone furoate delivered alone or in a free or fixed dose combination in healthy subjects
Pulmonary Pharmacology & Therapeutics 37 (2016) 30e36
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Pharmacokinetics of indacaterol and mometasone furoate delivered alone or in a free or fixed dose combination in healthy subjects Soniya S. Vaidya a, *, Sanjeev Khindri b, Nicole Calder b, Surendra Machineni c, Hisanori Hara d, Tapan Majumdar e, Salvatore Febbraro f, Rainard Fuhr g, Ralph Woessner d a
Drug Metabolism and Pharmacokinetics, Clinical Pharmacokinetics/Pharmacodynamics, Novartis Institutes for BioMedical Research, Cambridge, MA, USA Translational Medicine, Novartis Institutes for BioMedical Research, Horsham, UK Integrated Information Sciences, Novartis Healthcare Pvt. Ltd., Hyderabad, India d Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, Basel, Switzerland e Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA f Simbec Research Ltd., Merthyr Tydfil, UK g Early Phase Clinical Unit, PAREXEL, Berlin, Germany b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 July 2015 Received in revised form 28 January 2016 Accepted 30 January 2016 Available online 1 February 2016
Purpose: QMF149 is a fixed-dose combination of the long-acting b2 agonist, indacaterol and the corticosteroid, mometasone furoate that is currently under development for treatment of patients with asthma and chronic obstructive pulmonary disease. We describe here a study designed to assess any pharmacokinetic (PK) and/or biopharmaceutical interaction between indacaterol and mometasone furoate when administered via the Breezhaler® device, either alone or in a free or fixed combination (QMF149) in healthy adult subjects. Methods: In this randomized, open-label, four-way crossover study, subjects were randomized to receive indacaterol acetate 150 mg, mometasone furoate 320 mg, alone and as free combination of the individual components, or QMF149 (indacaterol acetate 150 mg/mometasone furoate 320 mg) once daily for 14 days in each period, followed by a 7-day washout between periods. PK profiles were characterized on Day 14 up to 168 h post-dose. Results: Indacaterol AUC0-24h,ss and Cmax,ss after administration of QMF149 were 13% [ratio: 1.13; 90%CI: 1.09, 1.17] and 18% [ratio: 1.18; 90%CI: 1.12, 1.25] higher, respectively, than indacaterol monotherapy. Mometasone furoate AUC0-24h,ss and Cmax,ss after administration of QMF149 were 14% [ratio: 1.14; 90%CI: 1.09, 1.20] and 19% [ratio: 1.19; 90%CI: 1.13, 1.26], higher, respectively than mometasone furoate monotherapy. The majority (three of four comparisons between QMF149 and monotherapy) of the 90% confidence intervals of the between-treatment ratios for AUC0-24h,ss and Cmax,ss were within the 0.80 to 1.25 interval and therefore fulfilled bioequivalence criteria. The 90% confidence interval for Cmax,ss for MF for the QMF149 vs. monotherapy comparison was [1.13, 1.26]. Although no definitive data can be provided on the basis of the present study results, it is unlikely that the small observed differences in expsoure are clinically meaningful. Multiple inhaled doses of indacaterol and mometasone furoate, when administered alone, in free combination or as QMF149 were well tolerated. Conclusions: The QMF149 fixed dose combination treatment showed comparable systemic exposure to the free combination and monotherapy treatments in terms of AUC0-24h,ss and Cmax,ss for both indacaterol and mometasone furoate, indicating an absence of clinically relevant PK or biopharmaceutical interactions. These data support further development of QMF149 without dose adjustment. © 2016 Elsevier Ltd. All rights reserved.
Keywords: QMF149 Indacaterol Mometasone furoate Pharmacokinetics Biopharmaceutical interaction
1. Introduction * Corresponding author. Drug Metabolism and Pharmacokinetics, Clinical Pharmacokinetics/Pharmacodynamics, Novartis Institutes for BioMedical Research, 220 Massachusetts Avenue, Cambridge, MA, USA. E-mail address: [email protected] (S.S. Vaidya). http://dx.doi.org/10.1016/j.pupt.2016.01.004 1094-5539/© 2016 Elsevier Ltd. All rights reserved.
Patients with uncontrolled chronic respiratory airway disorders, such as asthma or chronic obstructive pulmonary disease (COPD)
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are at a high risk of potentially life-threatening exacerbations, necessitating additional treatment, health-care consultations and often hospitalizations. In such patients, adequate symptom control may be achieved either by addition of a long-acting beta agonist (LABA) to inhaled corticosteroids (ICS), for patients with asthma; or addition of ICS to LABA, for patients with COPD [1,2]. Thus LABA/ICS combination therapy remains a cornerstone of treatment for patients with these persistent respiratory airway diseases [1,2]. It is known that use of separate inhalers for administering LABA and ICS as a free combination leads to LABA monotherapy in patients who are non-compliant with their ICS, resulting in increased risk of asthma mortality [3,4]. In order to avoid complications of LABA monotherapy [5] and achieve patient compliance to prescribed ICS regimens, it is important to administer the combination as a fixed dose via a single inhaler [6e8]. QMF149, administered via a single dose dry powder lowresistance inhaler, the Breezhaler® device, is currently being developed as a once-daily (o.d.) fixed-dose combination of the LABA indacaterol acetate and the ICS mometasone furoate, for the treatment of patients with asthma as well as patients with COPD that require ICS. The mono-components, indacaterol maleate (Onbrez® Breezhaler® or Arcapta™ Neohaler™; inhalation powder at doses between 75 and 300 mg o.d, Novartis Pharma AG, Basel, Switzerland) and mometasone furoate (Asmanex® Twisthaler® inhalation powder at doses of 100, 200 and 400 mg [per delivered dose] up to a maximum daily dose of 800 mg, Merck, Sharp & Dohme Corp., Whitehouse Station, New Jersey, USA) are approved for maintenance treatment of COPD and asthma, respectively. The advantage of the fixed-dose combination, QMF149, is that it combines the efficacy and rapid onset of action of indacaterol with the anti-inflammatory activity of mometasone furoate. Furthermore, both the mono-components also exhibit bronchodilation that is sustained over a period of 24 h [9,10]. Previous studies demonstrated that 80, 160 and 320 mg doses of mometasone furoate in the Breezhaler® device were comparable to the 200, 400 and 2 400 mg doses of mometasone furoate in the Twisthaler® device, respectively, based on the pharmacokinetic (PK) data, in-vitro fine particle mass adjustments and subsequent confirmation in a safety and efficacy study in asthma patients [11,12]. In vitro investigations indicated that cytochrome P450 isoform 3A4 (CYP3A4) is the predominant isoenzyme responsible for hydroxylation of indacaterol. CYP isoforms 1A1 and 2D6, and uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1) play a minor role in the metabolism of indacaterol, and it is a low affinity substrate for the efflux pump P-glycoprotein. Indacaterol has not been shown to cause interactions with concomitantly administered medicinal products. In vitro investigations indicated that indacaterol has negligible potential to cause metabolic interactions at the systemic exposure levels achieved in clinical practice. The portion of an inhaled mometasone furoate dose that is swallowed is absorbed in the gastrointestinal tract and undergoes extensive metabolism to multiple metabolites. Although the information available on the hepatic metabolism of mometasone furoate is limited, it is known that mometasone furoate is metabolized by CYP3A4 in vitro in human liver microsomes. Overall, the potential for systemic pharmacokinetic interaction between MF and indacaterol acetate is low based on in vitro data and clinical drug interaction studies conducted for indacaterol maleate and for mometasone furoate. Both indacaterol and MF are metabolized by CYP3A4 but are not known to be inhibitors or inducers of CYP3A4. Furthermore, the potential for pulmonary pharmacokinetic interaction is also considered to be low. In vitro incubation of MF in human lung S9 fractions (post-mitochondrial supernatant fraction containing phase I and phase II metabolic enzymes) indicated that MF does not undergo significant pulmonary metabolism. Similarly,
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no metabolites of indacaterol were detected in human lung slices or human pulmonary microsomes. These data suggested that the contribution of the lung to the metabolism of these compounds is low. The present study was designed to assess potential PK interactions or biopharmaceutical interaction (i.e: the interaction of the two active components when physically combined into a new product formulation in a single capsule to be inhaled via the Breezhaler® device) between indacaterol and mometasone furoate when delivered as a fixed-dose combination (QMF149) via the Breezhaler® device in healthy adult subjects. Although the potential for systemic or pulmonary interactions was considered low, evaluation of systemic exposure following inhaled administration of the fixed dose combinations (QMF149) was undertaken to assess whether the systemic exposure of each of the components (indacaterol and mometasone furoate) was similar to that in the monotherapy products. Demonstration of similar exposure between the fixed dose combination and monotherapy products is important in order to ensure that the safety profile for the combination product will be similar to that of the monotherapy products. 2. Methods The study was conducted according to the ethical principles of the Declaration of Helsinki. The study protocol (Study CQMF149E2102) was reviewed by the Independent Ethics Committees at the two study centers (Simbec Research Ltd, Merthyr Tydfil, United Kingdom, and the PAREXEL Early Phase Clinical Unit Berlin, Berlin, Germany). Informed consent was obtained from each subject in writing before any screening procedures were performed as per the clinics' standard operating procedures. 2.1. Study objectives The objective of this study was to evaluate the potential for a PK drug interaction or a biopharmaceutical interaction between indacaterol acetate and mometasone furoate as determined by their steady-state systemic exposure after administration via the Breezhaler® device, either alone (150 mg indacaterol acetate or 320 mg mometasone furoate) or after concurrent administration (free combination) or as a fixed dose combination QMF149 (150 mg indacaterol acetate/320 mg mometasone furoate) in healthy subjects. Additionally, safety and tolerability of multiple inhaled doses of indacaterol acetate and mometasone furoate when administered alone, in free combination or as QMF149 in healthy subjects was also assessed. 2.2. Study design This was a randomized, open-label, four-period, four-sequence complete crossover study in 64 healthy subjects, conducted at two centers. The subjects were assigned to one of four treatment sequences in the ratio 1:1:1:1 (Sequence 1: Treatment A/B/C/D; Sequence 2: Treatment B/D/A/C; Sequence 3: Treatment C/A/D/B; or Sequence 4: Treatment D/C/B/A) to receive treatments that were all delivered via the Breezhaler® device and defined as follows: Treatment A: Indacaterol acetate 150 mg Treatment B: Mometasone furoate 320 mg Treatment C: Free combination (indacaterol acetate 150 mg and mometasone furoate 320 mg, both single ingredient formulations inhaled concurrently via separate Breezhlaer® devices) Treatment D: QMF149 150/320 mg (fixed-dose combination of indacaterol acetate 150 mg and mometasone furoate 320 mg)
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The doses chosen for indacaterol (150 mg), MF (320 mg), and QMF149 (150/320 mg) in this study represented the highest doses which maximizes the possibility of detecting an interaction. In each period, the study medications were administered once daily in the mornings for 14 days via oral inhalation with a minimum 7-day washout period between periods. The systemic exposure of indacaterol and mometasone furoate was determined on Day 14 in each treatment period when PK steady state was achieved for both compounds. A washout period of at least seven days, followed by a treatment period of 14 days (daily dosing) ensured that the PK profile data in Periods 2, 3 and 4 were collected following at least three weeks after the last dose of the preceding treatment. Based on the PK characteristics of both compounds, a period of at least three weeks was sufficient for the washout of any residual concentrations (of indacaterol and mometasone furoate) from the previous treatment period. In order to minimize increased systemic exposure of mometasone furoate due to bronchodilatory effect of indacaterol in the free combination, the ICS was administered before the LABA (both delivered via separate Breezhaler® devices). For all treatments, mouth rinsing was performed post-dose in order to minimize the incidence of candidiasis, which is common with ICS [14]. The subjects were provided training on how to use the inhaler device correctly since demonstration of proper inhalation technique at baseline was a requirement for eligibility to participate in the study. Placebo Breezhaler® devices, including placebo capsules were supplied to the site for training purposes. Each dose administration was done at the study site and observed by study personnel. A sample size of 64 subjects was selected to allow for a drop-out rate of 25% and to provide at least 80% power that the 90% CI (for AUC0-24h, ss and Cmax,ss) for the ratio of geometric means for the test treatment/reference treatment would lie within 0.80e1.25 (for both indacaterol and mometasone furoate analytes). 2.3. Study population The study recruited healthy male and female subjects aged between 18 and 45 years, with a body mass index in the range of 18e29.9 kg/m2 and a forced expiratory volume in 1 s (FEV1) >90% predicted normal at screening. Healthy subjects were selected in order to minimize the impact of comorbid conditions and concomitant medications on the PK profiles of indacaterol and mometasone furoate, and to ensure maximum systemic exposure to the study drugs for better PK characterization. Subjects with a history of clinically significant electrocardiography abnormalities or long QT syndrome, women of child-bearing potential and those with smoking history >10 pack-years were excluded from the study. 2.4. Pharmacokinetic parameters and assessments Venous blood samples (3 mL in lithium heparin tubes for indacaterol and 6 mL in EDTA-containing tubes for mometasone furoate) were taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein. In each period except Treatment B, on Day 14, sample collection time points for indacaterol were as follows: prior to dosing and at 0.083, 0.167, 0.25, 0.5, 1, 2, 3, 4, 6, 12, 24 and 168 h post-dose. In each period except Treatment A, on Day 14, sample collection time points for mometasone furoate were as follows: prior to dosing and at 0.25, 0.5, 1, 1.5, 2, 3, 6, 12, 24 and 168 h post-dose. PK samples were centrifuged at 4 C for about 15 min at approximately 1500 g to separate plasma, and plasma was kept frozen at 20 C until analysis. In addition to the full PK profiles collected on Day 14, pre-dose (trough) concentrations were measured on Day 1 (Period 1 only), Days 12 and 13 of every period.
Indacaterol (free base) and mometasone furoate in plasma were assayed using separate liquid chromatography-tandem mass spectroscopy (LC-MS/MS) methods with lower limits of quantification (LLOQ) of 10.0 and 0.25 pg/mL, respectively [15]. The following PK parameters were estimated by noncompartmental analysis using WinNonlin Phoenix v 6.2 (Pharsight Corporation, Mountain View, CA): area under the plasma concentrationetime curve from time 0e24 h post-dose at steady state (AUC0e24h,ss), maximum plasma concentration at steady state (Cmax,ss) and time to Cmax at steady state (Tmax,ss). The PK parameters, Cmax,ss and AUC0-24h,ss for indacaterol and mometasone furoate were used to estimate systemic exposure ratios of the combination therapy (QMF149 or free dose combination) vs. indacaterol acetate or mometasone furoate, respectively, administered as monotherapy. The systemic exposure ratio of QMF149 vs. freeedose combination of indacaterol acetate and mometasone furoate for each analyte was also estimated from these parameters. 2.5. Safety assessment Safety was assessed by recording all adverse events (AEs) and serious AEs (SAEs), with their severity and relationship with the study drug. 2.6. Statistical analysis Subjects who received any study drug and experienced no protocol deviations that could impact the PK data and contributed to at least one available valid PK concentration measurement, were included in the PK analysis set. For each analyte (indacaterol and mometasone furoate), the log transformed PK parameters (Cmax,ss and AUC0-24h,ss) were analyzed with an analysis of variance model including sequence, subject nested within sequence, period and treatment as fixed factors. For comparison of all study drugs, the least-squares mean treatment differences with their corresponding 90% confidence intervals (CIs) were back-transformed onto the original scale to estimate the systemic exposure ratio (test vs. reference treatment) and their associated 90% CIs for the following treatment comparisons: a. fixed-dose combination QMF149 (Test Treatment D) versus mometasone furoate (Treatment B) (or indacaterol acetate, Treatment A, respectively) administered as monotherapy (reference treatment), b. freeedose combination (Test Treatment C) versus mometasone furoate (Treatment B) (or indacaterol acetate, Treatment A, respectively) administered as monotherapy (reference treatment) and c. fixed-dose combination QMF149 (Test Treatment D) versus freeedose combination (Treatment C), for each analyte. For all treatment comparisons, the 90% CI was compared vs. the reference bioequivalence limits of 0.80e1.25. All subjects who received at least one dose of the study drug were included in the safety analysis set. 3. Results 3.1. Study subjects A total of 64 subjects were enrolled and dosed in this study, of which 57 subjects completed the study as planned and 7 subjects discontinued prior to study completion (Supplementary Table 1). The baseline and demographic characteristics were similar across treatment sequences with majority of the overall study population comprising of males (54, 84%). All but one subject were Caucasians (98%). The mean (SD) age, height, and body mass index (BMI) at baseline were 33.1 (7.70) years, 177.6 (8.00) cm, and 24.9 (2.90) kg/ m2, respectively (Supplementary Table 2).
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3.2. Analysis of pharmacokinetic data The dataset for indacaterol PK parameter estimation included data from 57 subjects receiving indacaterol acetate 150 mg (mono), 58 subjects receiving the free combination and 59 subjects receiving QMF149 150/320 mg. The dataset for mometasone furoate PK parameter estimation included 58 subjects receiving mometasone furoate 320 mg (mono) or free combination and 59 subjects receiving QMF149 150/320 mg.
Mean (+ SD) Indacaterol Plasma Concentration (pg/mL)
3.2.1. Pharmacokinetics of indacaterol Following once-daily inhalation for 14 days, the mean plasma indacaterol concentrations rose rapidly after oral inhalation via the Breezhaler® device and reached a peak at 15 min post-dose. For indacaterol, the PK profiles after inhalation of indacaterol acetate alone (monotherapy), in free combination with MF, or within QMF149, appeared to be similar (Fig. 1). Between subject variability of PK parameters was generally moderate with coefficients of variation (CV%) ranging from 21.4 to 29.2% (Table 1). The trough plasma concentrations of indacaterol were stable from Day 12 to Day 14 (Table 2) for treatments that included indacaterol, indicating that PK steady state was reached by Day 14. In order to assess the relative bioavailability of indacaterol in the presence of mometasone furoate, either in the free or fixed-dose combination, QMF149, the geometric mean exposure ratios were calculated for QMF149 vs. monotherapy, free combination vs. monotherapy and the QMF149 vs. free combination. AUC0-24h,ss and Cmax,ss were 13% and 18% higher, respectively, for the QMF149 vs. indacaterol acetate 150 mg alone comparison, but were similar for the free combination vs. indacaterol acetate 150 mg alone comparison (Table 3). AUC0-24h,ss and Cmax,ss parameters were 13% and 20% higher, respectively, for QMF149 vs. free combination (Table 3). Although a trend toward slightly higher systemic exposure was noted for QMF149, the 90% CIs for all comparisons were within the bioequivalence limit of 0.80e1.25, with the exception of Cmax,ss for indacaterol for the QMF149 vs. free combination comparison (90% CI of 1.14e1.26).
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Time (hours) Treatment A: Indacaterol acetate 150 μg Treatment C: Free combination (Indacaterol acetate 150 μg + Mometasone furoate 320 μg) Treatment D: QMF149 150/320 μg Fig. 1. Plasma concentrationetime profiles for indacaterol on Day 14. Data are presented as arithmetic mean (þSD). Samples were collected up to 168 h. For clarity, the profiles are depicted up to 24 h after dosing. Inset represents data for 0e4 h plasma profiles.
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3.2.2. Pharmacokinetics of mometasone furoate Following once-daily inhalation for 14 days, the mean plasma mometasone furoate concentrations peaked at around 1-h postdose and the concentration vs. time profiles were approximately similar between the different treatments (Fig. 2). Variability of PK parameters was generally moderate with coefficients of variation (CV%) ranging from 21.0 to 25.2% (Table 4). The trough plasma concentrations of mometasone furoate were stable from Day 12 to Day 14 after the treatment with the monotherapy, free combination and QMF149, indicating that PK steady state was reached by Day 14 (Table 2). Relative bioavailability of mometasone furoate in the presence of indacaterol, either in the free or fixed-dose combination, QMF149, was estimated by calculation of the geometric mean exposure ratios for QMF149 vs. monotherapy, free combination vs. monotherapy and the QMF149 vs. free combination (Table 3). AUC024h,ss and Cmax,ss were 14% and 19% higher, respectively, when administered as QMF149 vs. mometasone furoate alone, while both AUC0-24h,ss and Cmax,ss were 11% higher when administered as a free combination vs. mometasone furoate alone. Mometasone furoate AUC0-24h,ss and Cmax,ss for QMF149 were 3% and 7% higher, respectively, compared to the free combination. Although a trend toward slightly higher mometasone furoate systemic exposure was noted for the combination treatments, the 90% CIs for all comparisons were within the bioequivalence limit of 0.80e1.25, with the exception of Cmax,ss for MF for the QMF149 vs. mono comparison (90% CI of 1.13e1.26). 3.3. Safety Patients reported experiencing similar incidence of AEs when administered with mometasone furoate, free combination and QMF149 (reported by 40e46.7% of patients), and slightly lower incidence rates upon administration of indacaterol (reported by 32.8% of patients). Most AEs were mild or moderate in intensity and not suspected to be related to the study medication. There were no reports of SAEs or deaths during the study period. 4. Discussion We report the results of a Phase I study providing pharmacokinetic data for the LABA/ICS combination of indacaterol acetate/ mometasone furoate. This multiple dose study assessed the safety, tolerability and pharmacokinetics of indacaterol acetate and mometasone furoate administered as monotherapies or as free or fixed combinations following once daily dosing for 14 days. Daily inhaled doses of indacaterol acetate and mometasone furoate over a period of 14 days when administered alone, in free combination or as QMF149 in healthy subjects were safe and well tolerated. As evidenced by the stable trough plasma levels of both compounds between Day 12 and Day 14, PK steady state of both indacaterol and MF had been reached by Day 14. Therefore, the treatment duration was adequate to determine the systemic exposure of indacaterol and MF under steady-state conditions which most accurately reflect the clinical situation. Based on prior data for the mono-components, the median time to reach peak serum concentrations of indacaterol was approximately 15 min after single or repeated inhaled doses. Median time to reach peak plasma mometasone furoate concentrations was between 0.375 and 2 h following administration via the Breezhaler® device. The average terminal elimination half-life of indacaterol ranged from 45.5 to 126 h [13] while that for mometasone furoate ranged from 12 to 13 h following administration via the Breezhaler® device [11]. Systemic exposure to indacaterol (dose range: 150 mge600 mg) [13] and mometasone furoate (dose
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Table 1 Summary statistics of PK parameters for indacaterol on Day 14 following once-daily oral inhalation via the Breezhaler® device. Parameters (unit)
Indacaterol (N ¼ 57)
Indacaterol þ Mometasone furoate (N ¼ 58)
QMF149 (N ¼ 59)
AUC0-24h,ss (h pg/mL) Cmax,ss (pg/mL) Tmax,ss (h)
1950 ± 418 (21.4%) 317 ± 72.5 (22.9%) 0.25 [0.23; 0.50]
1910 ± 480 (25.1%) 307 ± 89.7 (29.2%) 0.25 [0.17; 0.53]
2180 ± 511 (23.4%) 374 ± 105 (27.9%) 0.25 [0.17; 0.50]
Data are presented as mean ± SD (CV%), except Tmax,ss, which is presented as median [min; max]. Indacaterol acetate 150 mg (Treatment A); free combination of indacaterol acetate 150 mg and mometasone furoate 320 mg (Treatment C); QMF149 150/320 mg (Treatment D). CV%, coefficient of variation ¼ SD/mean 100; PK, pharmacokinetic; SD, standard deviation.
Table 2 Summary statistics of PK trough concentrations (pg/ml) by treatment and profile day. Indacaterol Profile day
Statistic
Indacaterol
Indacaterol þ Mometasone furoate
QMF149
12
n Mean (SD) CV% mean n Mean (SD) CV% mean n Mean (SD) CV% mean
60 56.9 (13.9) 24.4 60 58.1 (14.0) 24.0 57 52.5 (11.8) 22.4
58 55.1 (16.1) 29.3 58 56.9 (16.4) 28.9 58 51.6 (14.3) 27.7
59 65.5 (19.9) 30.3 59 65.7 (17.3) 26.3 59 58.6 (14.5) 24.8
Profile day
Statistic
Mometasone furoate
Indacaterol þ Mometasone furoate
QMF149
12
n Mean (SD) CV% mean n Mean (SD) CV% mean n Mean (SD) CV% mean
59 22.1 (7.01) 31.8 57 21.6 (7.02) 32.6 58 19.3 (6.50) 33.6
58 21.1 (6.72) 31.8 58 21.0 (6.00) 28.6 58 19.5 (6.23) 32.0
59 22.0 (6.68) 30.4 59 21.7 (6.63) 30.6 59 19.2 (6.26) 32.5
13
14
Mometasone furoate
13
14
All values are for 0 h time point. Indacaterol acetate 150 mg (Treatment A); mometasone furoate 320 mg (Treatment B); free combination of indacaterol acetate 150 mg and mometsone furoate 320 mg (Treatment C); QMF149 150/320 mg (Treatment D). CV%, coefficient of variation, SD/mean 100; PK, pharmacokinetic SD, standard deviation.
Table 3 Geometric mean ratio (test/reference) and 90% CI of PK parameters for the assessment of drugedrug interaction of indacaterol acetate and mometasone furoate delivered via the Breezhaler® device. Adjusted geometric meansa for indacaterol PK parameter a
AUC0-24h,ss (h pg/mL)
Cmax,ss (pg/mL)
Comparison
Indacaterol (A)
Indacaterol þ Mometasone furoate (C)
QMF149 (D)
Ratio of geometric means [90% CI]a
D (T) vs. A (R) C (T) vs. A (R) D (T) vs. C (R) D (T) vs. A (R) C (T) vs. A (R) D (T) vs. C (R)
1868.65 1868.65 e 303.21 303.21 e
e 1868.35 1868.35 e 299.84 299.84
2110.51 e 2110.51 358.89 e 358.89
1.13 1.00 1.13 1.18 0.99 1.20
[1.09, [0.96, [1.09, [1.12, [0.94, [1.14,
1.17] 1.04] 1.17] 1.25] 1.04] 1.26]
Adjusted geometric meansa for mometasone furoate PK parameter
Comparison
Mometasone furoate (B)
Indacaterol þ Mometasone furoate (C)
QMF149 (D)
Ratio of geometric means [90% CI]a
AUC0-24h,ss (hapg/mL)
D (T) vs. B (R) C (T) vs. B (R) D (T) vs. C (R) D (T) vs. B (R) C (T) vs. B (R) D (T) vs. C (R)
1499.96 1499.96 e 177.56 177.56 e
e 1665.03 1665.03 e 197.18 197.18
1713.21 e 1713.21 211.05 e 211.05
1.14 1.11 1.03 1.19 1.11 1.07
Cmax,ss (pg/mL)
[1.09, [1.06, [0.98, [1.13, [1.05, [1.01,
1.20] 1.17] 1.08] 1.26] 1.17] 1.13]
a Back transformed from log scale; indacaterol acetate 150 mg (Treatment A); mometasone furoate 320 mg (Treatment B); free combination of indacaterol acetate 150 mg and mometasone furoate 320 mg (Treatment C); QMF149 150/320 mg (Treatment D). T, test; R, reference; ss, steady state; CI, confidence interval.
range: 50e400 mg) [11], increased in a dose proportional manner, when administered via the Breezhaler® device. A trend towards higher exposure for the free as well as for the fixed combination vs. monotherapy was noted for mometasone furoate Cmax,ss and AUC0-24h,ss. Although speculative, this could potentially be caused by improved delivery of mometasone
furoate due to the bronchodilatory effect of concomitantly administered indacaterol, although the ICS was administered before the LABA for the free dose combination treatment in order to minimize this effect. Alternately, a minor increase in mometasone furoate exposure due to PK interaction or slightly different delivery performance may have contributed to its
Mean (+ SD) Mometasone furoate Plasma Concentration (pg/mL)
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dose proportional pharmacokinetics. Therefore, it is expected that the findings from this study can be extrapolated to lower doses of the fixed dose combination. Inclusion of both the free and fixed dose combination treatment arms in this study enabled characterization of both pharmacokinetic (free combination vs. monotherapy) and biopharmaceutical interactions (QMF149 vs. free combination) in order to gain a better understanding of the mechanisms for potential differences in systemic exposure. These findings in healthy volunteers upon multiple dose administration are expected to adequately predict findings in the patient population (asthma and COPD patients) for whom the drug is intended. This will be further evaluated during the onward development of QMF149.
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Time (hours)
Treatment B: Mometasone furoate 320 μg Treatment C: Free combination (Indacaterol acetate 150 μg + Mometasone furoate 320 μg) Treatment D: FDC QMF149 150/320 μg Fig. 2. Plasma concentrationetime profiles for mometasone furoate on Day 14. Data are presented as arithmetic mean (þSD). Samples were collected up to 168 h. For clarity, the profiles are depicted up to 24 h after dosing.
5. Conclusion In conclusion, multiple inhaled doses of indacaterol acetate (150 mg) and mometasone furoate (320 mg) alone, as a free combination or as a fixed dose combination QMF149, administered via the Breezhlaer® device to healthy subjects, were safe and well tolerated and were not associated with clinically meaningful changes in systemic exposure. These data support further development of QMF149 without dose adjustment of either component.
Table 4 Summary statistics of PK parameters for mometasone furoate on Day 14 following once-daily oral inhalation via the Breezhaler® device. Parameters (unit)
Mometasone furoate (N ¼ 58)
Indacaterol þ Mometasone furoate (N ¼ 58)
QMF149 (N ¼ 59)
AUC0-24h,ss (h pg/mL) Cmax,ss (pg/mL) Tmax,ss (hour)
1560 ± 377 (24.2%) 183 ± 44.5 (24.3%) 1.23 [0.23; 3.00]
1710 ± 431 (25.2%) 202 ± 50.9 (25.2%) 1.00 [0.23; 3.00]
1780 ± 402 (22.5%) 217 ± 45.6 (21.0%) 1.00 [0.25; 3.00]
Data are presented as mean ± SD (CV%), except Tmax,ss that is presented as median [min; max]. Treatment B ¼ mometasone furoate 320 mg; Treatment C ¼ free combination of indacaterol acetate 150 mg and mometsone furoate 320 mg; Treatment D ¼ QMF149 150/320 mg. CV%, coefficient of variation, SD/mean 100; PK, pharmacokinetic; SD, standard deviation; ss, steady state.
slightly higher exposure following administration of the free dose combination or QMF149. Similar to the observations for mometasone furoate, there was also a trend towards increased systemic expsoure for indacaterol both in terms of AUC0-24h,ss and Cmax,ss. However, the increase in systemic exposure was only seen for the comparison between fixed dose combination and monotherapy, while the free combination and the monotherapy treatments showed very similar exposure. As the difference was only seen in one of the two combination treatment arms, small biopharmaceutical interactions specific to the fixed dose combination may have contributed to the slightly higher Cmax,ss for indacaterol following QMF149 administration. While a slight increase in systemic exposure for indacaterol as well as mometasone furoate was noticed in this study, the statistical analysis revealed that all the comparisons between the fixed-dose combination QMF149 and monotherapy treatments fulfilled bioequivalence criteria except for the Cmax,ss of mometasone furoate in the comparison between QMF149 and mometasone furoate 320 mg. Previous data indicate that inhaled doses up to 600 mg/day indacaterol administered via the Breezhaler® device up to 1 year [16] and 1600 mg/day (administered as 800 mg twice daily) of mometasone furoate in the Twisthaler® device up to 28 days [17] were not associated with any clinical safety concerns, therefore the slight increase in exposure of the individual components is judged as not clinically meaningful. Both indacaterol and MF delivered via the Breezhaler® device exhibit
Conflict of interest SSV is an employee of Novartis Institutes for BioMedical Research, Cambridge, MA, USA. SK and NC were employees of Novartis Institutes for BioMedical Research, Horsham, UK at the time of study completion. SM is an employee of Novartis Healthcare Pvt. Ltd., Hyderabad, India. HH and RW are employees of Novartis Institutes for BioMedical Research, Basel, Switzerland. TM was an employee of Novartis Institutes for BioMedical Research, East Hanover, NJ, USA at the time of study completion. SF is an employee of Simbec Research Ltd., Merthyr Tydfil, UK. RF is an employee of PAREXEL, Berlin, Germany. Statement of authorship SSV, SK, NC and SM were involved in designing the study. SF and RF were responsible for conducting the study. Data were analyzed and interpreted by SSV, SK, HH, TM and RW. All the authors were involved in drafting and reviewing the manuscript and were responsible for the decision to submit for publication. Role of sponsors This study was funded by Novartis Pharma AG, Basel,
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Switzerland. Acknowledgment The authors acknowledge Praveen Kaul and Vasavi Yada, Novartis Healthcare Pvt. Ltd., India, for medical writing support. The authors also thank all the clinical investigators, study coordinators and subjects at the participating centers and members of the clinical trial team and project team.
[7]
[8]
[9]
[10]
Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.pupt.2016.01.004.
[11]
[12]
References [13] [1] Global Initiative for Asthma (GINA), The Global Initiative for Asthma. GINA Report, Global Strategy for Asthma Management and Prevention, Available from:, 2015 http://www.ginasthma.org. Accessed April 22 2015. [2] Global Initiative for Chronic Obstructive Lung Disease (GOLD), Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease, Available from:, 2015 http://www.goldcopd.com. Accessed April 22 2015. [3] R. Beasley, K. Perrin, M. Weatherall, M. Wijesinghe, Call for withdrawal of LABA single-therapy inhaler in asthma, Lancet 376 (2010) 750e751. [4] R. Beasley, J. Fingleton, M. Weatherall, Restriction of LABA use to combination ICS/LABA inhaler therapy in asthma, Thorax 68 (2013) 119e120. [5] G.J. Rodrigo, J.A. Castro-Rodriguez, Safety of long-acting beta agonists for the treatment of asthma: clearing the air, Thorax 67 (2012) 342e349. [6] S.W. Stoloff, D.A. Stempel, J. Meyer, R.H. Stanford, J.R. Carranza Rosenzweig, Improved refill persistence with fluticasone propionate and salmeterol in a
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single inhaler compared with other controller therapies, J. Allergy Clin. Immunol. 113 (2004) 245e251. D.A. Stempel, S.W. Stoloff, J.R. Carranza Rosenzweig, R.H. Stanford, K.L. Ryskina, A.P. Legorreta, Adherence to asthma controller medication regimens, Respir. Med. 99 (2005) 1263e1267. re, D. Berbiche, S. Perreault, L. Blais, Persistence, adherC. Marceau, C. Lemie ence, and effectiveness of combination therapy among adult patients with asthma, J. Allergy Clin. Immunol. 118 (2006) 574e581. C. LaForce, P. Korenblat, P. Osborne, F. Dong, M. Higgins, 24-hour bronchodilator efficacy of single doses of indacaterol in patients with persistent asthma: comparison with placebo and formoterol, Curr. Med. Res. Opin. 25 (2009) 2353e2359. P.L. McCormack, G.L. Plosker, Inhaled mometasone furoate: A review of its use in persistent asthma in adults and adolescents, Drugs 66 (2006) 1151e1168. S. Vaidya, S. Khindri, J. Robinson, T. Smith, B. Magnusson, G. Kaiser, et al., Pharmacokinetics (PK) of single doses of mometasone furoate (MF) delivered via the Breezhaler® (BH) and Twisthaler® (TH) devices in healthy subjects, Eur. Respir. J. 40 (2012) P382. F. Kanniess, G. Hanf, H. Hosoe, A.M. Tanase, S. Vaidya, R. Banerjee, et al., Mometasone furoate delivered via the Breezhaler® and Twisthaler® devices in asthma, Eur. Respir. J. 44 (2014) P915. European medicines evaluation agency. Indacaterol (Onbrez® Breezhaler®) Summary of product characteristics. Available at: www.ema.europa.eu Accessed 28 May 2015. Merck: Asmanex® Twisthaler® Prescribing Information Available from http:// www.merck.com Accessed April 22 2015. S. Shimada, S. Vaidya, S. Khindri, N. Tashiro, Y. Cheng, H. Hara, et al., Pharmacokinetics of QMF149 in Japanese versus Caucasian subjects: an openlabel, randomized phase I study, Int. J. Clin. Pharmacol. Ther. 53 (2015) 398e407. R. Beasley, B. Lanier, I. Varkonyi, B. Novakova, A. Moton, H.J. Kim, et al., Safety of once-daily QMF149 in patients with persistent asthma, Eur. Respir. J. 40 (2012) P2093. M.B. Affrime, T. Kosoglou, C.M. Thonoor, B.E. Flannery, J.M. Herron, Mometasone furoate has minimal effects on the hypothalamic-pituitary-adrenal axis when delivered at high doses, Chest 118 (2000) 1538e1546.
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Pharmacokinetics of indacaterol and mometasone furoate delivered alone or in a free or fixed dose combination in healthy subjects Soniya S. Vaidya a, *, Sanjeev Khindri b, Nicole Calder b, Surendra Machineni c, Hisanori Hara d, Tapan Majumdar e, Salvatore Febbraro f, Rainard Fuhr g, Ralph Woessner d a
Drug Metabolism and Pharmacokinetics, Clinical Pharmacokinetics/Pharmacodynamics, Novartis Institutes for BioMedical Research, Cambridge, MA, USA Translational Medicine, Novartis Institutes for BioMedical Research, Horsham, UK Integrated Information Sciences, Novartis Healthcare Pvt. Ltd., Hyderabad, India d Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, Basel, Switzerland e Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA f Simbec Research Ltd., Merthyr Tydfil, UK g Early Phase Clinical Unit, PAREXEL, Berlin, Germany b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 July 2015 Received in revised form 28 January 2016 Accepted 30 January 2016 Available online 1 February 2016
Purpose: QMF149 is a fixed-dose combination of the long-acting b2 agonist, indacaterol and the corticosteroid, mometasone furoate that is currently under development for treatment of patients with asthma and chronic obstructive pulmonary disease. We describe here a study designed to assess any pharmacokinetic (PK) and/or biopharmaceutical interaction between indacaterol and mometasone furoate when administered via the Breezhaler® device, either alone or in a free or fixed combination (QMF149) in healthy adult subjects. Methods: In this randomized, open-label, four-way crossover study, subjects were randomized to receive indacaterol acetate 150 mg, mometasone furoate 320 mg, alone and as free combination of the individual components, or QMF149 (indacaterol acetate 150 mg/mometasone furoate 320 mg) once daily for 14 days in each period, followed by a 7-day washout between periods. PK profiles were characterized on Day 14 up to 168 h post-dose. Results: Indacaterol AUC0-24h,ss and Cmax,ss after administration of QMF149 were 13% [ratio: 1.13; 90%CI: 1.09, 1.17] and 18% [ratio: 1.18; 90%CI: 1.12, 1.25] higher, respectively, than indacaterol monotherapy. Mometasone furoate AUC0-24h,ss and Cmax,ss after administration of QMF149 were 14% [ratio: 1.14; 90%CI: 1.09, 1.20] and 19% [ratio: 1.19; 90%CI: 1.13, 1.26], higher, respectively than mometasone furoate monotherapy. The majority (three of four comparisons between QMF149 and monotherapy) of the 90% confidence intervals of the between-treatment ratios for AUC0-24h,ss and Cmax,ss were within the 0.80 to 1.25 interval and therefore fulfilled bioequivalence criteria. The 90% confidence interval for Cmax,ss for MF for the QMF149 vs. monotherapy comparison was [1.13, 1.26]. Although no definitive data can be provided on the basis of the present study results, it is unlikely that the small observed differences in expsoure are clinically meaningful. Multiple inhaled doses of indacaterol and mometasone furoate, when administered alone, in free combination or as QMF149 were well tolerated. Conclusions: The QMF149 fixed dose combination treatment showed comparable systemic exposure to the free combination and monotherapy treatments in terms of AUC0-24h,ss and Cmax,ss for both indacaterol and mometasone furoate, indicating an absence of clinically relevant PK or biopharmaceutical interactions. These data support further development of QMF149 without dose adjustment. © 2016 Elsevier Ltd. All rights reserved.
Keywords: QMF149 Indacaterol Mometasone furoate Pharmacokinetics Biopharmaceutical interaction
1. Introduction * Corresponding author. Drug Metabolism and Pharmacokinetics, Clinical Pharmacokinetics/Pharmacodynamics, Novartis Institutes for BioMedical Research, 220 Massachusetts Avenue, Cambridge, MA, USA. E-mail address: [email protected] (S.S. Vaidya). http://dx.doi.org/10.1016/j.pupt.2016.01.004 1094-5539/© 2016 Elsevier Ltd. All rights reserved.
Patients with uncontrolled chronic respiratory airway disorders, such as asthma or chronic obstructive pulmonary disease (COPD)
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are at a high risk of potentially life-threatening exacerbations, necessitating additional treatment, health-care consultations and often hospitalizations. In such patients, adequate symptom control may be achieved either by addition of a long-acting beta agonist (LABA) to inhaled corticosteroids (ICS), for patients with asthma; or addition of ICS to LABA, for patients with COPD [1,2]. Thus LABA/ICS combination therapy remains a cornerstone of treatment for patients with these persistent respiratory airway diseases [1,2]. It is known that use of separate inhalers for administering LABA and ICS as a free combination leads to LABA monotherapy in patients who are non-compliant with their ICS, resulting in increased risk of asthma mortality [3,4]. In order to avoid complications of LABA monotherapy [5] and achieve patient compliance to prescribed ICS regimens, it is important to administer the combination as a fixed dose via a single inhaler [6e8]. QMF149, administered via a single dose dry powder lowresistance inhaler, the Breezhaler® device, is currently being developed as a once-daily (o.d.) fixed-dose combination of the LABA indacaterol acetate and the ICS mometasone furoate, for the treatment of patients with asthma as well as patients with COPD that require ICS. The mono-components, indacaterol maleate (Onbrez® Breezhaler® or Arcapta™ Neohaler™; inhalation powder at doses between 75 and 300 mg o.d, Novartis Pharma AG, Basel, Switzerland) and mometasone furoate (Asmanex® Twisthaler® inhalation powder at doses of 100, 200 and 400 mg [per delivered dose] up to a maximum daily dose of 800 mg, Merck, Sharp & Dohme Corp., Whitehouse Station, New Jersey, USA) are approved for maintenance treatment of COPD and asthma, respectively. The advantage of the fixed-dose combination, QMF149, is that it combines the efficacy and rapid onset of action of indacaterol with the anti-inflammatory activity of mometasone furoate. Furthermore, both the mono-components also exhibit bronchodilation that is sustained over a period of 24 h [9,10]. Previous studies demonstrated that 80, 160 and 320 mg doses of mometasone furoate in the Breezhaler® device were comparable to the 200, 400 and 2 400 mg doses of mometasone furoate in the Twisthaler® device, respectively, based on the pharmacokinetic (PK) data, in-vitro fine particle mass adjustments and subsequent confirmation in a safety and efficacy study in asthma patients [11,12]. In vitro investigations indicated that cytochrome P450 isoform 3A4 (CYP3A4) is the predominant isoenzyme responsible for hydroxylation of indacaterol. CYP isoforms 1A1 and 2D6, and uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1) play a minor role in the metabolism of indacaterol, and it is a low affinity substrate for the efflux pump P-glycoprotein. Indacaterol has not been shown to cause interactions with concomitantly administered medicinal products. In vitro investigations indicated that indacaterol has negligible potential to cause metabolic interactions at the systemic exposure levels achieved in clinical practice. The portion of an inhaled mometasone furoate dose that is swallowed is absorbed in the gastrointestinal tract and undergoes extensive metabolism to multiple metabolites. Although the information available on the hepatic metabolism of mometasone furoate is limited, it is known that mometasone furoate is metabolized by CYP3A4 in vitro in human liver microsomes. Overall, the potential for systemic pharmacokinetic interaction between MF and indacaterol acetate is low based on in vitro data and clinical drug interaction studies conducted for indacaterol maleate and for mometasone furoate. Both indacaterol and MF are metabolized by CYP3A4 but are not known to be inhibitors or inducers of CYP3A4. Furthermore, the potential for pulmonary pharmacokinetic interaction is also considered to be low. In vitro incubation of MF in human lung S9 fractions (post-mitochondrial supernatant fraction containing phase I and phase II metabolic enzymes) indicated that MF does not undergo significant pulmonary metabolism. Similarly,
31
no metabolites of indacaterol were detected in human lung slices or human pulmonary microsomes. These data suggested that the contribution of the lung to the metabolism of these compounds is low. The present study was designed to assess potential PK interactions or biopharmaceutical interaction (i.e: the interaction of the two active components when physically combined into a new product formulation in a single capsule to be inhaled via the Breezhaler® device) between indacaterol and mometasone furoate when delivered as a fixed-dose combination (QMF149) via the Breezhaler® device in healthy adult subjects. Although the potential for systemic or pulmonary interactions was considered low, evaluation of systemic exposure following inhaled administration of the fixed dose combinations (QMF149) was undertaken to assess whether the systemic exposure of each of the components (indacaterol and mometasone furoate) was similar to that in the monotherapy products. Demonstration of similar exposure between the fixed dose combination and monotherapy products is important in order to ensure that the safety profile for the combination product will be similar to that of the monotherapy products. 2. Methods The study was conducted according to the ethical principles of the Declaration of Helsinki. The study protocol (Study CQMF149E2102) was reviewed by the Independent Ethics Committees at the two study centers (Simbec Research Ltd, Merthyr Tydfil, United Kingdom, and the PAREXEL Early Phase Clinical Unit Berlin, Berlin, Germany). Informed consent was obtained from each subject in writing before any screening procedures were performed as per the clinics' standard operating procedures. 2.1. Study objectives The objective of this study was to evaluate the potential for a PK drug interaction or a biopharmaceutical interaction between indacaterol acetate and mometasone furoate as determined by their steady-state systemic exposure after administration via the Breezhaler® device, either alone (150 mg indacaterol acetate or 320 mg mometasone furoate) or after concurrent administration (free combination) or as a fixed dose combination QMF149 (150 mg indacaterol acetate/320 mg mometasone furoate) in healthy subjects. Additionally, safety and tolerability of multiple inhaled doses of indacaterol acetate and mometasone furoate when administered alone, in free combination or as QMF149 in healthy subjects was also assessed. 2.2. Study design This was a randomized, open-label, four-period, four-sequence complete crossover study in 64 healthy subjects, conducted at two centers. The subjects were assigned to one of four treatment sequences in the ratio 1:1:1:1 (Sequence 1: Treatment A/B/C/D; Sequence 2: Treatment B/D/A/C; Sequence 3: Treatment C/A/D/B; or Sequence 4: Treatment D/C/B/A) to receive treatments that were all delivered via the Breezhaler® device and defined as follows: Treatment A: Indacaterol acetate 150 mg Treatment B: Mometasone furoate 320 mg Treatment C: Free combination (indacaterol acetate 150 mg and mometasone furoate 320 mg, both single ingredient formulations inhaled concurrently via separate Breezhlaer® devices) Treatment D: QMF149 150/320 mg (fixed-dose combination of indacaterol acetate 150 mg and mometasone furoate 320 mg)
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The doses chosen for indacaterol (150 mg), MF (320 mg), and QMF149 (150/320 mg) in this study represented the highest doses which maximizes the possibility of detecting an interaction. In each period, the study medications were administered once daily in the mornings for 14 days via oral inhalation with a minimum 7-day washout period between periods. The systemic exposure of indacaterol and mometasone furoate was determined on Day 14 in each treatment period when PK steady state was achieved for both compounds. A washout period of at least seven days, followed by a treatment period of 14 days (daily dosing) ensured that the PK profile data in Periods 2, 3 and 4 were collected following at least three weeks after the last dose of the preceding treatment. Based on the PK characteristics of both compounds, a period of at least three weeks was sufficient for the washout of any residual concentrations (of indacaterol and mometasone furoate) from the previous treatment period. In order to minimize increased systemic exposure of mometasone furoate due to bronchodilatory effect of indacaterol in the free combination, the ICS was administered before the LABA (both delivered via separate Breezhaler® devices). For all treatments, mouth rinsing was performed post-dose in order to minimize the incidence of candidiasis, which is common with ICS [14]. The subjects were provided training on how to use the inhaler device correctly since demonstration of proper inhalation technique at baseline was a requirement for eligibility to participate in the study. Placebo Breezhaler® devices, including placebo capsules were supplied to the site for training purposes. Each dose administration was done at the study site and observed by study personnel. A sample size of 64 subjects was selected to allow for a drop-out rate of 25% and to provide at least 80% power that the 90% CI (for AUC0-24h, ss and Cmax,ss) for the ratio of geometric means for the test treatment/reference treatment would lie within 0.80e1.25 (for both indacaterol and mometasone furoate analytes). 2.3. Study population The study recruited healthy male and female subjects aged between 18 and 45 years, with a body mass index in the range of 18e29.9 kg/m2 and a forced expiratory volume in 1 s (FEV1) >90% predicted normal at screening. Healthy subjects were selected in order to minimize the impact of comorbid conditions and concomitant medications on the PK profiles of indacaterol and mometasone furoate, and to ensure maximum systemic exposure to the study drugs for better PK characterization. Subjects with a history of clinically significant electrocardiography abnormalities or long QT syndrome, women of child-bearing potential and those with smoking history >10 pack-years were excluded from the study. 2.4. Pharmacokinetic parameters and assessments Venous blood samples (3 mL in lithium heparin tubes for indacaterol and 6 mL in EDTA-containing tubes for mometasone furoate) were taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein. In each period except Treatment B, on Day 14, sample collection time points for indacaterol were as follows: prior to dosing and at 0.083, 0.167, 0.25, 0.5, 1, 2, 3, 4, 6, 12, 24 and 168 h post-dose. In each period except Treatment A, on Day 14, sample collection time points for mometasone furoate were as follows: prior to dosing and at 0.25, 0.5, 1, 1.5, 2, 3, 6, 12, 24 and 168 h post-dose. PK samples were centrifuged at 4 C for about 15 min at approximately 1500 g to separate plasma, and plasma was kept frozen at 20 C until analysis. In addition to the full PK profiles collected on Day 14, pre-dose (trough) concentrations were measured on Day 1 (Period 1 only), Days 12 and 13 of every period.
Indacaterol (free base) and mometasone furoate in plasma were assayed using separate liquid chromatography-tandem mass spectroscopy (LC-MS/MS) methods with lower limits of quantification (LLOQ) of 10.0 and 0.25 pg/mL, respectively [15]. The following PK parameters were estimated by noncompartmental analysis using WinNonlin Phoenix v 6.2 (Pharsight Corporation, Mountain View, CA): area under the plasma concentrationetime curve from time 0e24 h post-dose at steady state (AUC0e24h,ss), maximum plasma concentration at steady state (Cmax,ss) and time to Cmax at steady state (Tmax,ss). The PK parameters, Cmax,ss and AUC0-24h,ss for indacaterol and mometasone furoate were used to estimate systemic exposure ratios of the combination therapy (QMF149 or free dose combination) vs. indacaterol acetate or mometasone furoate, respectively, administered as monotherapy. The systemic exposure ratio of QMF149 vs. freeedose combination of indacaterol acetate and mometasone furoate for each analyte was also estimated from these parameters. 2.5. Safety assessment Safety was assessed by recording all adverse events (AEs) and serious AEs (SAEs), with their severity and relationship with the study drug. 2.6. Statistical analysis Subjects who received any study drug and experienced no protocol deviations that could impact the PK data and contributed to at least one available valid PK concentration measurement, were included in the PK analysis set. For each analyte (indacaterol and mometasone furoate), the log transformed PK parameters (Cmax,ss and AUC0-24h,ss) were analyzed with an analysis of variance model including sequence, subject nested within sequence, period and treatment as fixed factors. For comparison of all study drugs, the least-squares mean treatment differences with their corresponding 90% confidence intervals (CIs) were back-transformed onto the original scale to estimate the systemic exposure ratio (test vs. reference treatment) and their associated 90% CIs for the following treatment comparisons: a. fixed-dose combination QMF149 (Test Treatment D) versus mometasone furoate (Treatment B) (or indacaterol acetate, Treatment A, respectively) administered as monotherapy (reference treatment), b. freeedose combination (Test Treatment C) versus mometasone furoate (Treatment B) (or indacaterol acetate, Treatment A, respectively) administered as monotherapy (reference treatment) and c. fixed-dose combination QMF149 (Test Treatment D) versus freeedose combination (Treatment C), for each analyte. For all treatment comparisons, the 90% CI was compared vs. the reference bioequivalence limits of 0.80e1.25. All subjects who received at least one dose of the study drug were included in the safety analysis set. 3. Results 3.1. Study subjects A total of 64 subjects were enrolled and dosed in this study, of which 57 subjects completed the study as planned and 7 subjects discontinued prior to study completion (Supplementary Table 1). The baseline and demographic characteristics were similar across treatment sequences with majority of the overall study population comprising of males (54, 84%). All but one subject were Caucasians (98%). The mean (SD) age, height, and body mass index (BMI) at baseline were 33.1 (7.70) years, 177.6 (8.00) cm, and 24.9 (2.90) kg/ m2, respectively (Supplementary Table 2).
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3.2. Analysis of pharmacokinetic data The dataset for indacaterol PK parameter estimation included data from 57 subjects receiving indacaterol acetate 150 mg (mono), 58 subjects receiving the free combination and 59 subjects receiving QMF149 150/320 mg. The dataset for mometasone furoate PK parameter estimation included 58 subjects receiving mometasone furoate 320 mg (mono) or free combination and 59 subjects receiving QMF149 150/320 mg.
Mean (+ SD) Indacaterol Plasma Concentration (pg/mL)
3.2.1. Pharmacokinetics of indacaterol Following once-daily inhalation for 14 days, the mean plasma indacaterol concentrations rose rapidly after oral inhalation via the Breezhaler® device and reached a peak at 15 min post-dose. For indacaterol, the PK profiles after inhalation of indacaterol acetate alone (monotherapy), in free combination with MF, or within QMF149, appeared to be similar (Fig. 1). Between subject variability of PK parameters was generally moderate with coefficients of variation (CV%) ranging from 21.4 to 29.2% (Table 1). The trough plasma concentrations of indacaterol were stable from Day 12 to Day 14 (Table 2) for treatments that included indacaterol, indicating that PK steady state was reached by Day 14. In order to assess the relative bioavailability of indacaterol in the presence of mometasone furoate, either in the free or fixed-dose combination, QMF149, the geometric mean exposure ratios were calculated for QMF149 vs. monotherapy, free combination vs. monotherapy and the QMF149 vs. free combination. AUC0-24h,ss and Cmax,ss were 13% and 18% higher, respectively, for the QMF149 vs. indacaterol acetate 150 mg alone comparison, but were similar for the free combination vs. indacaterol acetate 150 mg alone comparison (Table 3). AUC0-24h,ss and Cmax,ss parameters were 13% and 20% higher, respectively, for QMF149 vs. free combination (Table 3). Although a trend toward slightly higher systemic exposure was noted for QMF149, the 90% CIs for all comparisons were within the bioequivalence limit of 0.80e1.25, with the exception of Cmax,ss for indacaterol for the QMF149 vs. free combination comparison (90% CI of 1.14e1.26).
500
500
400
400
300
300 200
200
100
0
100
0
4
8
12
16
4
20
24
Time (hours) Treatment A: Indacaterol acetate 150 μg Treatment C: Free combination (Indacaterol acetate 150 μg + Mometasone furoate 320 μg) Treatment D: QMF149 150/320 μg Fig. 1. Plasma concentrationetime profiles for indacaterol on Day 14. Data are presented as arithmetic mean (þSD). Samples were collected up to 168 h. For clarity, the profiles are depicted up to 24 h after dosing. Inset represents data for 0e4 h plasma profiles.
33
3.2.2. Pharmacokinetics of mometasone furoate Following once-daily inhalation for 14 days, the mean plasma mometasone furoate concentrations peaked at around 1-h postdose and the concentration vs. time profiles were approximately similar between the different treatments (Fig. 2). Variability of PK parameters was generally moderate with coefficients of variation (CV%) ranging from 21.0 to 25.2% (Table 4). The trough plasma concentrations of mometasone furoate were stable from Day 12 to Day 14 after the treatment with the monotherapy, free combination and QMF149, indicating that PK steady state was reached by Day 14 (Table 2). Relative bioavailability of mometasone furoate in the presence of indacaterol, either in the free or fixed-dose combination, QMF149, was estimated by calculation of the geometric mean exposure ratios for QMF149 vs. monotherapy, free combination vs. monotherapy and the QMF149 vs. free combination (Table 3). AUC024h,ss and Cmax,ss were 14% and 19% higher, respectively, when administered as QMF149 vs. mometasone furoate alone, while both AUC0-24h,ss and Cmax,ss were 11% higher when administered as a free combination vs. mometasone furoate alone. Mometasone furoate AUC0-24h,ss and Cmax,ss for QMF149 were 3% and 7% higher, respectively, compared to the free combination. Although a trend toward slightly higher mometasone furoate systemic exposure was noted for the combination treatments, the 90% CIs for all comparisons were within the bioequivalence limit of 0.80e1.25, with the exception of Cmax,ss for MF for the QMF149 vs. mono comparison (90% CI of 1.13e1.26). 3.3. Safety Patients reported experiencing similar incidence of AEs when administered with mometasone furoate, free combination and QMF149 (reported by 40e46.7% of patients), and slightly lower incidence rates upon administration of indacaterol (reported by 32.8% of patients). Most AEs were mild or moderate in intensity and not suspected to be related to the study medication. There were no reports of SAEs or deaths during the study period. 4. Discussion We report the results of a Phase I study providing pharmacokinetic data for the LABA/ICS combination of indacaterol acetate/ mometasone furoate. This multiple dose study assessed the safety, tolerability and pharmacokinetics of indacaterol acetate and mometasone furoate administered as monotherapies or as free or fixed combinations following once daily dosing for 14 days. Daily inhaled doses of indacaterol acetate and mometasone furoate over a period of 14 days when administered alone, in free combination or as QMF149 in healthy subjects were safe and well tolerated. As evidenced by the stable trough plasma levels of both compounds between Day 12 and Day 14, PK steady state of both indacaterol and MF had been reached by Day 14. Therefore, the treatment duration was adequate to determine the systemic exposure of indacaterol and MF under steady-state conditions which most accurately reflect the clinical situation. Based on prior data for the mono-components, the median time to reach peak serum concentrations of indacaterol was approximately 15 min after single or repeated inhaled doses. Median time to reach peak plasma mometasone furoate concentrations was between 0.375 and 2 h following administration via the Breezhaler® device. The average terminal elimination half-life of indacaterol ranged from 45.5 to 126 h [13] while that for mometasone furoate ranged from 12 to 13 h following administration via the Breezhaler® device [11]. Systemic exposure to indacaterol (dose range: 150 mge600 mg) [13] and mometasone furoate (dose
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Table 1 Summary statistics of PK parameters for indacaterol on Day 14 following once-daily oral inhalation via the Breezhaler® device. Parameters (unit)
Indacaterol (N ¼ 57)
Indacaterol þ Mometasone furoate (N ¼ 58)
QMF149 (N ¼ 59)
AUC0-24h,ss (h pg/mL) Cmax,ss (pg/mL) Tmax,ss (h)
1950 ± 418 (21.4%) 317 ± 72.5 (22.9%) 0.25 [0.23; 0.50]
1910 ± 480 (25.1%) 307 ± 89.7 (29.2%) 0.25 [0.17; 0.53]
2180 ± 511 (23.4%) 374 ± 105 (27.9%) 0.25 [0.17; 0.50]
Data are presented as mean ± SD (CV%), except Tmax,ss, which is presented as median [min; max]. Indacaterol acetate 150 mg (Treatment A); free combination of indacaterol acetate 150 mg and mometasone furoate 320 mg (Treatment C); QMF149 150/320 mg (Treatment D). CV%, coefficient of variation ¼ SD/mean 100; PK, pharmacokinetic; SD, standard deviation.
Table 2 Summary statistics of PK trough concentrations (pg/ml) by treatment and profile day. Indacaterol Profile day
Statistic
Indacaterol
Indacaterol þ Mometasone furoate
QMF149
12
n Mean (SD) CV% mean n Mean (SD) CV% mean n Mean (SD) CV% mean
60 56.9 (13.9) 24.4 60 58.1 (14.0) 24.0 57 52.5 (11.8) 22.4
58 55.1 (16.1) 29.3 58 56.9 (16.4) 28.9 58 51.6 (14.3) 27.7
59 65.5 (19.9) 30.3 59 65.7 (17.3) 26.3 59 58.6 (14.5) 24.8
Profile day
Statistic
Mometasone furoate
Indacaterol þ Mometasone furoate
QMF149
12
n Mean (SD) CV% mean n Mean (SD) CV% mean n Mean (SD) CV% mean
59 22.1 (7.01) 31.8 57 21.6 (7.02) 32.6 58 19.3 (6.50) 33.6
58 21.1 (6.72) 31.8 58 21.0 (6.00) 28.6 58 19.5 (6.23) 32.0
59 22.0 (6.68) 30.4 59 21.7 (6.63) 30.6 59 19.2 (6.26) 32.5
13
14
Mometasone furoate
13
14
All values are for 0 h time point. Indacaterol acetate 150 mg (Treatment A); mometasone furoate 320 mg (Treatment B); free combination of indacaterol acetate 150 mg and mometsone furoate 320 mg (Treatment C); QMF149 150/320 mg (Treatment D). CV%, coefficient of variation, SD/mean 100; PK, pharmacokinetic SD, standard deviation.
Table 3 Geometric mean ratio (test/reference) and 90% CI of PK parameters for the assessment of drugedrug interaction of indacaterol acetate and mometasone furoate delivered via the Breezhaler® device. Adjusted geometric meansa for indacaterol PK parameter a
AUC0-24h,ss (h pg/mL)
Cmax,ss (pg/mL)
Comparison
Indacaterol (A)
Indacaterol þ Mometasone furoate (C)
QMF149 (D)
Ratio of geometric means [90% CI]a
D (T) vs. A (R) C (T) vs. A (R) D (T) vs. C (R) D (T) vs. A (R) C (T) vs. A (R) D (T) vs. C (R)
1868.65 1868.65 e 303.21 303.21 e
e 1868.35 1868.35 e 299.84 299.84
2110.51 e 2110.51 358.89 e 358.89
1.13 1.00 1.13 1.18 0.99 1.20
[1.09, [0.96, [1.09, [1.12, [0.94, [1.14,
1.17] 1.04] 1.17] 1.25] 1.04] 1.26]
Adjusted geometric meansa for mometasone furoate PK parameter
Comparison
Mometasone furoate (B)
Indacaterol þ Mometasone furoate (C)
QMF149 (D)
Ratio of geometric means [90% CI]a
AUC0-24h,ss (hapg/mL)
D (T) vs. B (R) C (T) vs. B (R) D (T) vs. C (R) D (T) vs. B (R) C (T) vs. B (R) D (T) vs. C (R)
1499.96 1499.96 e 177.56 177.56 e
e 1665.03 1665.03 e 197.18 197.18
1713.21 e 1713.21 211.05 e 211.05
1.14 1.11 1.03 1.19 1.11 1.07
Cmax,ss (pg/mL)
[1.09, [1.06, [0.98, [1.13, [1.05, [1.01,
1.20] 1.17] 1.08] 1.26] 1.17] 1.13]
a Back transformed from log scale; indacaterol acetate 150 mg (Treatment A); mometasone furoate 320 mg (Treatment B); free combination of indacaterol acetate 150 mg and mometasone furoate 320 mg (Treatment C); QMF149 150/320 mg (Treatment D). T, test; R, reference; ss, steady state; CI, confidence interval.
range: 50e400 mg) [11], increased in a dose proportional manner, when administered via the Breezhaler® device. A trend towards higher exposure for the free as well as for the fixed combination vs. monotherapy was noted for mometasone furoate Cmax,ss and AUC0-24h,ss. Although speculative, this could potentially be caused by improved delivery of mometasone
furoate due to the bronchodilatory effect of concomitantly administered indacaterol, although the ICS was administered before the LABA for the free dose combination treatment in order to minimize this effect. Alternately, a minor increase in mometasone furoate exposure due to PK interaction or slightly different delivery performance may have contributed to its
Mean (+ SD) Mometasone furoate Plasma Concentration (pg/mL)
S.S. Vaidya et al. / Pulmonary Pharmacology & Therapeutics 37 (2016) 30e36
35
dose proportional pharmacokinetics. Therefore, it is expected that the findings from this study can be extrapolated to lower doses of the fixed dose combination. Inclusion of both the free and fixed dose combination treatment arms in this study enabled characterization of both pharmacokinetic (free combination vs. monotherapy) and biopharmaceutical interactions (QMF149 vs. free combination) in order to gain a better understanding of the mechanisms for potential differences in systemic exposure. These findings in healthy volunteers upon multiple dose administration are expected to adequately predict findings in the patient population (asthma and COPD patients) for whom the drug is intended. This will be further evaluated during the onward development of QMF149.
250
200
150
100
50
0
4
8
12
16
20
24
Time (hours)
Treatment B: Mometasone furoate 320 μg Treatment C: Free combination (Indacaterol acetate 150 μg + Mometasone furoate 320 μg) Treatment D: FDC QMF149 150/320 μg Fig. 2. Plasma concentrationetime profiles for mometasone furoate on Day 14. Data are presented as arithmetic mean (þSD). Samples were collected up to 168 h. For clarity, the profiles are depicted up to 24 h after dosing.
5. Conclusion In conclusion, multiple inhaled doses of indacaterol acetate (150 mg) and mometasone furoate (320 mg) alone, as a free combination or as a fixed dose combination QMF149, administered via the Breezhlaer® device to healthy subjects, were safe and well tolerated and were not associated with clinically meaningful changes in systemic exposure. These data support further development of QMF149 without dose adjustment of either component.
Table 4 Summary statistics of PK parameters for mometasone furoate on Day 14 following once-daily oral inhalation via the Breezhaler® device. Parameters (unit)
Mometasone furoate (N ¼ 58)
Indacaterol þ Mometasone furoate (N ¼ 58)
QMF149 (N ¼ 59)
AUC0-24h,ss (h pg/mL) Cmax,ss (pg/mL) Tmax,ss (hour)
1560 ± 377 (24.2%) 183 ± 44.5 (24.3%) 1.23 [0.23; 3.00]
1710 ± 431 (25.2%) 202 ± 50.9 (25.2%) 1.00 [0.23; 3.00]
1780 ± 402 (22.5%) 217 ± 45.6 (21.0%) 1.00 [0.25; 3.00]
Data are presented as mean ± SD (CV%), except Tmax,ss that is presented as median [min; max]. Treatment B ¼ mometasone furoate 320 mg; Treatment C ¼ free combination of indacaterol acetate 150 mg and mometsone furoate 320 mg; Treatment D ¼ QMF149 150/320 mg. CV%, coefficient of variation, SD/mean 100; PK, pharmacokinetic; SD, standard deviation; ss, steady state.
slightly higher exposure following administration of the free dose combination or QMF149. Similar to the observations for mometasone furoate, there was also a trend towards increased systemic expsoure for indacaterol both in terms of AUC0-24h,ss and Cmax,ss. However, the increase in systemic exposure was only seen for the comparison between fixed dose combination and monotherapy, while the free combination and the monotherapy treatments showed very similar exposure. As the difference was only seen in one of the two combination treatment arms, small biopharmaceutical interactions specific to the fixed dose combination may have contributed to the slightly higher Cmax,ss for indacaterol following QMF149 administration. While a slight increase in systemic exposure for indacaterol as well as mometasone furoate was noticed in this study, the statistical analysis revealed that all the comparisons between the fixed-dose combination QMF149 and monotherapy treatments fulfilled bioequivalence criteria except for the Cmax,ss of mometasone furoate in the comparison between QMF149 and mometasone furoate 320 mg. Previous data indicate that inhaled doses up to 600 mg/day indacaterol administered via the Breezhaler® device up to 1 year [16] and 1600 mg/day (administered as 800 mg twice daily) of mometasone furoate in the Twisthaler® device up to 28 days [17] were not associated with any clinical safety concerns, therefore the slight increase in exposure of the individual components is judged as not clinically meaningful. Both indacaterol and MF delivered via the Breezhaler® device exhibit
Conflict of interest SSV is an employee of Novartis Institutes for BioMedical Research, Cambridge, MA, USA. SK and NC were employees of Novartis Institutes for BioMedical Research, Horsham, UK at the time of study completion. SM is an employee of Novartis Healthcare Pvt. Ltd., Hyderabad, India. HH and RW are employees of Novartis Institutes for BioMedical Research, Basel, Switzerland. TM was an employee of Novartis Institutes for BioMedical Research, East Hanover, NJ, USA at the time of study completion. SF is an employee of Simbec Research Ltd., Merthyr Tydfil, UK. RF is an employee of PAREXEL, Berlin, Germany. Statement of authorship SSV, SK, NC and SM were involved in designing the study. SF and RF were responsible for conducting the study. Data were analyzed and interpreted by SSV, SK, HH, TM and RW. All the authors were involved in drafting and reviewing the manuscript and were responsible for the decision to submit for publication. Role of sponsors This study was funded by Novartis Pharma AG, Basel,
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Switzerland. Acknowledgment The authors acknowledge Praveen Kaul and Vasavi Yada, Novartis Healthcare Pvt. Ltd., India, for medical writing support. The authors also thank all the clinical investigators, study coordinators and subjects at the participating centers and members of the clinical trial team and project team.
[7]
[8]
[9]
[10]
Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.pupt.2016.01.004.
[11]
[12]
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