Salmeterol Administered Through Metered-Dose Inhaler

CHEST

Original Research ASTHMA

Hypothalamic-Pituitary-Adrenal Axis Effects of Mometasone Furoate/Formoterol Fumarate vs Fluticasone Propionate/Salmeterol Administered Through Metered-Dose Inhaler Teddy Kosoglou, PharmD; James Hubbell, PhD; David L. Cutler, MD; Amy O. Johnson-Levonas, PhD; Danlin Xu, PhD; Bhavna S. Kantesaria, MS; Kenneth Kim, MD; and S. David Miller, MD

Background: The effects of mometasone furoate and fluticasone propionate on the hypothalamicpituitary-adrenal axis were compared when administered from combination metered-dose inhaler (MDI) products. Methods: In a randomized, open-label, placebo-controlled, parallel group study, 66 patients with mild to moderate asthma received one of the following four treatments bid through an MDI for 42 days: mometasone furoate/formoterol (MF/F) 200 mg/10 mg, MF/F 400 mg/10 mg, fluticasone propionate/salmeterol (FP/S) 460 mg/42 mg, or placebo. Plasma cortisol concentrations were measured over 24 h on days 21 (baseline) and 42. Geometric mean ratio (GMR) and 90% CI for mean change from baseline to day 42 in 24-h plasma cortisol area under the curve (AUC) were calculated for each treatment. If the 90% CI for the GMRs fell within 70% to 143%, treatments were deemed comparable. Results: Mean baseline cortisol AUCs were similar across groups. Mean cortisol effects (change from baseline) were similar for MF/F 400 mg/10 mg and FP/S 460 mg/42 mg (GMR, 119%; 90% CI, 101%-140%). Effects of MF/F 200 mg/10 mg on cortisol AUC were similar to placebo (GMR, 92%; 90% CI, 78%-110%), whereas MF/F 400 mg/10 mg and FP/S 460 mg/42 mg lowered cortisol AUC vs placebo (GMR, 78% [90% CI, 66%-92%] and 66% [90% CI 56%-78%], respectively). All treatments were generally well tolerated. Conclusions: MF/F 400 mg/10 mg or FP/S 460 mg/42 mg bid through an MDI led to similar reductions from baseline in mean cortisol AUC (22% and 34% lower than placebo, respectively), whereas the effect of MF/F 200 mg/10 mg was similar to placebo. CHEST 2013; 144(6):1795–1802 Abbreviations: ANOVA 5 analysis of variance; AUC 5 area under the plasma concentration-time curve; AUCt 5 area under the plasma concentration-time curve 0 to 12 h postdose; Cmax 5 peak plasma concentration; Ctrough 5 plasma cortisol trough level; DPI 5 dry powder inhaler; F 5 formoterol fumarate; Feno 5 fractional exhaled nitric oxide; FP 5 fluticasone propionate; GMR 5 geometric mean ratio; HPA 5 hypothalamic-pituitary-adrenal; ICS 5 inhaled corticosteroid; LABA 5 long-acting b2-agonist; LC-MS/MS 5 liquid chromatography-tandem mass spectrometry; LLOQ 5 lower limit of quantitation; MDI 5 metered-dose inhaler; MF 5 mometasone furoate; ppb 5 parts per billion; S 5 salmeterol; Tmax 5 time to reach peak plasma concentration

treatment guidelines for the long-term manCurrent agement of asthma and COPD recommend com-

bination therapy with an inhaled corticosteroid (ICS) and a long-acting b2-agonist (LABA).1,2 Mometasone furoate (MF) is a potent ICS shown to produce clinical benefit in patients with asthma or COPD by reducing symptoms and exacerbations and improving lung function without significant safety risks. Formoterol fumarate (F) is a potent, selective LABA approved for maintenance treatment in patients

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with asthma or COPD that exerts a preferential effect on b2-adrenergic receptors of bronchial smooth muscle, thereby eliciting bronchodilator activity. A fixed-dose combination product combining MF and F in a pressurized metered-dose inhaler (MDI) with a hydrofluoroalkane-227 propellant (marketed as DULERA in the United States and ZENHALE in Canada and elsewhere) is approved for the treatment of asthma and is under development for the treatment of COPD.3-5 A marketed combination inhaled CHEST / 144 / 6 / DECEMBER 2013

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aerosol product containing an ICS (fluticasone propionate [FP]) and an LABA (salmeterol [S]) (ADVAIR HFA) was used to evaluate relative risk at the comparable highest recommended daily dose, and the effects of these drugs were compared with placebo. The doses chosen for this study represent the usual maintenance dose of MF/F MDI (200 mg/10 mg bid) and the highest approved dose of MF/F MDI (400 mg/10 mg bid) and FP/S MDI (460 mg/42 mg bid).6,7 ICSs are the foundation of pharmacologic treatment of patients with asthma and COPD. However, long-term ICS treatment can cause hypothalamicpituitary-adrenal (HPA) axis suppression, resulting in low serum/plasma cortisol levels and decreased urinary cortisol excretion. The potential for HPA axis suppression is one of the most important safety considerations with the long-term use of ICS therapy, and HPA axis function is a sensitive measure of the safety of an ICS regimen.8 The primary purpose of this study was to compare the effects of MF/F MDI with FP/S MDI and placebo on cortisol production (as a measure of HPA axis function) in subjects with mild to moderate asthma. The study also explored the dose response and time to maximum response of fractional exhaled nitric oxide (Feno), a biomarker associated with eosinophilic airway inflammation characteristic of atopic asthma, to treatment with MF/F MDI, FP/S MDI, or placebo and to compare the pharmacokinetics of MF and F following single- and multiple-dose administration of MF/F from two fixed-dose combination MDIs. Materials and Methods Inclusion Criteria Sixty-six patients with mild to moderate asthma (FEV1  60% and , 90% within 2 weeks prior to the baseline visit [day 22]) were recruited (men and women aged 18-65 years; BMI, 18-35 kg/m2). Subjects had to demonstrate reversibility of bronchospasm with  12% improvement in FEV1 from baseline after two inhalations (2 3 90 mg) of albuterol (MDI or nebulizer) or have a docuManuscript received March 1, 2013; revision accepted July 30, 2013. Affiliations: From Merck & Co, Inc (Drs Kosoglou, Hubbell, Cutler, Johnson-Levonas, and Xu and Ms Kantesaria), Whitehouse Station, NJ; WCCT Global (Dr Kim), Cypress, CA; and Northeast Medical Research Associates (Dr Miller), North Dartmouth, MA. Part of this article has been presented in abstract form (Kosoglou T, Hubbell J, Xuan F, et al. Chest. 2012;142(4_MeetingAbstracts): 685A). Funding/Support: Schering Corporation (now Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc) provided funding for the conduct of the study. Corresponding author: David L. Cutler, MD, Clinical Pharmacology, Merck & Co, Inc, 351 N Sumneytown Pike, UG4-D34, North Wales, PA 19454; e-mail: [email protected] © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-0505 1796

mented history of reversibility in the past 5 years. Vital signs and ECG conduction intervals had to be within clinically acceptable ranges. Female subjects had to have a negative serum pregnancy test at screening and at subsequent evaluations and had to agree to use medically accepted methods of contraception during the study. Morning serum and plasma cortisol concentrations at screening had to be  5 mg/dL. Exclusion Criteria Subjects were excluded if they were a current smoker or an exsmoker with at least 10 pack-years of smoking history. Other exclusion criteria were use of high doses of ICSs or intraarticular corticosteroids within 1 month, oral corticosteroids within 3 months, or intramuscular corticosteroids within 6 months of study start; had been hospitalized or required ED treatment of an asthma exacerbation within 4 weeks before drug administration; had a history of infectious disease within 4 weeks prior to drug administration; or had positive test results for hepatitis B surface antigen, hepatitis C antibodies, or HIV. Study Design This randomized, open-label, placebo-controlled, active comparator, parallel group, multiple-dose study was conducted at six study centers in the United States. Subjects (n 5 20 per treatment) were randomized to one of the following four open-label treatments self-administered by oral inhalation bid in the morning and evening approximately every 12 h (ie, 8:00 am and 8:00 pm) for 42 consecutive days: Treatment A: MF/F 200 mg/10 mg (2 puffs of MF/F 100 mg/5 mg MDI) Treatment B: MF/F 400 mg/10 mg (2 puffs of MF/F 200 mg/5 mg MDI) Treatment C: FP/S 460 mg/42 mg (2 puffs of FP/S 230 mg/21 mg MDI) Treatment D: placebo (2 puffs from an inhaler matching MF/F MDI) Subjects were instructed to rinse their mouth with water after each treatment and to not swallow the water. Written consent was obtained from all subjects prior to the conduct of any study-related procedures. The protocol and informed consent were approved by Independent IRB, Inc (now Schulman IRB, Inc) and the Copernicus Group IRB. The study was conducted in accordance with good clinical practice and was approved by the appropriate institutional review boards and regulatory agencies. Primary and Secondary End Points The primary end point was change from baseline (day 21) in area under the plasma concentration-time curve (AUC) of logplasma cortisol (AUC from time 0 to 24 h [AUC0-24 h]) on day 42. The secondary end point was change from baseline in log-plasma cortisol trough level (Ctrough) on day 42. Exploratory end points were Feno and descriptive single (ie, day 1) and multiple dose (ie, day 42; steady state) pharmacokinetics for MF (AUC 0-12 h postdose [AUCt], peak plasma concentration [Cmax], and time to reach Cmax [Tmax]) and F (AUCt, Cmax, Tmax, Ae0-t [amount of F excreted in the urine over the 42-day dosing interval], renal clearance, accumulation ratio). Pharmacodynamic Assessments For the measurement of plasma cortisol concentrations, blood samples (3 mL each) were collected into K2-ethylenediaminetetraacetic acid tubes on days 21 and 42 at predose (0 h) and 2, 4, 8, 12, 16, Original Research

and 24 h postdose. For completion of these samplings and measurements, subjects were admitted to the study center 2 days before the first dose (day 22) and the evening before day 42. Plasma cortisol concentrations were determined by a central laboratory (Taylor Technology, Inc) using a liquid chromatographytandem mass spectrometry (LC-MS/MS) assay with a lower limit of quantitation (LLOQ) of 2.00 ng/mL. Feno was determined at predose (0 h) or equivalent time on nondosing days (days 21, 1, 8, 15, 22, 29, 36, and 42) where feasible (ie, in three study centers having a recently calibrated instrument capable of measuring Feno). Feno was measured with a nitric oxide analyzer (NIOX; Aerocrine), a monitoring system that uses biofeedback to maintain a constant expiratory flow rate. At each protocol-defined evaluation, the average of three good exhalation efforts (standardized 50 mL/s flow rate) was used for assessment purposes, with values reported in parts per billion (ppb). The mean of day 21 and predose day 1 was used as the baseline value.

the basis of log-transformed AUC and Cmax values for both MF and F and the log-transformed Ae0-t by treatment group. Dose proportionality for MF was assessed with log-transformed, dosenormalized AUC and Cmax. Steady state was tested for both MF and F by day 8, 15, 22, 29, 36, and 42 predose concentrations. Safety and Tolerability Safety and tolerability of study medications were assessed by clinical evaluation of adverse events and inspection of other safety parameters, including physical examinations, vital signs, and routine laboratory safety measurements (hematology, blood chemistry, and ECGs). Adverse events were monitored throughout the study and evaluated in terms of intensity (mild, moderate, or severe), duration, severity, outcome, and relationship to study drug. All subjects randomized to treatment and who took at least one dose of study medication were included in the safety and tolerability analyses.

Results

Pharmacokinetic Assessments Within each treatment period, blood samples (7 mL each) were drawn into chilled tubes containing ethylenediaminetetraacetic acid on days 1 and 42 at predose (0 h) and 10 min and 0.25, 0.5, 1, 2, 4, 8, and 12 h after the morning dose for measurement of MF and F plasma concentrations. Additional blood samples were drawn at the premorning dose for days 8, 15, 22, 29, and 36 to measure steady-state plasma concentrations. Plasma MF concentrations were determined by a central laboratory (Pharmaceutical Product Development, LLC) using LC-MS/MS assay with an LLOQ 5 0.250 pg/mL. Plasma F concentrations were determined by a central laboratory (Pharmaceutical Product Development) using LC-MS/MS assay with an LLOQ 5 1.45 pmol/L. Pharmacokinetic parameters were calculated with WinNonlin version 5.0.1 software (Pharsight, a Centara company). Individual plasma concentration-time data were used to determine pharmacokinetic parameters with noncompartmental analyses. The AUC0-24 h (mg  h/mL) was calculated by the linear trapezoidal method for ascending concentrations and the log-trapezoidal method for descending concentrations. Cmax (mg/mL) and Tmax (h) were obtained by visual inspection of individual plasma concentrationtime profiles. Statistical Analysis Changes from baseline in plasma cortisol AUC0-24 h were logtransformed and analyzed with a one-way analysis of variance (ANOVA) model extracting the effect due to treatment. Point estimates and two-sided 90% CIs for the geometric mean ratios (GMRs) of MF/F 400 mg/10 mg bid and fluticasone FP/S 460 mg/42 mg bid were constructed from the one-way ANOVA model. If 90% CIs for the GMRs fell within the prespecified range of 0.70 to 1.43, then the treatments were deemed comparable. If the lower bound of the 90% CI was , 0.70 (ie, greater suppression of MF/F), then MF/F 200 mg/10 mg bid and FP/S 460 mg/42 mg bid were subsequently tested. Otherwise, the examination of MF/F 200 mg/10 mg bid was considered primarily informative. Secondary treatment comparisons included 90% CIs for both doses of MF/F and FP/S vs placebo. For each treatment arm, change from baseline (day 21) at day 42 in log-Ctrough was analyzed with a one-way ANOVA model extracting the effect due to treatment. Point estimates and 90% CIs of the ratio of both MF/F arms vs FP/S and all three active arms vs placebo were constructed from the one-way ANOVA model. Feno, an exploratory parameter, was examined using 95% CIs for all pairwise comparisons. Single- and multiple-dose plasma concentrations and the derived pharmacokinetic parameters for both MF and F were calculated with descriptive statistics. Ninety percent CIs were calculated on journal.publications.chestnet.org

Pharmacodynamics The treatment groups were generally well balanced with respect to baseline demographics and disease characteristics (Feno range, 25.2-38.0 ppb across treatment groups) (Table 1). At baseline, the plasma cortisol AUC0-24 h and Ctrough values were similar across the individual treatment groups (Table 2). Treatment with placebo bid for 42 days led to a small increase of 7% in serum cortisol AUC0-24 h values and a small decrease of 1% in serum cortisol Ctrough vs baseline values (Table 3). At day 42, serum cortisol AUC0-24 h and Ctrough values decreased from baseline in all the active treatment groups (Fig 1, Table 3). Multiple-dose oral inhalations of MF/F 200 mg/10 mg bid, MF/F 400 mg/10 mg bid, or FP/S 460 mg/42 mg bid led to reductions from baseline in mean serum cortisol AUC0-24 h values of 1% (GMR, 99; 90% CI, 87-113), 16% (GMR, 84; 90% CI, 75-95), and 29% (GMR, 71; 90% CI, 63-80), respectively (Table 3). Treatment with MF/F 400 mg/10 mg bid and FP/S 460 mg/42 mg bid produced comparable effects on the GMRs (day 42/day 21) of log-plasma cortisol AUC0-24 h (Table 3). Although MF/F 400 mg/10 mg bid led to smaller mean reductions from baseline in plasma cortisol AUC0-24 h compared with FP/S 460 mg/42 mg bid values, the 90% CI (101-140) of the GMR (119) of logcortisol AUC0-24 h (day 42/day 21) fell entirely within the prespecified comparability range of 70% to 143% (Table 3). The effects of MF/F 200 mg/10 mg bid and placebo bid on GMRs (day 42/day 21) of log-plasma cortisol AUC0-24 h were comparable (92; 90% CI, 78-110), whereas reductions of 22% (90% CI, 66-92) and 34% (90% CI, 56-78) were observed following MF/F 400 mg/10 mg bid or FP/S 460 mg/42 mg bid vs placebo, respectively (Table 3). Multiple-dose oral inhalations of MF/F 200 mg/10 mg bid, MF/F 400 mg/10 mg bid, or FP/S 460 mg/42 mg bid CHEST / 144 / 6 / DECEMBER 2013

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Table 1—Subject Demographics at Baseline Treatment Characteristic

A: MF/F 200 mg/10 mg bid (n 5 15)

Sex Female Male Race White Nonwhite Age, mean (range), y Weight, kg Height, cm Feno, ppb

B: MF/F 400 mg/10 mg bid (n 5 17)

C: FP/S 460 mg/42 mg bid (n 5 16)

D: Placebo bid (n 5 18)

Total (N 5 66)

10 (67) 5 (33)

9 (53) 8 (47)

10 (63) 6 (38)

11 (61) 7 (39)

40 (61) 26 (39)

9 (60) 6 (40) 31.5 (19-58)

12 (71) 5 (29) 32.9 (18-64)

12 (75) 4 (25) 33.9 (20-58)

9 (50) 9 (50) 34.9 (18-55)

42 (64) 24 (36) 33.4 (18-64)

71.4  16.5 163.9  10.7 34.2  24.0a

76.9  11.5 166.4  10.8 38.0  19.3b

78.5  14.2 168.0  8.6 25.2  19.9c

73.6  15.8 165.6  10.9 35.3  26.4d

75.1  14.5 166.0  10.2 …

Data are presented as No. (%) or mean  SD, unless otherwise indicated. Feno 5 fractional exhaled nitric oxide; FP/S 5 fluticasone propionate/salmeterol fixed-dose combination; MF/F 5 mometasone furoate/formoterol fumarate fixed-dose combination; ppb 5 parts per billion. an 5 6. bn 5 9. cn 5 9. dn 5 8.

led to reductions from baseline in mean Ctrough values of 5%, 32%, and 37%, respectively (Table 3). The effects of MF/F 200 mg/10 mg bid or placebo bid on GMRs (day 42/day 21) of log-Ctrough values were comparable (96; 90% CI, 70-132), whereas reductions were 32% (90% CI, 50-93) and 36% (90% CI, 47-86) following MF/F 400 mg/10 mg bid or FP/S 460 mg/42 mg bid vs placebo, respectively (Table 3). Mean reductions in Feno from baseline were similar across the active treatment groups, ranging from 37% to 39% for the three active treatments vs placebo (Table 4). For each active treatment group, maximum reductions in Feno values from baseline were observed by day 8 and were sustained until day 42 (Fig 2). Pharmacokinetics Mean MF and F plasma concentration-time profiles after single- and multiple-dose oral inhalation of MF/F 200 mg/10 mg bid and MF/F 400 mg/10 mg bid

showed rapid and prolonged absorption (Figs 3, 4). MF Cmax and AUCt values increased with increasing dose (Table 5). Day 42 MF and F exposure values were higher than day 1 exposure values (Table 5). Safety and Tolerability Twenty-nine subjects (44%) reported at least one adverse event during the study: six (40%) during treatment A (MF/F 200 mg/10 mg), nine (53%) during treatment B (MF/F 400 mg/10 mg), eight (50%) during treatment C (FP/S 460 mg/42 mg), and six (33%) during treatment D (placebo). The most common adverse events were headache in five subjects (8%), pharyngolaryngeal pain in four (6%), urinary tract infection in three (5%), nausea in three (5%), and back pain in three (5%). The reported adverse events were nonspecific and across different body system/organ class categories, with a similar incidence and severity among all treatment groups.

Table 2—Plasma Cortisol Parameters in Subjects With Asthma Following Twice-Daily MF/F 200 mg/10 mg, MF/F 400 mg/10 mg, FP/S 460 mg/42 mg, or Placebo Through MDI Day 21 Treatment A: MF/F 200 mg/10 mg bid B: MF/F 400 mg/10 mg bid C: FP/S 460 mg/42 mg bid D: Placebo bid (n 5 17)

Day 42

AUC0-24 h, ng  h/mL

Ctrough, ng/mL

AUC0-24 h, ng  h/mL

Ctrough, ng/mL

1,620 (19) 1,570 (22) 1,680 (31) 1,700 (38)

23.6 (40) 20.3 (37) 20.4 (44) 21.5 (61)

1,670 (29)a 1,390 (49)b 1,240 (46) 1,830 (39)c

24.1 (57)a 14.9 (50)b 16.4 (90) 22.9 (71)c

Data are presented as mean (% coefficient of variation). AUC0-24 h 5 area under the plasma concentration-time curve from time 0 to 24 h (postmorning dose); Ctrough 5 plasma cortisol trough level (minimum observed concentration during 24-h period); MDI 5 metered-dose inhaler. See Table 1 legend for expansion of other abbreviations. an 5 13. bn 5 15. cn 5 16. 1798

Original Research

96 (70-132) 68 (50-93) 64 (47-86) 107 (79-146) 150 (109-207) 71 (52-99) A vs D B vs D C vs D B vs C A vs C B vs A

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GMR 5 geometric mean ratio; LS 5 least squares. See Table 1 and 2 legends for expansion of other abbreviations. Subjects missing day 42 cortisol samples were excluded from the pharmacodynamic analyses. bModel-based (LS) GMR for day 42/day 21 values using an analysis of variance model extracting the effects due to treatment. a

92 (78-110) 78 (66-92) 66 (56-78) 119 (101-140) 140 (118-166) 85 (71-101) 99 (87-113) 84 (75-95) 71 (63-80) 107 (97-120) A: MF/F 200 mg/10 mg bid B: MF/F 400 mg/10 mg bid C: FP/S 460 mg/42mg bid D: Placebo bid

13 15 16 16

A vs D B vs D C vs D B vs C A vs C B vs A

95 (75-120) 68 (54-84) 63 (51-78) 99 (80-123)

GMR (90% CI) Between-Treatment Comparison GMR (90% CI) LS Meanb (90% CI) Treatment

No. Subjectsa

Between-Treatment Comparison

LS Meanb (90% CI)

Ctrough, ng/mL AUC0-24 h, ng  h/mL

Table 3—LS Mean Ratio (Day 42/Day 21) for Serum Cortisol AUC0-24 h and Ctrough

Figure 1. Distribution by treatment of individual ratios of day 42-to-baseline plasma cortisol AUC from time 0 to 24 h in subjects with asthma. AUC 5 area under the plasma concentrationtime curve; FP/S 5 fluticasone propionate/salmeterol fixed-dose combination; MF/F 5 mometasone furoate/formoterol fumarate fixed-dose combination.

Two subjects dropped out of the study because of adverse events: one each from the MF/F 200 mg/10 mg bid (loss of consciousness) and MF/F 400 mg/10 mg bid (anxiety and insomnia) groups. No death occurred during the study. One subject in the MF/F 200 mg/10 mg bid group who dropped out because of pregnancy had three serious adverse events (fetal distress syndrome, fetal growth retardation, and oligohydramnios) occurring 222 days after the last dose of study medication. At follow-up, the mother and baby were reported to be doing well. There were no clinically significant changes in blood chemistry or hematologic parameters, vital signs, or ECGs in any treatment group. Discussion In this study, MF/F 400 mg/10 mg or FP/S 460 mg/42 mg bid through MDI for 42 days led to similar mean reductions from baseline in plasma cortisol AUC0-24 h (22% and 34% lower than placebo, respectively) and Ctrough (32% and 36% lower than placebo, respectively), whereas the effect of MF/F 200 mg/10 mg on plasma cortisol AUC0-24 h and Ctrough were comparable to placebo. Taken together, these results suggest that low-dose MF/F MDI does not have demonstrable effects on plasma cortisol levels, whereas high-dose MF/F or FP/S MDI appeared to suppress plasma cortisol levels in adults with mild to moderate asthma, although these effects are not considered clinically significant. These results are consistent with those previously published for MF and FP administered as single-ingredient products through MDI.9,10 Over the years, a number of approaches have been used to assess HPA axis function, including the measurement of a single morning (8:00 am) cortisol value, CHEST / 144 / 6 / DECEMBER 2013

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Table 4—LS Mean Percent Change from Baseline in FENO Compared With Placebo Following 42 d of Treatment Treatment A: MF/F 200 mg/10 mg bid B: MF/F 400 mg/10 mg bid C: FP/S 460 mg/42 mg bid D: Placebo bid

No. Subjects

LS mean (95% CI)

Between-Treatment Comparison

Difference in LS Mean (95% CI)

6 9 9 8

240.8 (260.9 to 220.7) 242.5 (258.9 to 226.1) 243.1 (259.5 to 226.6) 24.1 (221.5 to 13.3)

A vs D B vs D C vs D …

236.7 (263.3 to 210.1) 238.4 (262.3 to 214.5) 238.9 (262.8 to 215.0) …

See Table 1 and 3 legends for expansion of abbreviations.

a 24-h serum/plasma cortisol AUC, or 24-h urinary free cortisol excretion and the response to cosyntropin stimulation.9 Although changes in the HPA axis function can be assessed by any and all of these methods, the clinical relevance of any observed changes from pretreatment baseline is of considerable debate and can only be defined in the context of a relative comparator for which the effects are known and well characterized (eg, a positive control such as prednisone 10 mg daily) or by evaluating the integrity of the HPA axis in response to cosyntropin stimulation. According to previous studies,9 observed changes in HPA axis function were deemed clinically relevant if the treatment caused considerably smaller (eg, . 35%) reductions in plasma cortisol AUC than placebo or had effects on cortisol AUC or response to cosyntropin similar in magnitude to those observed with a positive control (eg, prednisone 10 mg daily). Our conclusion that the high-dose MF/F MDI treatment does not cause clinically significant changes in HPA axis function is primarily based on the results of two placeboand positive-controlled studies that also assessed HPA axis function by the cosyntropin stimulation test.9 In the first study, MF dry powder inhaler (DPI) at doses up to 1,200 mg qid for 28 days was shown to have a minimal impact on cortisol AUC compared with placebo and no effect on adrenal response to a low-dose cosyntropin test (ie, all subjects had poststimulation serum cortisol levels . 18 mg/dL in response to 250 mg IM

Figure 2. Mean FeNO concentration by treatment group and nominal day. FeNO 5 fractional exhaled nitric oxide; ppb 5 parts per billion. See Figure 1 legend for expansion of other abbreviations. 1800

cosyntropin injection).9 In the second study, the day-28 cortisol AUC reductions from baseline relative to placebo were 10%, 21%, and 64% for MF MDI 400 mg bid, MF MDI 800 mg bid, and oral prednisone 10 mg qid, respectively.9 In that same study, 15, 14, 11, and one of 16 subjects had poststimulation serum cortisol levels . 18 mg/dL in the placebo, MF 400 mg bid, MF 800 mg bid, and prednisone 10 mg qid groups, respectively, in response to 250 mg IM cosyntropin.9 In this study, only the MF MDI 800 mg bid dose (1,600 mg/d), twice the recommended daily dose of MF, was associated with detectable systemic activity, which could be clinically relevant, although much less than the effect of prednisone 10 mg qid.9 Considering that the systemic exposure to MF from the MF/F MDI product is approximately 25% lower than the exposure from the marketed MF DPI product (ASMANEX TWISTHALER),11 we believe that it is reasonable to consider previous experience with MF DPI to infer clinical relevance for the MF/F MDI product used in the present study. Therapy with an ICS/LABA combination is individualized with the treatment goal to control the patient’s symptoms and reduce exacerbations by using the lowest

Figure 3. Mean  SD plasma concentration-time profiles of MF on days 1 (ie, single dose) and 42 (ie, multiple doses) following inhalation of MF/F 200 mg/10 mg bid or MF/F 400 mg/10 mg bid from metered-dose inhalers. MF 5 mometasone furoate. See Figure 1 legend for expansion of other abbreviation. Original Research

Feno, a biomarker of airway inflammation in subjects with atopic asthma, has been shown to be a good predictor of corticosteroid responsiveness and can be used to monitor airway inflammation.12 In the present study, Feno levels were reduced following treatment with MF/F 200 mg/10 mg bid, MF/F 400 mg/10 mg bid, and FP/S 460 mg/42 mg bid through MDI for 42 days relative to baseline and placebo. The effects of active treatment on Feno were observed as early as day 8 and were sustained throughout the treatment period. All active treatments caused a mean reduction in Feno of approximately 40%, which is considered clinically important and indicated that corticosteroid treatment was successful in reducing airway inflammation.12 Although a treatment effect on Feno was demonstrated, there was a small numerical trend but no clear dose-response relationship between the two doses of MF/F or difference between MF/F and FP/S in this parameter, despite observed differences in plasma cortisol concentrations. Because a Feno dose-response relationship has been observed with ICSs,13 including MF/F,14 the lack of a dose-response relationship in this study may be due to the small sample size (six to nine subjects per treatment) and intermediate (mean, 25.2-38.0 ppb) rather than high (. 50 ppb) baseline Feno levels, indicative of the primarily mild asthmatic population in this study, which limits the magnitude of the response.12 Single and multiple oral inhalations of MF/F 200 mg/10 mg bid and MF/F 400 mg/10 mg bid for 6 weeks were generally well tolerated in this population of patients with mild to moderate asthma. The adverse events reported were nonspecific, with a similar

Figure 4. Mean  SD plasma concentration-time profiles of formoterol on days 1 (ie, single dose) and 42 (ie, multiple doses) following inhalation of MF/F 200 mg/10 mg bid or MF/F 400 mg/10 mg bid from metered-dose inhalers. See Figure 1 legend for expansion of abbreviation.

effective dose of ICS/LABA and, where warranted, to step down therapy to ICS monotherapy. The high doses of MF/F and FP/S used in the present study are the highest approved doses for these products,6,7 for which the safety and efficacy as well as favorable benefit-risk ratio have been demonstrated. The effects of these high-dose treatments on plasma cortisol concentrations are considered as either not clinically significant or clinically acceptable on the basis of their favorable benefit-risk ratio.

Table 5—Plasma Pharmacokinetic Parameters for MF and F Following Single- and Multiple-Dose Inhalation of MF/F 200 mg/10 mg or MF/F 400 mg/10 mg From MDIs Pharmacokinetic Parameter

Day-1 Treatment

Day-42 Treatment

A: MF/F 200 mg/10 mg bid

B: MF/F 400 mg/10 mg bid

A: MF/F 200 mg/10 mg bid

B: MF/F 400 mg/10 mg bid

15

17

13

15

1.00 (0.433-8.08) 12.5 (42.0) 90.1 (63.0) …a

1.03 (0.500-8.07) 20.0 (88.0) 170.0 (94.0) …a

2.00 (0.00-4.07) 25.7 (71.0) 227.0 (70.0) 2.64 (53.0)

2.00 (0.500-4.00) 60.0 (36.0) 577.0 (40.0) 4.46 (46.0)

15

15b

13

13b

1.97 (0.167-12.0) 28.3 (49.4) 160.0 (57.2) …a

1.0 (0.167-4.0) 22.4 (29.4) 125.0 (42.2) …a

1.0 (0.167-4.05) 32.8 (60.9) 181.0 (58.8) 1.23 (35.6)

1.0 (0.167-2.05) 40.6 (58.7) 226.0 (54.3) 1.7 (23.0)

MF No. subjects contributing to the analysis Tmax, median (range), h Cmax, pg/mL AUCt, pg  h/mL R Formoterol No. subjects contributing to the analysis Tmax, median (range), h Cmax, pmol/L AUCt, pmol  h/L R

Data are presented as arithmetic mean (% coefficient of variation) unless otherwise indicated. AUCt 5 area under the plasma concentration-time curve 0 to 12 h postdose; Cmax 5 peak plasma concentration; F 5 formoterol fumarate; MF 5 mometasone furoate; R 5accumulation ratio; Tmax 5 time to peak plasma concentration. See Table 1 legend for expansion of other abbreviations. aNot measurable following single-dose administration. bTwo subjects were excluded from the pharmacokinetic analyses because predose concentrations of F were . 10% of Cmax. journal.publications.chestnet.org

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incidence among treatment groups. Of note, there was a suggestion of tolerance to adverse events typical for F treatment (eg, headache, tremor, anxiety, nausea, dry mouth) because the subjects tended to report these adverse events earlier during the study (ie, within the first 10 days of treatment). Conclusions The results of this study show that high doses of MF/F or FP/S administered bid through MDI lead to similar reductions in mean cortisol AUC values, whereas the effects of a medium dose of MF/F (200 mg/10 mg bid) are similar to placebo. These results suggest that MF/F MDI is safe and does not cause a clinically significant suppression of HPA axis function in adult patients with mild to moderate asthma when administered at the recommended daily doses. Acknowledgments Author contributions: Dr Cutler had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr Kosoglou: contributed to the planning and design of the study, data analysis and interpretation, writing and review of the manuscript, and approval of the final version. Dr Hubbell: contributed to the data interpretation, review of the manuscript, and approval of the final version. Dr Cutler: contributed to the planning and design of the study, data analysis and interpretation, writing and review of the manuscript, and approval of the final version. Dr Johnson-Levonas: contributed to the data collection and assembly, data analysis and interpretation, writing and review of the manuscript, and approval of the final version. Dr Xu: contributed to the data collection and assembly, data analysis, review of the manuscript, and approval of the final version. Ms Kantesaria: contributed to the data collection and assembly, review of the manuscript, and approval of the final version. Dr Kim: contributed to the data collection, provision of materials and patients, review of the manuscript, and approval of the final version. Dr Miller: contributed to the data collection and assembly, review of the manuscript, and approval of the final version. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Drs Kosoglou, Hubbell, Cutler, Johnson-Levonas, and Xu and Ms Kantesaria are current or former employees of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, and may own stock or stock options in the company. Dr Miller is an employee of Northeast Medical Research Associates, which received funding for this study. Dr Kim has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: Schering Corporation (now Merck & Co, Inc) provided drug and editorial and statistical support as well as financial support to the study. Other contributions: The authors thank Fengjuan Xuan, PhD, Merck & Co, Inc, for statistical support and Kathleen Newcomb and Kristen Lewis, BA, Merck & Co, Inc, for editorial support in the preparation of this manuscript.

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