Asthma and Allergy Physicians, Taunton, Massachusetts; Allergy and Asthma ... and Asthma Center, North Dartmouth, Massachusetts; Glaxo Wellcome Inc.,.
Efficacy of Inhaled Fluticasone Propionate in Asthma Results from Topical and Not from Systemic Activity MICHAEL LAWRENCE, JAMES WOLFE, D. ROBERT WEBB, PAUL CHERVINSKY, DONALD KELLERMAN, JOHN P. SCHAUMBERG, and TUSHAR SHAH Asthma and Allergy Physicians, Taunton, Massachusetts; Allergy and Asthma Associates of Santa Clara Valley, San Jose, California; Allergy and Asthma Center, North Dartmouth, Massachusetts; Glaxo Wellcome Inc., Research Triangle Park, North Carolina
The objective of this study was to determine whether the therapeutic benefits of inhaled fluticasone propionate are mediated through topical or systemic effects. Two hundred seventy-four patients with asthma receiving beclomethasone dipropionate or triamcinolone acetonide during a 2-wk, single-blind, run-in period were randomized to inhaled fluticasone propionate powder 100 or 500 mg twice daily, oral fluticasone propionate 20 mg once daily, or placebo during a 6-wk treatment period. Patients receiving inhaled fluticasone propionate had a significantly greater probability of remaining in the study over time compared with patients receiving oral fluticasone propionate or placebo (p 5 0.001). FEV1 and PEF rates at end point were significantly higher with inhaled fluticasone propionate treatment regimens than with oral fluticasone propionate (with the exception of PEF rates for inhaled fluticasone propionate 100 mg) or placebo treatments (p < 0.004). Systemic exposure to fluticasone propionate as assessed by trough plasma concentrations and/or 12-hr plasma concentration area under the curve analyses (AUC12) was higher with the oral fluticasone propionate than with the two inhaled fluticasone propionate treatment groups. The results of this study suggest that the therapeutic benefits of inhaled fluticasone propionate are mediated through topical effects in the lungs and not through systemic effects. Lawrence M, Wolfe J, Webb DR, Chervinsky P, Kellerman D, Schaumberg JP, Shah T. Efficacy of inhaled fluticasone propionate in asthma results from AM J RESPIR CRIT CARE MED 1997;156:744–751. topical and not from systemic activity.
Orally administered glucocorticosteroids such as prednisone have to be absorbed systemically in order to be efficacious for the treatment of asthma. Unfortunately, systemic absorption of oral glucocorticosteroids after chronic administration may cause such adverse effects as weight gain, skin atrophy, osteoporosis, and cataracts as well as changes in hypothalamicpituitary-adrenal (HPA)-axis measurements (1). In contrast, inhaled glucocorticosteroids have shown an improved thera-
(Received in original form August 16, 1996 and in revised form March 12, 1997) The principal investigators and clinical sites are listed as follows: D. W. Aaronson, M.D., Aaronson Asthma and Allergy Assoc. Ltd., Des Plaines, IL; C. Banov, M.D., Charleston, SC; B. P. deBoisblanc, M.D., LSU Medical Center, New Orleans, LA; J. Condemi, M.D., Allergy, Asthma, Immunology, Rochester, NY; L. Cosmo, M.D., Tampa Medical Research Associates, Tampa, FL; R. J. Dockhorn, M.D., International Medical Technical Consultants, Inc., Lenexa, KS; F. C. Hampel, M.D., Central Texas Health Research, New Braunfels, TX; W. Howland, M.D., Health Quest, Austin, TX; M. Kramer, M.D., Spokane Allergy and Asthma Clinic, Spokane, WA; E. O. Meltzer, M.D., Allergy & Asthma Medical Group & Research Center, APC, San Diego, CA; F. J. Picone, M.D., Tinton Falls, NJ; B. Prenner, M.D., Allergy Associates Medical Group, San Diego, CA; P. Ratner, M.D., Sylvana Research, San Antonio, TX; J. R. Taylor, M.D., Tacoma, WA; and J. VanBavel, M.D., Austin, TX. Supported by the Glaxo Research Institute. Correspondence and requests for reprints should be addressed to M. Lawrence, M.D., Asthma & Allergy Physicians, 35 Summer Street, Suite 202B, Taunton, MA 02780. Am J Respir Crit Care Med Vol. 156. pp. 744–751, 1997
peutic ratio (topical efficacy/systemic safety). Although it is generally accepted that inhaled glucocorticosteroids act topically in the lungs, evidence in support of this concept is limited (2–5). Inhaled glucocorticosteroids at high doses have been associated with systemic absorption and side effects (6). Systemic absorption after inhaled administration can occur by direct absorption from the lung as well as from the large fraction (approximately 75%) of the inhaled dose that is deposited in the mouth and pharynx and swallowed (7–11). If inhaled glucocorticosteroids can be absorbed systemically to cause side effects, it is conceivable that the systemically absorbed portion of an inhaled dose may also contribute to some or to all of a drug’s therapeutic effect. Fluticasone propionate is a potent glucocorticosteroid with a favorable topical efficacy to systemic safety ratio (2, 12). Clinical studies have shown that inhaled fluticasone propionate is effective and well-tolerated in the treatment of patients with asthma (13–16). Orally administered fluticasone propionate has been shown to have low systemic bioavailability because of poor absorption and extensive first-pass metabolism by the liver and gastrointestinal tract (17–19); therefore, the fraction of the inhaled fluticasone propionate dose delivered to the lungs is the primary source available for systemic absorption. Although the low oral bioavailability of fluticasone propionate suggested that its efficacy was more likely to be from a direct topical effect on the lungs, further evidence was needed to clarify whether systemic or local effects medi-
Lawrence, Wolfe, Webb, et al.: Inhaled Fluticasone Propionate Acts Topically
ated the benefits of inhaled fluticasone propionate in the treatment of asthma. The objective of this trial was to determine if the action of fluticasone propionate in the treatment of asthma was mediated via a direct topical effect on the lungs. This was accomplished by comparing the efficacy of inhaled and oral fluticasone propionate at doses that yielded comparable systemic exposure as assessed by measurement of plasma fluticasone propionate concentrations. Because of the low oral bioavailability of fluticasone propionate, an oral dose 20- to 100-fold higher than the inhaled daily doses was necessary to attain similar plasma concentrations compared with those observed with inhaled fluticasone propionate.
METHODS Patient Selection Eligible patients were nonsmokers, at least 18 yr of age, with a diagnosis of asthma as defined by the American Thoracic Society (20), who had been using inhaled glucocorticosteroids for maintenance treatment of asthma for at least the preceding 3 mo, and had been treated with beclomethasone dipropionate (> 336 mg/d) or triamcinolone acetonide (> 800 mg/d) in fixed doses for at least 14 d prior to the run-in period. Patients were required to have a morning predose FEV1 of 50 to 80% of their predicted normal value (21) and to demonstrate at least a 15% reversibility in FEV1 after inhalation of a bronchodilator. All women enrolled had negative pregnancy tests, and those of childbearing potential were required to use contraception for at least 2 mo prior to and throughout the study. Patients were excluded from the study if they used oral, intranasal, ophthalmic, topical, or injectable glucocorticosteroids during the month prior to entering the study, or if they used oral glucocorticosteroids daily for 2 mo or longer within 6 mo of entering the study. An institutional review board approved the protocol at each of the 19 participating study sites, and all patients provided written informed consent.
Study Design and Intervention A randomized parallel design was used in this double-blind, doubledummy, placebo-controlled study. During a single-blind, 2-wk screening period, patients received placebo Rotadisks® powder via DISKHALER® (Glaxo Wellcome, Evreau, France) for inhalation and continued beclomethasone dipropionate or triamcinolone acetonide in fixed doses. This period served to assess patients’ asthma stability and as a baseline for post-treatment efficacy and safety comparisons. All patients discontinued oral or inhaled beta-agonist bronchodilator therapy, with the exception of inhaled albuterol, which was permitted as needed to relieve asthma symptoms throughout the study. Patients receiving theophylline at study entry continued to do so without any change in dosage throughout the study. During the study, patients used the MiniWright® peak flow meter to measure peak expiratory flow (PEF) before their morning (8:00 A.M.) treatment doses and recorded the best of three attempts on diary cards. Albuterol inhaler use and asthma symptoms were also recorded in the diary; daytime asthma symptoms of wheeze, cough, and shortness-of-breath were self-rated on a scale of 0 to 3 (0 5 none, 1 5 mild, 2 5 moderate, 3 5 severe). Patients who qualified during the screening period were randomly assigned to receive treatment for 6 wk with one of the following: inhaled fluticasone propionate 500 mg (two inhalations of fluticasone propionate 250 mg powder twice daily and four placebo tablets once daily), inhaled fluticasone propionate 100 mg (two inhalations of fluticasone propionate 50 mg powder twice daily and four placebo tablets once daily), oral fluticasone propionate (two inhalations of placebo powder twice daily and four 5 mg fluticasone propionate tablets once daily), or placebo (two inhalations of placebo powder twice daily and four placebo tablets once daily). During the 6-wk double-blind period, patients returned to the study center on a weekly basis to perform spirometry and to review diary cards and medication use. Inhaled al-
745
buterol was withheld for 6 h before study visits, and immediate- and sustained-release theophylline was withheld 24 to 36 h before visits. Patients were withdrawn from the study if they met any of the following prospectively defined criteria for lack of efficacy or signs of unstable asthma during the 7 d before a study visit: (1) > 20% decrease in FEV1 compared with baseline; (2) > 20% decrease in PEF on more than 3 d compared with baseline; (3) awakenings caused by asthma requiring treatment on . 2 nights during the 7 d immediately preceding each visit; (4) inhaled albuterol use of . 12 puffs/d on . 2 of 7 d immediately preceding a visit; (5) an asthma exacerbation requiring emergency intervention, hospitalization, or treatment with any asthma medication other than those allowed by the protocol. All adverse events were recorded, irrespective of their causality in relation to the study drug. Clinical laboratory tests were conducted at screening, baseline, the end of the treatment period, and at follow-up post-treatment visits if abnormal results occurred at the end of the treatment period. HPA-axis function was assessed by measuring morning plasma cortisol concentrations at screening, baseline, and at the end of treatment. Patients had to have a morning plasma cortisol concentration . 5 mg/dl during screening in order to participate in the trial.
Blood Sample Collection for Plasma FP Analyses Blood samples were collected at baseline and at 12 h after study drug administration at Weeks 1 and 6 in all patients. In addition, at three of the investigators’ sites (Chervinsky, Dockhorn, and Howland), a full pharmacokinetic profile was collected in 37 patients after blinded study drug administration at Visit 2, Visit 3, and Visit 6 (corresponding to after the first dose and 1 and 4 wk after starting randomized treatment). Blood for plasma fluticasone propionate concentrations was obtained predose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 h after blinded study drug administration at each of the three visits. Results for 12-h area under the plasma concentration/time curves (AUC12) for fluticasone propionate were calculated using the trapezoidal method. Over the course of the 12-h pharmacokinetic analysis, patients had to have at least two consecutive detectable fluticasone propionate measurements in order for the analysis to be performed. Plasma fluticasone propionate concentrations were determined by a reference laboratory (Hazleton, WA; Vienna, VA) using a radioimmunoassay with a limit of quantification of 25 pg/ml. The interassay and intra-assay coefficient of variance for this measurement was less than 10%.
Statistical Analysis The primary efficacy variables were the probability of remaining in the study over time and FEV1. An a priori power analysis was performed based on change from baseline to end-point FEV1. Baseline values were measured during the second week of the 2-wk screening period. Testing was performed as a change from baseline to end point (defined as the final measurement for the patient, regardless of whether or not the patient completed the study). End point for morning predose FEV1 was based on the last evaluable spirometry data and for morning predose PEF, total daily asthma symptom scores, and inhaled albuterol use was based on the last evaluable week of diary card data. Analyses by visit were performed only on data from patients still remaining in the study at that specific visit. Individual symptom scores of wheeze, cough, and shortness of breath were averaged for each day to yield the total daily symptom scores. All statistical tests were two-sided, with probability values of < 0.05 considered statistically significant. In order to correct for multiple comparisons for each efficacy and safety measure, pairwise treatment comparisons were considered statistically significant only when the overall treatment comparison was statistically significant. Assessments of morning predose FEV1 and PEF were tested using an analysis of variance F-test. The probability of patients remaining in the study over time were plotted using Kaplan-Meier estimates of survival (22). Overall and pairwise treatment comparisons of the probability of remaining in the study over time were based on the log rank test of the Kaplan-Meier estimates. Results for PEF, total daily symptom scores, and total daily inhaled albuterol use were averaged over 1-wk intervals for analysis. Pairwise testings was based on the nonparametric van Elteren test (23).
746
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
VOL. 156
1997
TABLE 1 PATIENT CHARACTERISTICS AT BASELINE* Characteristic
Inhaled FP (100 mg BID)
Inhaled FP (500 mg BID)
Oral FP (20 mg QD)
Placebo
Patients, n Sex, % M/ F† Age, yr (range) FEV1, L FEV1, % pred. Morning PEF, L/min Total Asthma Symptom Score Albuterol use, puffs/24 h
63 63/37 40 (19–66) 2.50 6 0.07 67 437 6 11 0.56 6 0.05 3.6 6 0.3
69 39/61 38 (20–61) 2.36 6 0.07 68 417 6 12 0.65 6 0.05 3.2 6 0.3
65 60/40 38 (18–69) 2.52 6 0.07 66 428 6 12 0.59 6 0.05 3.9 6 0.4
64 59/41 38 (18–71) 2.42 6 0.07 65 422 6 12 0.61 6 0.05 4.2 6 0.4
Definition of abbreviations: FP 5 fluticasone; BID 5 twice daily; QD 5 once daily. * Values expressed as means 6 SE unless otherwise indicated. † p 5 0.03 across treatment groups.
RESULTS Patients
Two hundred seventy-four patients were enrolled in the study. Data from 261 patients were considered evaluable and included in the efficacy analyses. The primary reason for excluding patient’s data from the efficacy analysis was failure to meet enrollment criteria but receiving study drug. Decisions regarding data exclusion were made prior to unblinding. The safety analyses were conducted on the intent-to-treat population (n 5 274). The demographic and baseline asthma characteristics for the efficacy population are shown in Table 1. These results were similar for the intent-to-treat and efficacy populations (results not shown). The treatment groups were comparable at baseline, with one exception: the ratio of men to women was lower in the fluticasone propionate 500 mg group than in the other treatment groups (Table 1). Probability of Remaining in the Study over Time
Patients in both of the inhaled fluticasone propionate groups had a significantly greater probability of remaining in the study over time than did the patients in the oral fluticasone propionate group of the placebo group (p 5 0.001) (Figure 1). By the end of the study, a total of 52% of the patients in the placebo group and 43% of patients in the oral fluticasone propionate group compared with 6 and 12% in the inhaled fluticasone propionate 100 and 500 mg groups, respectively, were withdrawn because they failed to meet the predetermined criteria for asthma stability. There were no statistically significant differences between the two inhaled fluticasone propionate groups or between the oral fluticasone propionate and placebo groups with respect to the probability of remaining in the study over time.
study, though the statistical significance compared with oral fluticasone propionate was not maintained for the fluticasone propionate 100 mg group beyond the second week after randomization. Patients treated with fluticasone propionate 500 mg also achieved a significantly greater improvement in FEV1 than did patients treated with placebo at most time points after starting study drug. However, statistical differences in FEV1 compared with placebo did not occur throughout the study in patients treated with fluticasone propionate 100 mg except at end point. There were no significant differences in FEV1 between the oral fluticasone propionate and the placebo treatment groups. At end point, each of the inhaled fluticasone propionate groups had a significantly greater improvement in FEV1 from baseline than did either oral fluticasone propionate or placebo groups (p < 0.004) (Table 2). Patients in the inhaled fluticasone propionate 100 and 500 mg groups had mean increases in morning predose FEV1 of 0.27 and 0.42 L, respectively, whereas patients in the oral fluticasone propionate and placebo groups had mean decreases of 0.20 and 0.19 L, respectively. Differences at end point in FEV1 between the FP 100 and 500 mg
FEV1
The by-visit mean change from baseline (when patients had been receiving beclomethasone dipropionate or triamcinolone acetonide) in morning predose FEV1 over the course of the study is depicted in Figure 2. Near maximal improvements in FEV1 with inhaled fluticasone propionate treatment were noted by the first spirometric assessment 1 wk after initiation of study drug, and the improvements were significantly greater with both of the inhaled fluticasone propionate treatment groups than with the oral fluticasone propionate treatment groups. This trend remained constant throughout the
Figure 1. Probability of remaining in study over time in patients treated with placebo, inhaled fluticasone propionate (100 and 500 mg twice daily), or oral fluticasone propionate, 20 mg once daily.
747
Lawrence, Wolfe, Webb, et al.: Inhaled Fluticasone Propionate Acts Topically
Figure 2. Mean change from baseline in morning predose FEV 1 during 6 wk of treatment with placebo, inhaled fluticasone propionate (100 and 500 mg twice daily), or oral fluticasone propionate 20 mg once daily.
groups or between the oral fluticasone propionate and placebo groups were not statistically significant. PEF
Mean change from baseline in morning predose PEF measurements is depicted in Figure 3. At end point, there was a statistically significant difference (p < 0.003) between the two inhaled fluticasone propionate and placebo treatment groups with improvements in the inhaled fluticasone propionate 100 and 500 mg groups of 15 and 18 L/min, respectively, and a decrease of 15 L/min in the placebo group (Table 2). Although both the inhaled fluticasone propionate groups had a greater improvement in PEF relative to the oral fluticasone propionate group at end point (decrease of 6 L/min), only the improve-
ment in the fluticasone propionate 500 mg group achieved statistical significance (p , 0.001). There were no statistically significant differences in PEF between the two inhaled fluticasone propionate treatment groups or between the oral fluticasone propionate and placebo treatment groups. Asthma Symptoms and Albuterol Use
Results of the mean change from baseline to end point in total patient-rated symptoms scores and inhaled albuterol use are presented in Table 2. The total patient-rated symptom scores at end point decreased from baseline 30 and 34% in the 100 and 500 mg inhaled fluticasone propionate groups, respectively, and increased 7 and 10% in the oral fluticasone propionate and placebo treatment groups, respectively. Likewise,
TABLE 2 CHANGE IN EFFICACY VARIABLES FROM BASELINE TO END POINT*
Morning FEV1, L Morning PEF, L/min Total Asthma Symptom Score Albuterol use, puffs/24 h
Inhaled FP (100 mg BID)
Inhaled FP (500 mg BID)
Oral FP (20 mg QD)
Placebo
0.27 6 0.06 15 6 5‡ 20.17 6 0.05†‡ 21.0 6 0.3†‡
0.42 6 0.06 18 6 5†‡ 20.22 6 0.06†‡ 21.1 6 0.3†‡
20.20 6 0.06 26 6 5 0.04 6 0.05 0.6 6 0.3
20.19 6 0.08 215 6 5 0.06 6 0.06 0.7 6 0.4
For definition of abbreviations, see Table 1. * Values are means 6 SE. † p < 0.005 versus oral FP. ‡ p < 0.008 versus placebo.
†‡
†‡
748
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
VOL. 156
1997
Figure 3. Mean change from baseline in morning predose PEF during 6 wk of treatment with placebo, inhaled fluticasone propionate (100 and 500 mg twice daily), or oral fluticasone propionate 20 mg once daily.
albuterol use decreased 28 and 34% in the 100 and 500 mg inhaled fluticasone propionate groups, respectively, and increased 14 and 16% in the oral fluticasone propionate and placebo treatment groups, respectively. Differences in total daily asthma symptom scores and albuterol use were statistically significant between the inhaled fluticasone propionate and placebo treatment groups as well as between inhaled and oral fluticasone propionate groups (p < 0.008). No statistically significant differences were observed between the inhaled fluticasone propionate treatment groups or between the oral fluticasone propionate and placebo treatment groups. Plasma Fluticasone Propionate Concentrations
The mean trough fluticasone propionate plasma concentrations after 6 wk of treatment are displayed in Figure 4. False positive findings for trough fluticasone propionate plasma concentrations ranged from 6 to 11% across all treatment groups. This was observed at baseline prior to study drug administration in all groups (data not shown) and in the placebo group at the last treatment visit. A large percentage of patients did not have detectable trough plasma fluticasone propionate concentrations after treatment with twice daily inhaled fluticasone propionate 100 mg (75 to 77%) and fluticasone propionate 500 mg (29 to 38%). Patients treated with oral fluticasone propionate had the greatest systemic exposure to fluticasone propionate compared with patients treated with inhaled fluticasone propionate. At Week 6, mean trough plasma fluticasone propionate concentrations after treatment with oral fluticasone propi-
onate were approximately twice those after treatment with inhaled fluticasone propionate. The AUC12 and Cmax results from the 12-h pharmacokinetic assessments made in a subset of 37 patients are presented in Table 3. These results confirm the findings of the trough plasma fluticasone propionate results. At two of the three time points, patients receiving fluticasone propionate 100 mg twice daily had plasma concentrations below the detection limit of the assay to determine AUC12. This assessment could only be made in patients receiving inhaled fluticasone propionate 500 mg and oral fluticasone propionate 20 mg. As seen for the trough plasma fluticasone propionate values, the oral fluticasone propionate group had approximately twice the AUC12 and Cmax values relative to the fluticasone propionate 500 mg group, further supporting that greater systemic exposure occurred after oral fluticasone propionate administration. Safety
Fluticasone propionate was well-tolerated during the trial. No serious drug-related adverse events or laboratory abnormalities were observed with fluticasone propionate treatment. The most common drug-related adverse events were those expected with administration of topical inhaled glucocorticosteroids (oropharyngeal candidiasis and dysphonia), and they occurred at higher incidences in the inhaled fluticasone propionate treatment groups than in the placebo or oral fluticasone propionate treatment groups (Table 4). Despite the slightly higher
Lawrence, Wolfe, Webb, et al.: Inhaled Fluticasone Propionate Acts Topically
749
Figure 4. Detectable (> 25 pg/ml) trough fluticasone propionate plasma concentrations after 6 wk of treatment with placebo, inhaled fluticasone propionate (100 and 500 mg), and oral fluticasone propionate 20 mg. *Patients with FP plasma concentrations below the level of quantification of the assay; placebo, n 5 24/28; FP100 mg, n 5 38/48; FP 500 mg, n 5 17/53; oral FP 20 mg, n 5 2/32.
incidence of these topical side effects with inhaled fluticasone propionate treatment, none of the patients withdrew from study participation because of adverse events. Mean baseline and change from baseline to end point in morning plasma cortisol concentrations are shown in Table 5. The mean change from baseline in morning plasma cortisol concentrations was significantly more pronounced in patients treated with oral fluticasone propionate 20 mg than in those treated with placebo. These changes were not significantly dif-
DISCUSSION
TABLE 3 MEDIAN AUC12 AND Cmax RESULTS* Median AUC12 [Cmax] Dose Placebo Inhaled FP, 100 mg BID Inhaled FP, 500 mg BID Oral FP, 20 mg QD
ferent from those observed with placebo in patients treated with inhaled fluticasone propionate 100 or 500 mg twice daily. In addition, there was a significantly (p 5 0.022) greater reduction in cortisol concentrations in patients receiving oral fluticasone propionate than in patients receiving inhaled fluticasone propionate 100 mg; no significant difference was noted in mean change from baseline cortisol concentrations between the oral fluticasone propionate and inhaled fluticasone propionate 500 mg groups.
Visit 2 (First Dose)
Visit 3 (Week 1)
Visit 6 (Week 4)
(9) BLQ [BLQ] (10) BLQ [BLQ] (10) 348 [43] (8) 624 [89]
(7) BLQ [BLQ] (8) 40 [40] (9) 517 [92] (7) 1,400 [169]
(6) BLQ [BLQ] (6) BLQ [BLQ] (9) 629 [116] (5) 1,230 [248]
AUC12 5 area under the plasma fluticasone propionate concentration time curve over the 12-h dosing interval (pg/h/ml); Cmax 5 peak plasma concentration (pg/ml); FP 5 fluticasone propionate; BID 5 twice daily; QD 5 once daily; BLQ 5 below limit of quantification for the assay. * Number of patients at each visit is shown in parentheses. Cmax results are shown in brackets.
Results from this trial clearly establish that the efficacy of inhaled fluticasone propionate is mediated topically in the lungs and not from systemic absorption of the inhaled dose. Patients receiving oral fluticasone propionate did not experience greater efficacy than patients receiving placebo with respect to probability of remaining in the study over time, morning FEV1 or PEF, patient-rated asthma symptoms, or inhaled albuterol use, despite achieving the highest systemic exposure to fluticasone propionate as assessed by plasma fluticasone propionate concentrations. In contrast, both of the inhaled fluticasone propionate groups improved significantly at end point relative to the placebo group in all of these outcomes. In many instances, the improvement in pulmonary function noted with inhaled
750
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
VOL. 156
1997
TABLE 4 FREQUENCY OF MOST COMMONLY REPORTED (> 2%) DRUG-RELATED ADVERSE EVENTS* Adverse Event
Placebo
Inhaled (FP 100 mg BID)
Inhaled (FP 500 mg BID)
Oral (FP 20 mg QD)
0 3 0
6 3 0
4 11 3
1 1 0
Dysphonia, % Oropharyngeal candidiasis, % Irritation caused by inhalant, %
For definition of abbreviations, see Table 1. * Events considered possibly, probably, or almost certainly related to drug treatment.
fluticasone propionate were achieved without detectable fluticasone propionate in the systemic circulation, and these improvements were also significantly greater than those observed with oral fluticasone propionate treatment. Although there is a general belief that inhaled glucocorticosteroids mediate their effects topically in the lungs rather than from systemic absorption after inhaled administration, limited data in support of this concept are available. Toogood and coworkers (5) found that the action of budesonide in asthma was also mediated via a topical mechanism. Using PEF criteria, these investigators showed that patients treated with oral budesonide and placebo had a shorter time to asthma relapse than did patients treated with inhaled budesonide. However, direct assessment of systemic exposure between the two routes of budesonide administration was not performed in that trial. In the current study, approximately 9% of the trough plasma fluticasone propionate samples assayed at baseline (prior to study drug administration) and during placebo treatment had detectable plasma concentrations or false positive values. Most of the detectable values were near the sensitivity limits for the assay (25 pg/ml). However, by measurement of trough plasma fluticasone propionate concentrations and 12-h pharmacokinetic assessments after treatment with oral and inhaled fluticasone propionate, we clearly established that greater systemic exposure occurred with oral fluticasone propionate than with inhaled fluticasone propionate treatment in this trial. The use of withdrawal criteria allowed for an additional method of comparing efficacy between the fluticasone propionate and the placebo groups. Although these criteria were utilized to ensure patient safety in this placebo-controlled trial in patients previously treated with inhaled glucocorticosteroids, they also provided a global assessment of asthma stability since they were based on clinical parameters (13). However, a consequence of using these criteria was that differences in drop-out rates caused by lack of efficacy between the oral fluticasone propionate and placebo groups compared with the inhaled fluticasone propionate groups complicated assessments of efficacy at later time points in the trial. Patients in
TABLE 5 BASELINE AND CHANGE FROM BASELINE TO END POINT IN MORNING PLASMA CORTISOL CONCENTRATIONS* Visit Baseline Change
Placebo
Inhaled FP 100 mg BID
Inhaled FP 500 mg BID
Oral FP 20 mg QD
13.8 (1) 0.9 (0.7)
15.8 (1) 20.7 (0.8)‡
16.9 (1.2) 22.2 (1.2)
13.7 (0.9) 23 (0.8)†
For definition of abbreviations, see Table 1. * Values are means with SE shown in parentheses. † p , 0.001 versus placebo. ‡ p 5 0.022 versus oral FP.
the placebo and oral fluticasone propionate groups who were least able to tolerate the absence of inhaled glucocorticosteroids withdrew from the study early, whereas patients with more stable asthma in these groups were able to complete study participation. This may explain the apparent “improvement” in FEV1 and other efficacy measures in the placebo and oral fluticasone propionate groups observed at later time points of the trial (Figure 2). However, the use of end point analyses corrects for the differences noted in drop-out rates between placebo and inhaled fluticasone propionate so that significant differences were apparent between these treatment groups for all efficacy measurements at end point. Inhaled fluticasone propionate was well tolerated by patients in this study, and its effects on morning plasma cortisol concentrations were comparable to those observed in the placebo group. These results are consistent with those of others reporting a good safety profile for inhaled fluticasone propionate (13–15). The greatest effects on morning cortisol were seen in the group treated with oral fluticasone propionate, which was associated with the highest systemic exposure. This finding suggests that systemic exposure is predictive of systemic effects as assessed by HPA-axis measurements; whereas, it is not predictive of topical efficacy. In this trial, a large dose (20 mg) of oral fluticasone propionate (20- to 100-fold higher than the two inhaled fluticasone propionate dosages) was utilized in order to obtain detectable plasma concentrations of fluticasone propionate administered via the oral route, thereby indirectly supporting previous study results that have demonstrated the low bioavailability of orally administered fluticasone propionate (17–19). This provides reassurance that the swallowed portion of an inhaled dose is not likely to contribute to systemic effects. Despite the high oral fluticasone propionate doses, significant improvement in pulmonary function was not observed with oral fluticasone propionate treatment. Because fluticasone propionate is a glucocorticosteroid, we would anticipate that with higher oral fluticasone propionate doses (higher than those used in this study) and greater associated systemic exposure, some degree of efficacy would occur. However, as with other orally administered glucocorticosteroids, this would be associated with greater risk of systemic side effects. Mean cortisol concentrations were affected to a greater extent by treatment with oral fluticasone propionate compared with either placebo or inhaled fluticasone propionate. Thus, enough oral fluticasone propionate was utilized in this trial to exhibit effects on HPA-axis measurements but efficacy with the oral formulation was indistinguishable from placebo. These findings indicate that greater separation between desirable and undesirable effects occur with inhaled versus oral fluticasone propionate treatment and thereby confirm an enhanced therapeutic ratio and topical activity of inhaled fluticasone propionate treatment in asthma. In conclusion, both subjective (symptom scores and supple-
Lawrence, Wolfe, Webb, et al.: Inhaled Fluticasone Propionate Acts Topically
mental albuterol use) and objective (pulmonary function) findings in this study demonstrated that the efficacy of inhaled fluticasone propionate was derived from its direct effect in the lungs rather than from systemic activity. These findings confirm the belief that inhaled administration of fluticasone propionate has improved the therapeutic ratio between efficacy and side effects compared with the oral route. Results from this trial support a greater role of fluticasone propionate and other inhaled glucocorticosteroids, by analogy, in the treatment of asthma as proposed in various treatment guidelines (24–27). Acknowledgment : The writers wish to thank Abbas Hamedani for the statistical analyses and John Pitts and Kim Poinsett-Holmes for assistance in writing the manuscript.
13.
14.
15.
16.
References 1. Schleimer, R. P. 1993. Glucocorticosteroids: their mechanisms of action and use in allergic diseases. In E. Middleton, Jr., editor. Allergy: Principles and Practice, 4th ed. Mosby-Year Book, Inc., St. Louis, MO. 893–925. 2. Phillips, G. H. 1990. Structure-activity relationships of topically active steroids: the selection of fluticasone propionate. Respir. Med. 84 (Suppl. A):19–24. 3. Morrow-Brown, H., G. Storey, and W. H. S. George. 1972. Beclomethasone dipropionate: a new steroid aerosol for the treatment of allergic asthma. B.M.J. 1:585–590. 4. Orgel, H. A., E. O. Meltzer, and J. P. Kemp. 1983. Flunisolide aerosol in treatment of steroid-dependent asthma in children. Ann. Allergy 51: 21–25. 5. Toogood, J. H., C. W. Frankish, B. H. Jennings, J. C. Baskerville, N. M. Lefcoe, and S. A. Johansson. 1990. A study of the mechanism of the antiasthmatic action of inhaled budesonide. J. Allergy Clin. Immunol. 85:872–880. 6. Barnes, P. J., and S. Pedersen. 1993. Efficacy and safety of inhaled corticosteroids in asthma. Am. Rev. Respir. Dis. 148:S1–S26. 7. Davies, D. S. 1975. Pharmacokinetics of inhaled substances. Postgrad. Med. J. 51(Suppl. 7):69–75. 8. Ryfeldt, A., P. Andersson, S. Edsbacker, M. Tonnesson, D. Davies, and R. Pauwels. 1982. Pharmacokinetics and metabolism of budesonide, a selective glucocorticoid. Eur. J. Respir. Dis. 63(Suppl. 122):86–95. 9. Barnes, N. 1994. Role of inhaled corticosteroids in the treatment of asthma. Respir. Med. 88(Suppl. A):1–4. 10. Shaw, R. J. 1994. Pharmacology of fluticasone propionate. Respir. Med. 88(Suppl. A):5–8. 11. Hickey, A. J. 1993. Characteristics influencing the effective administration of drugs as inhalation aerosols. Chest 103:657–658. 12. Holliday, S. M., D. Faulds, and E. M. Sorkin. 1994. Inhaled fluticasone
17. 18. 19.
20.
21.
22. 23. 24.
25.
26. 27.
751
propionate: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in asthma. Drugs 47:318–331. Chervinsky, P., A. van As, E. Bronsky, R. Dockhorn, M. Noonan, C. LaForce, and W. Pleskow. 1994. Fluticasone propionate aerosol for the treatment of adults with mild to moderate asthma. J. Allergy Clin. Immunol. 94:676–683. Dahl, R., Bo. Lundback, J.-L. Malo, J. A. Mazza, M. M. Nieminen, P. Saarelainen, and H. Baracle. 1993. A dose-ranging study of fluticasone propionate in adult patients with moderate asthma. Chest 104: 1352–1358. Leblanc, P., S. Mink, T. Keistinen, P. A. Saarelainen, N. Ringdal, and S. L. Payne. 1994. A comparison of fluticasone propionate 200 mg/day with beclomethasone dipropionate 400 mg/day in adult asthma. Allergy 49:380–385. Noonan, M. J., P. Chervinsky, W. W. Busse, S. C. Weisberg, J. Pinnas, B. P. de Boisblanc, H. Boltansky, D. Pearlman, L. Repsher, and D. J. Kellerman. 1995. Fluticasone propionate reduces oral prednisone use while it improves asthma control and quality of life. Am. J. Respir. Crit. Care Med. 152:1467–1473. Harding, S. M. 1990. The human pharmacology of fluticasone propionate. Respir. Med. 84(Suppl. A):24–29. Bye, A. 1993. The oral systemic availability of fluticasone propionate in man: preliminary data. Br. J. Clin. Pharmacol. 36:136–137. Ventresca, G. P., A. E. Mackie, J. A. Moss, J. E. McDowall, and A. Bye. 1994. Absorption of oral fluticasone propionate in healthy subjects (abstract). Am. J. Respir. Crit. Care Med. 194:A214. American Thoracic Society. 1987. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. ATS statement. Am. Rev. Respir. Dis. 136:225–244. Crapo, R. O., A. H. Morris, and R. M. Gardner. 1981. Reference spirometric values using techniques and equipment that meet ATS recommendations. Am. Rev. Respir. Dis. 123:659–664. SAS Institute. 1985. Statistics. SAS User’s Guide 5:433–507. SAS Institute, Cary, NC. Van Elteren, P. H. 1960. On the combination of independent two-sample tests of Wilcoxon. Bull. Int. Stat. Inst. 37:351–361. National Asthma Education Program. Expert Panel on the Management of Asthma, National Heart, Lung, and Blood Institute. 1991. Guidelines for the Diagnosis and Management of Asthma. J. Allergy Clin. Immunol. 88:425–534. Sheffer, A. L., Chairman. 1992. International Consensus Report on Diagnosis and Management of Asthma. International Asthma Management Project. Clin. Exp. Allergy 22(Suppl. 1):1–72. British Thoracic Society. 1990. Guidelines for management of asthma in adults. I. Chronic persistent asthma. B.M.J. 301:651–653. National Institutes of Health. National Heart, Lung, and Blood Institute. 1995. Global Initiative for Asthma. Global Strategy for Asthma management and prevention. NHLBI/WHO Workshop Report. Publication No. 95-3659. NIH, Bethesda, MD.
