- Email: [email protected]
Relative potency of fexofenadine HCl 180 mg, loratadine 10 mg, and placebo using a skin test model of wheal-and-flare suppression
Relative potency of fexofenadine HCl 180 mg, loratadine 10 mg, and placebo using a skin test model of wheal-and-flare suppression Michael A. Kaliner, MD*; Martha V. White, MD*; Athena Economides, MD*; Tera Crisalida, PA-C*; Mary Hale, PA*; Yuning Liao, PhD†; Claire D. Christian, RN†; George C. Georges, MD†; Thomas H. Woodworth, BA†; and Suzanne G. Meeves, PharmD†
Background: H1-receptor antagonists differ in their ability to produce peripheral H1-blockade. Suppression of histamineinduced flares and wheals is a useful objective test for measuring these differences. Objective: To evaluate the relative potency of fexofenadine HCl 180 mg, loratadine 10 mg, and placebo (PBO) in suppressing histamine-induced flares and wheals and compare the onset, duration, and maximum suppression of histamine achieved with each agent. Methods: Thirty healthy volunteers were enrolled in this randomized, double-blind, single-dose, crossover study. Flares and wheals induced by skin-prick testing with histamine 1.8 mg/mL were measured before treatment, every 20 minutes during the first hour after dosing, and thereafter hourly between 2 and 12 hours and between 23 and 25 hours postdose. Results: Fexofenadine was significantly more effective than loratadine in suppressing the histamine-induced flare response at hours 2 through 7 and 10 through 12 and produced greater flare suppression than did PBO at hours 2 through 25. Onset of flare suppression occurred 2 hours after dosing with fexofenadine and 4 hours after dosing with loratadine. Likewise, fexofenadine was superior to loratadine in suppressing the wheal response from hours 1 through 12 and was more effective than PBO at hours 1 through 12, 24, and 25. Throughout the 25-hour measurement interval, the magnitude of difference in both wheal and flare suppression consistently favored fexofenadine over loratadine. Conclusions: In a skin test model of wheal-and-flare suppression, fexofenadine showed rapid distribution into the skin compartment with faster onset of action and greater potency vs loratadine. Ann Allergy Asthma Immunol. 2003;90:629– 634.
INTRODUCTION The second-generation histamine-1 (H1)-antagonists were developed with the goal of improving the tolerability of the original first-generation agents without compromising efficacy. Thus, the second-generation H1-antagonists are characterized by increased receptor specificity, resulting in potent, selective peripheral H1-receptor blocking activity coupled with reduced sedative and anticholinergic side effects.1 Their common properties notwithstanding, the second-generation antihistamines are actually an extremely heterogeneous family of compounds with different pharmacokinetic and pharmacodynamic profiles and varying degrees of antiallergic activity.2 A useful strategy for investigating the differences between H1-receptor antagonists is the study of peripheral H1-blockade, as reflected by objective measurements of pharmacologic suppression of histamine-induced wheals and flares.3
* The Institute for Asthma and Allergy, Chevy Chase, Maryland. † Aventis Pharmaceuticals, Bridgewater, New Jersey. This study was supported by an unrestricted research grant from Aventis Pharmaceuticals. Received for publication October 15, 2002. Accepted for publication in revised form February 9, 2003.
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This study utilized the wheal-and-flare suppression bioassay in order to explore possible differences in the degree, onset, and duration of H1-receptor blockade between fexofenadine hydrochloride and loratadine, two representative second-generation H1-antagonists. Fexofenadine and loratadine have both been classified as nonsedating by the US Food and Drug Administration1 and European regulatory authorities and are widely prescribed for allergic disorders such as seasonal allergic rhinitis (SAR) and chronic idiopathic urticaria (CIU). The objective of this study was to compare a single dose of fexofenadine HCl 180 mg, loratadine 10 mg, and placebo (PBO) in suppressing histamine-induced wheals and flares. METHODS Ethical Conduct This study was conducted in accordance with the ethical principles originating from the Declaration of Helsinki (October 2000). The study protocol was reviewed and approved by an appropriate independent ethics committee. All subjects provided informed consent prior to enrollment in the study. The investigators would remove a patient from the study if continued participation was believed to be detrimental based on clinically significant adverse events or laboratory abnormalities.
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Subjects Candidates for the study were healthy men and women between the ages of 18 and 55 years who displayed a positive histamine skin-prick test result with a summation flare (⌺F) ⬎20 mm larger than the diluent control and a summation wheal (⌺W) ⬎6 mm larger than the diluent control. Subjects were excluded from enrollment if they had asthma requiring treatment with medication other than an inhaled, short-acting -agonist; had signs and symptoms of currently active allergic disease (eg, SAR); had taken an H1-receptor antagonist regularly within the preceding year; were receiving escalating doses of immunotherapy, oral immunotherapy, or shortcourse immunotherapy; were receiving corticosteroids or other agents that affect the response to histamine (eg, agents such as antidepressants or antipsychotics that have antihistaminic/anticholinergic activity, prescription or over-thecounter antihistamines); or if they were pregnant. Women of childbearing age were required to use adequate contraception throughout the study. Study Design This randomized, double-blind, double-dummy, PBO-controlled, single-center study evaluated single doses of fexofenadine HCl 180 mg, loratadine 10 mg, and PBO in a threeway crossover design. Each of the three treatment periods consisted of two visits on consecutive days to permit collection of data from predose to 12 hours and from 23 to 25 hours after dosing (Fig 1). Treatment periods were separated by a washout period of 14 ⫾ 4 days. During the first visit of each treatment period, subjects received a single dose of 1 of the 3 study treatments in third-party, double-blind, double-dummy fashion (Table 1). Skin prick testing with histamine, 1.8 mg/mL, and with diluent was performed before dosing, every 20 minutes for the first hour after dosing, and thereafter hourly through 12 hours and between 23 and 25 hours. Duplicate skin prick tests were performed at baseline (predose) and at 6, 12, and 24 hours postdose to minimize within-subject data variability at these time points. At all other times, single skin prick tests were done. The same trained and certified technician administered all skin tests and measured all wheals and flares on a given subject. The average of the two histamine-induced wheal/flare measurements was used for efficacy analyses at previously identified time points. Wheal and flare responses were measured at all time points. The margins of the wheals and flares were outlined in black ink 10 minutes after histamine and diluent administration, and the outlines were then
Table 1. Randomization Schedule Sequence
Treatment 1
Treatment 2
Treatment 3
1 2 3 4 5 6
P P L L F F
L F P F P L
F L F P L P
Abbreviations: P, FEX PBO tablet and LOR PBO capsule; L, FEX PBO tablet and LOR 10 mg capsule; F, FEX 180 mg tablet and LOR PBO capsule; FEX, fexofenadine; PBO, placebo; LOR, loratadine.
transferred from the skin to transparent surgical tape. Flares and wheals were quantified by summing the longest diameter and the perpendicular diameter that passed through the midpoint of the longest diameter, according to the method of Turkeltaub et al.4 Efficacy Measures The primary endpoint of this study was the treatment-associated change from baseline in skin flare summation measurements for each subject who completed all three treatment periods without a protocol violation (per-protocol population). The treatment-induced change from baseline in skin wheal summation measurements represented the secondary study endpoint. Additional endpoints included the onset, duration, and maximum percentage suppression of histamine-induced flares and wheals. The onset of histamine block was defined as the first of two consecutive measurements for which the change in flare summation diameter relative to baseline was at least 5 mm greater with active treatment than with PBO. Cessation of histamine block, or offset, was defined as the first of two consecutive measurements (except at hour 25, when one measurement was considered sufficient) for which the difference in flare summation diameter change between active treatment and PBO dropped below 5 mm. The duration of histamine block was defined as the interval between the onset and offset of suppression. Definitions for wheal suppression were similar, except that between-treatment differences of ⱖ1 mm and ⬍1 mm in wheal-summation diameter were used as criteria for onset and offset, respectively. The percent suppression of histamine-induced flares and wheals was calculated according to the following equation: % suppression ⫽ Baseline
冘 (or 冘 ) ⫺ Postdose 冘 (or 冘 ) ⫻ 100 Baseline 冘 (or 冘 ) F
W
F
F
Figure 1. Study design.
630
W
W
Statistical Analyses Descriptive statistics were used to compare histamine-induced skin wheal and flare measurements and the onset, duration, and time of maximum histamine suppression (N, mean, median, and SD) according to treatment sequence and for all sequences combined. An analysis of variance model
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
was used to assess sequence, treatment, and further interactions. The comparisons among the three treatment groups were model-based and were tested at all time points, with P values provided. Pharmacodynamic analyses did not use the approach of last observation carried forward for missing or invalid observations within the three treatment periods; missing data (one wheal and flare measure for one subject) were considered missing at random. RESULTS Demographic Characteristics Of 38 volunteers enrolled in the study, 31 were randomized, 4 were deemed ineligible for randomization because of abnormal findings on physical examination, and 3 withdrew before randomization. Thirty of the 31 randomized subjects completed the study; the remaining subject was withdrawn from the study because of a dosing error during treatment 1. The per-protocol population included 20 women and 10 men, of whom 17 were Caucasian, 11 were African-American, and 2 were Asian or Pacific Islanders. The mean age of the study participants was 33.7 ⫾ 9.8 (SD) years and their mean weight was 154.7 ⫾ 24.9 pounds. Flare Suppression The mean predose histamine skin flare summation measurements were 38.0 ⫾ 16.5, 40.8 ⫾ 12.5, and 43.9 ⫾ 14.3 mm, respectively, for the fexofenadine, loratadine, and PBO groups. The sizes of the predose histamine-induced flare were similar in all six treatment sequence arms. Fexofenadine HCl 180 mg produced significantly greater suppression of histamine-induced flares than did PBO from 2 through 25 hours after dosing (P ⬍ 0.05; Figs 2 and 3). Flare suppression was also significantly greater with fexofenadine HCl 180 mg than with loratadine 10 mg, from 2 through 5
hours (P ⬍ 0.001), at hours 6 and 7 (P ⬍ 0.05), and from 10 through 12 hours postdose (P ⬍ 0.05) (Fig 2). Loratadine 10 mg significantly suppressed flares relative to PBO from 5 through 9 hours after dosing (P ⬍ 0.05; Fig 2). Wheal Suppression The mean predose histamine skin wheal summation measurements were 8.3 ⫾ 2.5, 7.3 ⫾ 1.9, and 7.9 ⫾ 2.1 mm, respectively, for the fexofenadine, loratadine, and PBO groups. Predose histamine-induced wheal sizes were similar for all treatment sequences. Fexofenadine HCl 180 mg significantly reduced histamineinduced wheals vs PBO from 1 through 12 hours and at 24 and 25 hours postdosing (P ⬍ 0.05; Fig 4). Fexofenadine HCl 180 mg also suppressed wheals vs loratadine from 1 to 12 hours inclusive (P ⬍ 0.05; Fig 4). Loratadine 10 mg suppressed wheals relative to PBO at 6, 8, 11, and 25 hours after dosing (P ⱕ 0.05; Fig 5). Onset of Action Onset of action of skin flare suppression occurred 2 hours after dosing with fexofenadine HCl 180 mg and 4 hours after dosing with loratadine 10 mg (P ⬍ 0.05). The onset of skin wheal suppression with fexofenadine HCl 180 mg was observed 40 minutes after dosing, with the response persisting through hour 25 (Figs 4 and 5). By prespecified definition, the onset of skin wheal suppression did not occur after treatment with loratadine 10 mg. Duration of Action The duration of action for both flare and wheal suppression was maintained for 25 hours after dosing with fexofenadine HCl 180 mg. For loratadine 10 mg, the duration of action for flare suppression was maintained for 25 hours after dosing. Since the onset of skin wheal suppression did not occur
Figure 2. Diameter (mean) of histamine-induced flare reaction before and for 25 hours after dosing with fexofenadine (FEX), loratadine (LOR), or placebo (PBO).
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Figure 3. Mean change from baseline in diameter of histamine-induced flare for 25 hours after dosing with fexofenadine (FEX), loratadine (LOR), or placebo (PBO).
Figure 4. Mean diameter of histamine-induced wheals before and for 25 hours after dosing with fexofenadine (FEX), loratadine (LOR), or placebo (PBO).
following treatment with loratadine 10 mg, the duration of action for loratadine could not be determined. Maximum Suppressive Effects The maximum percent suppression of skin flare area was 82.4% at 6 hours with single-dose fexofenadine HCl 180 mg, 60.5% at 8 hours with loratadine 10 mg, and 36.3% at 6 hours with PBO (Figs 2 and 3). Peak suppression of wheal area was 85.4% with fexofenadine HCl 180 mg, 49.3% with loratadine 10 mg, and 33.7% with PBO and occurred at 6 hours after dosing with each of the three agents (Figs 4 and 5).
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DISCUSSION Both pharmacodynamic and efficacy data should be considered when evaluating therapeutic options for the treatment of allergic diseases.3 As a complement to direct measures of clinical efficacy, skin wheal and flare suppression has been well established as an objective model for evaluating onset, strength, and duration of peripheral H1-blockade and for measuring the pharmacodynamic differences among various H1-receptor antagonists.3 In the present study, fexofenadine HCl 180 mg was shown to be significantly superior to loratadine 10 mg in suppressing histamine-induced flares and
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Figure 5. Mean change from baseline in diameter of histamine-induced wheals for 25 hours after dosing with fexofenadine (FEX), loratadine (LOR), or placebo (PBO).
wheals. Throughout the 25-hour measurement interval, the magnitude of both flare and wheal suppression consistently favored fexofenadine over loratadine. Compared with loratadine 10 mg, fexofenadine HCl 180 mg significantly reduced flare diameter from hours 2 through 7 and 10 through 12 postdose. Likewise, the suppressive effect on wheal diameter was significantly greater with fexofenadine HCl 180 mg than loratadine 10 mg for the first 12 hourly postdose measures. These findings suggest that fexofenadine HCl 180 mg is a stronger H1-receptor antagonist than loratadine 10 mg. In addition, fexofenadine HCl 180 mg exhibited a more rapid onset of action for wheal and flare than loratadine 10 mg, suggesting that fexofenadine is more rapidly distributed into the skin compartment than loratadine. The correlation between rapid penetration of the skin and the onset, degree, and duration of peripheral H1-blockade has been demonstrated recently in a randomized, double-blind study of healthy volunteers.5 Measurements performed in skin biopsy samples revealed that, at all six time points tested, skin fexofenadine concentrations were four- to fivefold higher than skin diphenhydramine concentrations.5 Relative to diphenhydramine 50 mg, fexofenadine HCl 120 mg produced significantly greater suppression of flare reactions at 4 of the 6 time points, and of wheal reactions at three time points.5 The investigators hypothesized that, because fexofenadine is present in the skin in higher concentrations than diphenhydramine, it is likely to be more effective in the treatment of allergic skin disorders.5 Rapid compartmentalization into the skin may explain the effectiveness of fexofenadine across a broad dose range for the treatment of CIU. The findings of the present study are also consistent with those of a previous randomized, double-blind, crossover study3 that compared fexofenadine HCl 60 mg twice daily,
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fexofenadine HCl 120 mg once daily, loratadine 10 mg once daily, and PBO in healthy subjects. The results of that study indicated that a 120-mg dose of fexofenadine was significantly more effective than loratadine 10 mg in suppressing flares from 2 through 5 hours after dosing and produced significantly greater wheal suppression from 2 through 6 hours and at 8 and 10 hours postdose.3 In addition, the onset of action for both flare and wheal suppression was significantly faster with fexofenadine than with loratadine.3 The formation of cutaneous wheals and flares after histamine injection mimics the early phase of the allergic response,6,7 and the suppression of this reaction is well accepted as an objective measure of peripheral H1-receptor blockade, both in healthy subjects and in patients with allergic disorders.8 When performed carefully in a standardized manner, the wheal-and-flare suppression test is highly sensitive, specific, and reproducible.8 Although histamine is the major mediator of the whealand-flare reaction, it plays only a limited role in the latephase reaction.6 While one clinical study9 has demonstrated a close correlation between peripheral H1-blockade and therapeutic benefit in allergic airway disease, other studies have failed to confirm a direct relationship between the extent of suppression of histamine-induced flares and wheals and control of clinical symptoms.7 In a review evaluating the usefulness of the skin wheal and flare model to predict clinical efficacy of cetirizine,7 the authors determined that cetirizine’s potency in wheal and flare suppression did not translate into greater efficacy in the treatment of CIU. Fexofenadine has been well established through both pharmacodynamic and efficacy measures as a useful treatment for SAR and, more recently, CIU.10 –16 In two multicenter, randomized, double-blind studies of CIU,15,16 fexofenadine HCl
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20, 60, 120, and 240 mg twice daily reduced pruritus, number of wheals, and interference with sleep and daily activities vs PBO. The 20-mg dose of fexofenadine was effective across all study parameters, and greater symptomatic improvement was observed with the three higher study doses. No doserelated adverse events were reported during the studies.
9.
10.
CONCLUSION The present study of suppression of histamine-induced wheals and flares has provided additional evidence that fexofenadine HCl 180 mg is superior to loratadine 10 mg in the onset, strength, and duration of H1-receptor blockade.
11.
REFERENCES
12.
1. Slater JW, Zechnich AD, Haxby DG. Second generation antihistamines: a comparative review. Drugs. 1999;57:31– 46. 2. Walsh GM, Annunziato L, Frossard N, Knol K, Levander S, et al. New insights into the second generation antihistamines. Drugs. 2001;61:207–236. 3. Simons FE, Simons KJ. Peripheral H1-blockade effect of fexofenadine. Ann Allergy Asthma Immunol. 1997;79:530 –532. 4. Turkeltaub PC, Rastogi SC, Baer H, Anderson MC, Norman PS. A standardized quantitative skin-test assay of allergen potency and stability: studies on the allergen dose-response curve and effect of wheal, erythema, and patient selection on assay results. J Allergy Clin Immunol. 1982;70:343–352. 5. Simons FE, Silver NA, Gu X, Simons KJ. Skin concentrations of H1-receptor antagonists. J Allergy Clin Immunol. 2001;107: 526 –530. 6. Bousquet J, Michel FB. In vivo methods for study of allergy. Skin tests, techniques and interpretation. In: Middleton E Jr, Reed CE, Ellis EF, Yunginger JW, editors. Allergy: Principles and Practice, 4th ed. St. Louis, MO: Mosby-Year Book, 1993: 573–594. 7. Monroe EW, Daly AF, Shalhoub RF. Appraisal of the validity of histamine-induced wheal and flare to predict the clinical efficacy of antihistamines. J Allergy Clin Immunol. 1997; 99(Suppl):S798 –S806. 8. Simons FE, McMillan JL, Simons KJ. A double-blind, single-dose, crossover comparison of cetirizine, terfenadine, loratadine, astemizole, and chlorpheniramine versus placebo: suppressive effects on histamine-induced wheals and flares
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16.
during 24 hours in normal subjects. J Allergy Clin Immunol. 1990;86:540 –547. Wood-Baker R, Holgate ST. The comparative actions and adverse effect profile of single doses of H1-receptor antihistamines in the airways and skin of subjects with asthma. J Allergy Clin Immunol. 1993;91:1005–1014. Bernstein DI, Schoenwetter WF, Nathan RA, Storms W, Ahlbrandt R, Mason J. Efficacy and safety of fexofenadine hydrochloride for treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 1997;79:443– 448. Bronsky EA, Falliers CJ, Kaiser HB, Ahlbrandt R, Mason JM. Effectiveness and safety of fexofenadine, a new nonsedating H1-receptor antagonist, in the treatment of fall allergies. Allergy Asthma Proc. 1998;19:135–141. Casale TB, Andrade C, Qu R. Safety and efficacy of once-daily fexofenadine HCl in the treatment of autumn seasonal allergic rhinitis. Allergy Asthma Proc. 1999;20:193–198. Howarth PH, Stern MA, Roi L, Reynolds R, Bousquet J. Double-blind, placebo-controlled study comparing the efficacy and safety of fexofenadine hydrochloride (120 and 180 mg once daily) and cetirizine in seasonal allergic rhinitis. J Allergy Clin Immunol. 1999;104:927–933. Van Cauwenberge P, Juniper EF, the Star Study Investigating Group. Comparison of the efficacy, safety and quality of life provided by fexofenadine hydrochloride 120 mg, loratadine 10 mg and placebo administered once daily for the treatment of seasonal allergic rhinitis. Clin Exp Allergy. 2000;30:891– 899. Finn AF Jr, Kaplan AP, Fretwell R, Qu R, Long J. A doubleblind, placebo-controlled trial of fexofenadine HCl in the treatment of chronic idiopathic urticaria. J Allergy Clin Immunol. 1999;104:1071–1078. Nelson HS, Reynolds R, Mason J. Fexofenadine HCl is safe and effective for treatment of chronic idiopathic urticaria. Ann Allergy Asthma Immunol. 2000;84:517–522.
Requests for reprints should be addressed to: M. A. Kaliner, MD Institute for Asthma and Allergy 5454 Wisconsin Avenue Suite 1700 Chevy Chase, MD 20815 E-mail: [email protected]
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Background: H1-receptor antagonists differ in their ability to produce peripheral H1-blockade. Suppression of histamineinduced flares and wheals is a useful objective test for measuring these differences. Objective: To evaluate the relative potency of fexofenadine HCl 180 mg, loratadine 10 mg, and placebo (PBO) in suppressing histamine-induced flares and wheals and compare the onset, duration, and maximum suppression of histamine achieved with each agent. Methods: Thirty healthy volunteers were enrolled in this randomized, double-blind, single-dose, crossover study. Flares and wheals induced by skin-prick testing with histamine 1.8 mg/mL were measured before treatment, every 20 minutes during the first hour after dosing, and thereafter hourly between 2 and 12 hours and between 23 and 25 hours postdose. Results: Fexofenadine was significantly more effective than loratadine in suppressing the histamine-induced flare response at hours 2 through 7 and 10 through 12 and produced greater flare suppression than did PBO at hours 2 through 25. Onset of flare suppression occurred 2 hours after dosing with fexofenadine and 4 hours after dosing with loratadine. Likewise, fexofenadine was superior to loratadine in suppressing the wheal response from hours 1 through 12 and was more effective than PBO at hours 1 through 12, 24, and 25. Throughout the 25-hour measurement interval, the magnitude of difference in both wheal and flare suppression consistently favored fexofenadine over loratadine. Conclusions: In a skin test model of wheal-and-flare suppression, fexofenadine showed rapid distribution into the skin compartment with faster onset of action and greater potency vs loratadine. Ann Allergy Asthma Immunol. 2003;90:629– 634.
INTRODUCTION The second-generation histamine-1 (H1)-antagonists were developed with the goal of improving the tolerability of the original first-generation agents without compromising efficacy. Thus, the second-generation H1-antagonists are characterized by increased receptor specificity, resulting in potent, selective peripheral H1-receptor blocking activity coupled with reduced sedative and anticholinergic side effects.1 Their common properties notwithstanding, the second-generation antihistamines are actually an extremely heterogeneous family of compounds with different pharmacokinetic and pharmacodynamic profiles and varying degrees of antiallergic activity.2 A useful strategy for investigating the differences between H1-receptor antagonists is the study of peripheral H1-blockade, as reflected by objective measurements of pharmacologic suppression of histamine-induced wheals and flares.3
* The Institute for Asthma and Allergy, Chevy Chase, Maryland. † Aventis Pharmaceuticals, Bridgewater, New Jersey. This study was supported by an unrestricted research grant from Aventis Pharmaceuticals. Received for publication October 15, 2002. Accepted for publication in revised form February 9, 2003.
VOLUME 90, JUNE, 2003
This study utilized the wheal-and-flare suppression bioassay in order to explore possible differences in the degree, onset, and duration of H1-receptor blockade between fexofenadine hydrochloride and loratadine, two representative second-generation H1-antagonists. Fexofenadine and loratadine have both been classified as nonsedating by the US Food and Drug Administration1 and European regulatory authorities and are widely prescribed for allergic disorders such as seasonal allergic rhinitis (SAR) and chronic idiopathic urticaria (CIU). The objective of this study was to compare a single dose of fexofenadine HCl 180 mg, loratadine 10 mg, and placebo (PBO) in suppressing histamine-induced wheals and flares. METHODS Ethical Conduct This study was conducted in accordance with the ethical principles originating from the Declaration of Helsinki (October 2000). The study protocol was reviewed and approved by an appropriate independent ethics committee. All subjects provided informed consent prior to enrollment in the study. The investigators would remove a patient from the study if continued participation was believed to be detrimental based on clinically significant adverse events or laboratory abnormalities.
629
Subjects Candidates for the study were healthy men and women between the ages of 18 and 55 years who displayed a positive histamine skin-prick test result with a summation flare (⌺F) ⬎20 mm larger than the diluent control and a summation wheal (⌺W) ⬎6 mm larger than the diluent control. Subjects were excluded from enrollment if they had asthma requiring treatment with medication other than an inhaled, short-acting -agonist; had signs and symptoms of currently active allergic disease (eg, SAR); had taken an H1-receptor antagonist regularly within the preceding year; were receiving escalating doses of immunotherapy, oral immunotherapy, or shortcourse immunotherapy; were receiving corticosteroids or other agents that affect the response to histamine (eg, agents such as antidepressants or antipsychotics that have antihistaminic/anticholinergic activity, prescription or over-thecounter antihistamines); or if they were pregnant. Women of childbearing age were required to use adequate contraception throughout the study. Study Design This randomized, double-blind, double-dummy, PBO-controlled, single-center study evaluated single doses of fexofenadine HCl 180 mg, loratadine 10 mg, and PBO in a threeway crossover design. Each of the three treatment periods consisted of two visits on consecutive days to permit collection of data from predose to 12 hours and from 23 to 25 hours after dosing (Fig 1). Treatment periods were separated by a washout period of 14 ⫾ 4 days. During the first visit of each treatment period, subjects received a single dose of 1 of the 3 study treatments in third-party, double-blind, double-dummy fashion (Table 1). Skin prick testing with histamine, 1.8 mg/mL, and with diluent was performed before dosing, every 20 minutes for the first hour after dosing, and thereafter hourly through 12 hours and between 23 and 25 hours. Duplicate skin prick tests were performed at baseline (predose) and at 6, 12, and 24 hours postdose to minimize within-subject data variability at these time points. At all other times, single skin prick tests were done. The same trained and certified technician administered all skin tests and measured all wheals and flares on a given subject. The average of the two histamine-induced wheal/flare measurements was used for efficacy analyses at previously identified time points. Wheal and flare responses were measured at all time points. The margins of the wheals and flares were outlined in black ink 10 minutes after histamine and diluent administration, and the outlines were then
Table 1. Randomization Schedule Sequence
Treatment 1
Treatment 2
Treatment 3
1 2 3 4 5 6
P P L L F F
L F P F P L
F L F P L P
Abbreviations: P, FEX PBO tablet and LOR PBO capsule; L, FEX PBO tablet and LOR 10 mg capsule; F, FEX 180 mg tablet and LOR PBO capsule; FEX, fexofenadine; PBO, placebo; LOR, loratadine.
transferred from the skin to transparent surgical tape. Flares and wheals were quantified by summing the longest diameter and the perpendicular diameter that passed through the midpoint of the longest diameter, according to the method of Turkeltaub et al.4 Efficacy Measures The primary endpoint of this study was the treatment-associated change from baseline in skin flare summation measurements for each subject who completed all three treatment periods without a protocol violation (per-protocol population). The treatment-induced change from baseline in skin wheal summation measurements represented the secondary study endpoint. Additional endpoints included the onset, duration, and maximum percentage suppression of histamine-induced flares and wheals. The onset of histamine block was defined as the first of two consecutive measurements for which the change in flare summation diameter relative to baseline was at least 5 mm greater with active treatment than with PBO. Cessation of histamine block, or offset, was defined as the first of two consecutive measurements (except at hour 25, when one measurement was considered sufficient) for which the difference in flare summation diameter change between active treatment and PBO dropped below 5 mm. The duration of histamine block was defined as the interval between the onset and offset of suppression. Definitions for wheal suppression were similar, except that between-treatment differences of ⱖ1 mm and ⬍1 mm in wheal-summation diameter were used as criteria for onset and offset, respectively. The percent suppression of histamine-induced flares and wheals was calculated according to the following equation: % suppression ⫽ Baseline
冘 (or 冘 ) ⫺ Postdose 冘 (or 冘 ) ⫻ 100 Baseline 冘 (or 冘 ) F
W
F
F
Figure 1. Study design.
630
W
W
Statistical Analyses Descriptive statistics were used to compare histamine-induced skin wheal and flare measurements and the onset, duration, and time of maximum histamine suppression (N, mean, median, and SD) according to treatment sequence and for all sequences combined. An analysis of variance model
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was used to assess sequence, treatment, and further interactions. The comparisons among the three treatment groups were model-based and were tested at all time points, with P values provided. Pharmacodynamic analyses did not use the approach of last observation carried forward for missing or invalid observations within the three treatment periods; missing data (one wheal and flare measure for one subject) were considered missing at random. RESULTS Demographic Characteristics Of 38 volunteers enrolled in the study, 31 were randomized, 4 were deemed ineligible for randomization because of abnormal findings on physical examination, and 3 withdrew before randomization. Thirty of the 31 randomized subjects completed the study; the remaining subject was withdrawn from the study because of a dosing error during treatment 1. The per-protocol population included 20 women and 10 men, of whom 17 were Caucasian, 11 were African-American, and 2 were Asian or Pacific Islanders. The mean age of the study participants was 33.7 ⫾ 9.8 (SD) years and their mean weight was 154.7 ⫾ 24.9 pounds. Flare Suppression The mean predose histamine skin flare summation measurements were 38.0 ⫾ 16.5, 40.8 ⫾ 12.5, and 43.9 ⫾ 14.3 mm, respectively, for the fexofenadine, loratadine, and PBO groups. The sizes of the predose histamine-induced flare were similar in all six treatment sequence arms. Fexofenadine HCl 180 mg produced significantly greater suppression of histamine-induced flares than did PBO from 2 through 25 hours after dosing (P ⬍ 0.05; Figs 2 and 3). Flare suppression was also significantly greater with fexofenadine HCl 180 mg than with loratadine 10 mg, from 2 through 5
hours (P ⬍ 0.001), at hours 6 and 7 (P ⬍ 0.05), and from 10 through 12 hours postdose (P ⬍ 0.05) (Fig 2). Loratadine 10 mg significantly suppressed flares relative to PBO from 5 through 9 hours after dosing (P ⬍ 0.05; Fig 2). Wheal Suppression The mean predose histamine skin wheal summation measurements were 8.3 ⫾ 2.5, 7.3 ⫾ 1.9, and 7.9 ⫾ 2.1 mm, respectively, for the fexofenadine, loratadine, and PBO groups. Predose histamine-induced wheal sizes were similar for all treatment sequences. Fexofenadine HCl 180 mg significantly reduced histamineinduced wheals vs PBO from 1 through 12 hours and at 24 and 25 hours postdosing (P ⬍ 0.05; Fig 4). Fexofenadine HCl 180 mg also suppressed wheals vs loratadine from 1 to 12 hours inclusive (P ⬍ 0.05; Fig 4). Loratadine 10 mg suppressed wheals relative to PBO at 6, 8, 11, and 25 hours after dosing (P ⱕ 0.05; Fig 5). Onset of Action Onset of action of skin flare suppression occurred 2 hours after dosing with fexofenadine HCl 180 mg and 4 hours after dosing with loratadine 10 mg (P ⬍ 0.05). The onset of skin wheal suppression with fexofenadine HCl 180 mg was observed 40 minutes after dosing, with the response persisting through hour 25 (Figs 4 and 5). By prespecified definition, the onset of skin wheal suppression did not occur after treatment with loratadine 10 mg. Duration of Action The duration of action for both flare and wheal suppression was maintained for 25 hours after dosing with fexofenadine HCl 180 mg. For loratadine 10 mg, the duration of action for flare suppression was maintained for 25 hours after dosing. Since the onset of skin wheal suppression did not occur
Figure 2. Diameter (mean) of histamine-induced flare reaction before and for 25 hours after dosing with fexofenadine (FEX), loratadine (LOR), or placebo (PBO).
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Figure 3. Mean change from baseline in diameter of histamine-induced flare for 25 hours after dosing with fexofenadine (FEX), loratadine (LOR), or placebo (PBO).
Figure 4. Mean diameter of histamine-induced wheals before and for 25 hours after dosing with fexofenadine (FEX), loratadine (LOR), or placebo (PBO).
following treatment with loratadine 10 mg, the duration of action for loratadine could not be determined. Maximum Suppressive Effects The maximum percent suppression of skin flare area was 82.4% at 6 hours with single-dose fexofenadine HCl 180 mg, 60.5% at 8 hours with loratadine 10 mg, and 36.3% at 6 hours with PBO (Figs 2 and 3). Peak suppression of wheal area was 85.4% with fexofenadine HCl 180 mg, 49.3% with loratadine 10 mg, and 33.7% with PBO and occurred at 6 hours after dosing with each of the three agents (Figs 4 and 5).
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DISCUSSION Both pharmacodynamic and efficacy data should be considered when evaluating therapeutic options for the treatment of allergic diseases.3 As a complement to direct measures of clinical efficacy, skin wheal and flare suppression has been well established as an objective model for evaluating onset, strength, and duration of peripheral H1-blockade and for measuring the pharmacodynamic differences among various H1-receptor antagonists.3 In the present study, fexofenadine HCl 180 mg was shown to be significantly superior to loratadine 10 mg in suppressing histamine-induced flares and
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Figure 5. Mean change from baseline in diameter of histamine-induced wheals for 25 hours after dosing with fexofenadine (FEX), loratadine (LOR), or placebo (PBO).
wheals. Throughout the 25-hour measurement interval, the magnitude of both flare and wheal suppression consistently favored fexofenadine over loratadine. Compared with loratadine 10 mg, fexofenadine HCl 180 mg significantly reduced flare diameter from hours 2 through 7 and 10 through 12 postdose. Likewise, the suppressive effect on wheal diameter was significantly greater with fexofenadine HCl 180 mg than loratadine 10 mg for the first 12 hourly postdose measures. These findings suggest that fexofenadine HCl 180 mg is a stronger H1-receptor antagonist than loratadine 10 mg. In addition, fexofenadine HCl 180 mg exhibited a more rapid onset of action for wheal and flare than loratadine 10 mg, suggesting that fexofenadine is more rapidly distributed into the skin compartment than loratadine. The correlation between rapid penetration of the skin and the onset, degree, and duration of peripheral H1-blockade has been demonstrated recently in a randomized, double-blind study of healthy volunteers.5 Measurements performed in skin biopsy samples revealed that, at all six time points tested, skin fexofenadine concentrations were four- to fivefold higher than skin diphenhydramine concentrations.5 Relative to diphenhydramine 50 mg, fexofenadine HCl 120 mg produced significantly greater suppression of flare reactions at 4 of the 6 time points, and of wheal reactions at three time points.5 The investigators hypothesized that, because fexofenadine is present in the skin in higher concentrations than diphenhydramine, it is likely to be more effective in the treatment of allergic skin disorders.5 Rapid compartmentalization into the skin may explain the effectiveness of fexofenadine across a broad dose range for the treatment of CIU. The findings of the present study are also consistent with those of a previous randomized, double-blind, crossover study3 that compared fexofenadine HCl 60 mg twice daily,
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fexofenadine HCl 120 mg once daily, loratadine 10 mg once daily, and PBO in healthy subjects. The results of that study indicated that a 120-mg dose of fexofenadine was significantly more effective than loratadine 10 mg in suppressing flares from 2 through 5 hours after dosing and produced significantly greater wheal suppression from 2 through 6 hours and at 8 and 10 hours postdose.3 In addition, the onset of action for both flare and wheal suppression was significantly faster with fexofenadine than with loratadine.3 The formation of cutaneous wheals and flares after histamine injection mimics the early phase of the allergic response,6,7 and the suppression of this reaction is well accepted as an objective measure of peripheral H1-receptor blockade, both in healthy subjects and in patients with allergic disorders.8 When performed carefully in a standardized manner, the wheal-and-flare suppression test is highly sensitive, specific, and reproducible.8 Although histamine is the major mediator of the whealand-flare reaction, it plays only a limited role in the latephase reaction.6 While one clinical study9 has demonstrated a close correlation between peripheral H1-blockade and therapeutic benefit in allergic airway disease, other studies have failed to confirm a direct relationship between the extent of suppression of histamine-induced flares and wheals and control of clinical symptoms.7 In a review evaluating the usefulness of the skin wheal and flare model to predict clinical efficacy of cetirizine,7 the authors determined that cetirizine’s potency in wheal and flare suppression did not translate into greater efficacy in the treatment of CIU. Fexofenadine has been well established through both pharmacodynamic and efficacy measures as a useful treatment for SAR and, more recently, CIU.10 –16 In two multicenter, randomized, double-blind studies of CIU,15,16 fexofenadine HCl
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20, 60, 120, and 240 mg twice daily reduced pruritus, number of wheals, and interference with sleep and daily activities vs PBO. The 20-mg dose of fexofenadine was effective across all study parameters, and greater symptomatic improvement was observed with the three higher study doses. No doserelated adverse events were reported during the studies.
9.
10.
CONCLUSION The present study of suppression of histamine-induced wheals and flares has provided additional evidence that fexofenadine HCl 180 mg is superior to loratadine 10 mg in the onset, strength, and duration of H1-receptor blockade.
11.
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1. Slater JW, Zechnich AD, Haxby DG. Second generation antihistamines: a comparative review. Drugs. 1999;57:31– 46. 2. Walsh GM, Annunziato L, Frossard N, Knol K, Levander S, et al. New insights into the second generation antihistamines. Drugs. 2001;61:207–236. 3. Simons FE, Simons KJ. Peripheral H1-blockade effect of fexofenadine. Ann Allergy Asthma Immunol. 1997;79:530 –532. 4. Turkeltaub PC, Rastogi SC, Baer H, Anderson MC, Norman PS. A standardized quantitative skin-test assay of allergen potency and stability: studies on the allergen dose-response curve and effect of wheal, erythema, and patient selection on assay results. J Allergy Clin Immunol. 1982;70:343–352. 5. Simons FE, Silver NA, Gu X, Simons KJ. Skin concentrations of H1-receptor antagonists. J Allergy Clin Immunol. 2001;107: 526 –530. 6. Bousquet J, Michel FB. In vivo methods for study of allergy. Skin tests, techniques and interpretation. In: Middleton E Jr, Reed CE, Ellis EF, Yunginger JW, editors. Allergy: Principles and Practice, 4th ed. St. Louis, MO: Mosby-Year Book, 1993: 573–594. 7. Monroe EW, Daly AF, Shalhoub RF. Appraisal of the validity of histamine-induced wheal and flare to predict the clinical efficacy of antihistamines. J Allergy Clin Immunol. 1997; 99(Suppl):S798 –S806. 8. Simons FE, McMillan JL, Simons KJ. A double-blind, single-dose, crossover comparison of cetirizine, terfenadine, loratadine, astemizole, and chlorpheniramine versus placebo: suppressive effects on histamine-induced wheals and flares
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during 24 hours in normal subjects. J Allergy Clin Immunol. 1990;86:540 –547. Wood-Baker R, Holgate ST. The comparative actions and adverse effect profile of single doses of H1-receptor antihistamines in the airways and skin of subjects with asthma. J Allergy Clin Immunol. 1993;91:1005–1014. Bernstein DI, Schoenwetter WF, Nathan RA, Storms W, Ahlbrandt R, Mason J. Efficacy and safety of fexofenadine hydrochloride for treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 1997;79:443– 448. Bronsky EA, Falliers CJ, Kaiser HB, Ahlbrandt R, Mason JM. Effectiveness and safety of fexofenadine, a new nonsedating H1-receptor antagonist, in the treatment of fall allergies. Allergy Asthma Proc. 1998;19:135–141. Casale TB, Andrade C, Qu R. Safety and efficacy of once-daily fexofenadine HCl in the treatment of autumn seasonal allergic rhinitis. Allergy Asthma Proc. 1999;20:193–198. Howarth PH, Stern MA, Roi L, Reynolds R, Bousquet J. Double-blind, placebo-controlled study comparing the efficacy and safety of fexofenadine hydrochloride (120 and 180 mg once daily) and cetirizine in seasonal allergic rhinitis. J Allergy Clin Immunol. 1999;104:927–933. Van Cauwenberge P, Juniper EF, the Star Study Investigating Group. Comparison of the efficacy, safety and quality of life provided by fexofenadine hydrochloride 120 mg, loratadine 10 mg and placebo administered once daily for the treatment of seasonal allergic rhinitis. Clin Exp Allergy. 2000;30:891– 899. Finn AF Jr, Kaplan AP, Fretwell R, Qu R, Long J. A doubleblind, placebo-controlled trial of fexofenadine HCl in the treatment of chronic idiopathic urticaria. J Allergy Clin Immunol. 1999;104:1071–1078. Nelson HS, Reynolds R, Mason J. Fexofenadine HCl is safe and effective for treatment of chronic idiopathic urticaria. Ann Allergy Asthma Immunol. 2000;84:517–522.
Requests for reprints should be addressed to: M. A. Kaliner, MD Institute for Asthma and Allergy 5454 Wisconsin Avenue Suite 1700 Chevy Chase, MD 20815 E-mail: [email protected]
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