Comparison of inhibition of cutaneous histamine reaction of ebastine fast-dissolving tablet (20 mg) versus desloratadine capsule (5 mg): a randomized, double-blind, double-dummy, placebo-controlled, three-period crossover study in healthy, nonatopic adults.
BACKGROUND
Ebastine is a long-acting, second-generation, selective histamine H1-receptor antagonist. A fast-dissolving tablet formulation of ebastine has been developed at 10- and 20-mg doses, with the intention of facilitating administration to patients experiencing problems with swallowing, including those confined to bed and elderly people, as well as those who may need to use ebastine when they do not have easy access to water to aid swallowing a tablet.


OBJECTIVE
This study was conducted to assess the pharmacodynamic effects (ie, inhibition of wheal response to cutaneous histamine challenge, and subjective assessments of itching, flare, and pain) and tolerability of the fast-dissolving 20-mg ebastine tablet formulation compared with desloratadine 5-mg capsule and placebo. Acceptability and convenience of the fast-dissolving tablet were also evaluated.


METHODS
This double-blind, double-dummy, randomized, placebo-controlled, 3-period crossover study was conducted at the Drug Research Centre, Department of Clinical Pharmacology, the Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. Healthy, nonatopic, white adults aged 18 to 40 years were randomly assigned to 1 of 6 study sequences: ABC, ACB, BAC, BCA, CBA, or CAB, where A was the ebastine fast-dissolving 20-mg tablet, B was the desloratadine 5-mg capsule, and C was placebo. All study drugs were given orally once daily (8-9 AM) on days 1 to 5 of each study period. Study periods were separated by a washout period of 7 to 10 days. Histamine skin-prick test (SPT) challenge was performed before study drug administration on day 1 of each period (baseline), and then every 20 minutes for 2 hours after administration and again after 24 hours. The final SPT was 24 hours after the day-5 dose was administered. The primary end point was inhibition o f the histamine response, defined as the percentage reduction from baseline wheal area 24 hours after 5 days of administration. Subjective symptoms (itching, flare, and pain) were assessed by subjects using visual analog scales every 20 minutes for 2 hours after administration on day 1. At study end, acceptability (taste, convenience, and overall preference) of the fast-dissolving tablet and capsule formulations were assessed using a questionnaire completed by subjects. Tolerability was assessed using physical examination, laboratory analysis, physician questioning, and spontaneous reporting.


RESULTS
Thirty-six people were randomized (22 women, 14 men; mean [SD] age, 24.7 [4.1] years; mean [SD] weight, 63.2 [9.9] kg); 35 completed the study (1 subject was lost to follow-up after the second study period). Unadjusted mean (SD) wheal areas 24 hours after dose administration on day 5 were 72.9 (29.5), 115.0 (32.1), and 146.7 (32.2) mm(2), for ebastine, desloratadine, and placebo, respectively. Mean differences in reduction from baseline in wheal area were 29.0% for ebastine versus desloratadine and 43.7% for ebastine versus placebo (both, P < 0.001). Corresponding unadjusted mean (SD) wheal areas 24 hours after administration of the first dose on day 1 were 76.5 (22.5), 128.9 (24.0), and 140.5 (33.1) mm(2). Mean itching, flare, and pain ratings were not significantly different between study drugs. Results from the preference questionnaire indicated that the majority (80%) preferred the ebastine fast-dissolving tablet to the desloratadine capsule (and hypothetically also to tablets and oral solution, which were not tested in this study). Ninety-seven percent of subjects were of the opinion that compliance in the home setting would be facilitated by the fas-tdissolving tablet formulation. Fourteen adverse events (AEs) were reported in 9 (25%) volunteers; all AEs were of mild or moderate intensity. Five occurred with ebastine 20 mg (intermittent somnolence, back pain, pharyngolaryngeal pain, pyrexia, and oral pain [1 patient each]), 5 occurred with desloratadine 5 mg (asthenia [2 patients] and dry mouth, somnolence, and back pain [1 patient each]), and 4 occurred with placebo (diarrhea [2 patients] and somnolence and headache [1 patient each]). The relationship with the study drugs was considered unlikely in 6 cases and possible in the remaining 8 cases. An additional AE (back pain) occurred during a washout period.


CONCLUSIONS
In this small study in healthy, nonatopic white subjects, inhibition of the response to histamine injection was significantly greater with the ebastine 20-mg fast-dissolving tablet compared with desloratadine 5-mg capsule and placebo after 1 and 5 days of administration. Most participants expressed an overall preference for the fast-dissolving tablet formulation over capsules. All study drugs were well tolerated.
Antonijoan
Rosa
R
Centre d Investigació de Medicaments, Hospital de la Santa Creu i Sant Pau, Departament de Farmacologia i Terapèutica, Barcelona, Spain.
García-Gea
Consuelo
C
Centre d Investigació de Medicaments, Hospital de la Santa Creu i Sant Pau, Departament de Farmacologia i Terapèutica, Barcelona, Spain.
Puntes
Montserrat
M
Centre d Investigació de Medicaments, Hospital de la Santa Creu i Sant Pau, Departament de Farmacologia i Terapèutica, Barcelona, Spain.
Pérez
Joselin
J
Centre d Investigació de Medicaments, Hospital de la Santa Creu i Sant Pau, Departament de Farmacologia i Terapèutica, Barcelona, Spain.
Esbrí
Ramón
R
Almirall SA, Barcelona, Spain.
Serra
Cristina
C
Almirall SA, Barcelona, Spain.
Fortea
Josep
J
Almirall SA, Barcelona, Spain. Electronic address: jfortea@almirall.es.
Barbanoj
Manuel J
MJ
Centre d Investigació de Medicaments, Hospital de la Santa Creu i Sant Pau, Departament de Farmacologia i Terapèutica, Barcelona, Spain.
D000293:Adolescent; D000328:Adult; D002090:Butyrophenones / Q000009:adverse effects / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006632:Histamine; D006634:Histamine H1 Antagonists / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D017336:Loratadine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D010147:Pain Measurement; D010880:Piperidines / Q000009:adverse effects / Q000494:pharmacology*; D011537:Pruritus / Q000139:chemically induced / Q000517:prevention & control; D012867:Skin / Q000473:pathology; D012882:Skin Tests
D002090:Butyrophenones; D006634:Histamine H1 Antagonists; D010880:Piperidines; D017336:Loratadine; D006632:Histamine; C121345:desloratadine; C058249:ebastine