Clinical Allergy – Research Article Int Arch Allergy Immunol 2022;183:1241–1250 Received: March 10, 2022 Accepted: April 20, 2022 DOI: 10.1159/000524856 Published online: June 14, 2022 Lack of Clinical Relevance of Bilastine- Food Interaction in Healthy Volunteers: A Wheal and Flare Study Jimena Coimbra a Montserrat Puntes a Ignasi Gich b Joan Martínez a Pol Molina a Rosa Antonijoan c Cristina Campo d Luis Labeaga d aCentre d’Investigació de Medicaments (CIM), Institut de Recerca i d’Investigació Biomèdica de l’Hospital de la Santa Creu i Sant Pau (IIB-Sant Pau), Barcelona, Spain; bDepartment of Epidemiology, Hospital de la Santa Creu i Sant Pau, CIM – Caiber – IIb Sant Pau, Universitat Autónoma de Barcelona (UAB), Barcelona, Spain; cDepartment of Clinical Pharmacology, Hospital de la Santa Creu i Sant Pau, Centre d’Investigació de Medicaments (CIM), Institut d’Investigació Biomèdica Sant Pau, Caiber- IIB-Sant Pau, Department of Pharmacology and Therapeutics, Universitat Autónoma de Barcelona (UAB), Barcelona, Spain; dMedical Department, FAES FARMA S. A., Leioa (Vizcaya), Spain Keywords mum plasma concentration and area under the curve from Bilastine · Food interaction · Pharmacodynamics · time 0 to 24 h decreased by 34.27% and 32.72% [day 1], re- Antihistaminic effect · Pharmacokinetics spectively, and 33.08% and 28.87% [day 4]). Despite this, the antihistaminic effect of bilastine 20 mg was not altered by food. On day 1, as assessed by wheal and flare surface inhibi- Abstract tion, the maximum effect and duration of action of bilastine Introduction: The aim of this study was to compare the phar- did not differ to a significant extent between fasting and fed macodynamic activity of bilastine administered under fast- conditions, with only a short 30-min delay in the onset of ing and fed conditions in healthy volunteers. Methods: In wheal inhibition. At steady state (day 4), bilastine’s pharma- this randomized, open-label, two-period, crossover study in- codynamic effects were not significantly affected under fast- volving 24 healthy subjects, once-daily oral bilastine 20 mg ing or fed conditions. Conclusion: The pharmacokinetic in- was administered for 4 days under fasting and fed condi- teraction of bilastine with food does not imply a significant tions, with a 7-day washout period. Bilastine plasma concen- reduction of its peripheral antihistaminic efficacy. Despite a trations were measured for 24 h after the first and fourth dos- slight delay in onset of action on the first treatment day, the es in each period. Pharmacodynamic activity was assessed global clinical efficacy of bilastine is not affected by coad- by wheal and flare surface inhibition and subjective assess- ministration with food. © 2022 The Author(s). ment of itching, after intradermal injection of histamine 5 μg. Published by S. Karger AG, Basel Results: When administered under fed versus fasting condi- tions, exposure to bilastine 20 mg decreased (mean maxi- Edited by: H.-U. Simon, Bern. Karger@karger.com © 2022 The Author(s). Correspondence to: www.karger.com/iaa Published by S. Karger AG, Basel Cristina Campo, ccampo @ faes.es This is an Open Access article licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense), applicable to the online version of the article only. Usage and distribution for com- mercial purposes requires written permission. Introduction The main objective of this clinical study, therefore, was to verify whether the pharmacokinetic interaction of bi- Bilastine is a second-generation antihistamine, has lastine with food leads to a significant reduction in anti- good selectivity for H1-receptors, and is considered a histamine activity, as assessed by the reduction of the sur- non-brain-penetrating antihistamine [1]. Bilastine was faces of wheal and flare induced by histamine injection. approved for the symptomatic treatment of allergic rhi- Wheal and flare responses were evaluated on the first (day noconjunctivitis (perennial and seasonal) and urticaria in 1) and fourth day (day 4) of bilastine administration Europe in 2010 and has been introduced into clinical (steady-state concentrations of bilastine are achieved on practice in about 120 countries worldwide. At the recom- day 4). mended adult dose of 20 mg once daily, clinical trials have demonstrated good efficacy, an excellent safety profile, and improvements in quality of life in patients with aller- Methods gic rhinitis or chronic urticaria [2, 3]. Objectives The pharmacokinetic profile of bilastine has been re- The primary objective was to compare the efficacy of bilastine ported in healthy Caucasian [4] and Japanese adults [5], administered under fasting and fed (with a moderate-fat breakfast) as well as in children with allergic rhinoconjunctivitis or conditions in reducing histamine-induced skin reactivity (wheal chronic urticaria [6]. After administration of a single oral and flare) in healthy volunteers, assessed on the first day of treat- ment (day 1) and at steady state (day 4). Secondary objectives were 20 mg dose, bilastine had a mean peak plasma concentra- to evaluate the onset of action, maximum effect, time to maximum tion of about 220 ng/mL at 1.3 h, an apparent volume of effect, duration of effect, subjective sensation of itching after his- distribution of 1.29 L/kg, a terminal elimination half-life tamine inoculation, and the safety and tolerability of bilastine. of 14.5 h, and reached steady state in 72–96 h in Cauca- sian adults [4]. The pharmacokinetic profile of bilastine Study Design The study design is shown in Figure 1. This was a randomized, 20 mg in Japanese adults [5] was similar to that previ- open-label, crossover study (EudraCT number: 2018-000913-19; ously reported in Caucasian adults, and the pharmacoki- protocol code BILA-3818/PD) conducted at Hospital Santa Creu i netics of bilastine 10 mg in pediatric patients [6] were Sant Pau, Barcelona, in 24 healthy volunteers. Subjects were re- consistent with those of bilastine 20 mg in adult subjects. cruited between May 17 and July 3, 2018. Four weeks before the The absolute oral bioavailability of bilastine is 60.67% [7], beginning of the experimental phase (from day −28 onwards), signed informed consent was obtained from all willing participants and no accumulation pattern was shown after repeated who met the study inclusion criteria prior to performing any study dosing in a 14-day pharmacokinetic study [8]. evaluation. On the day before the start of the experimental phase Bilastine is not metabolized and does not interact, ei- (day −1), all subjects selected for the study were randomly allo- ther as an inhibitor or inducer, with the cytochrome P450 cated (1:1) to the fasting or fed group, followed by treatment with enzyme system, suggesting a low probability for drug- oral bilastine 20 mg once daily for 4 days. After a 7-day washout period, the groups’ diets were switched, and all subjects received drug interactions when this metabolic pathway is in- another 4-day treatment period with bilastine at the same dosage volved [9]. However, the bioavailability of bilastine was but under opposite conditions to those in the first period. The tri- reduced by 30% when it was administered with high-fat al medication was administered orally with mineral water (240 food and by 25% with standard low-fat food, compared mL) in the presence of a member of the investigator team and a with values obtained under fasting conditions, indicating witness at the clinical trial unit. a significant pharmacokinetic food interaction [10, 11]. Selection Criteria The most widely used human model for assessing the on- Subjects had to be healthy volunteers (normal medical records set of action, efficacy, and duration of action for an anti- and physical examination at screening, no clinically significant ab- histamine drug is the wheal and flare response after a cu- normalities on laboratory tests, vital signs, and ECG record within taneous prick-test or intradermal injection of histamine the normal range), aged 18–45 years, and with a body mass index of ≥18.0 and ≤28.0 kg/m2. Participants had to have induced wheal [12–14]. It is possible that the antihistaminic effect of bi- area values within the reference range of the research institute lastine remains unaffected by concomitant administra- (0.5521–2.5941 cm2) in the histamine-induced skin reactivity test. tion with food. This is the main prediction obtained in a Subjects were excluded on the following grounds: history of al- recent analysis conducted by nonlinear mixed-effect lergy, idiosyncrasy, or hypersensitivity to drugs or any related products (including excipients of the formulations); heavy con- modeling performed under both fed and fasting condi- sumers of stimulating drinks (>5 cups of coffee, tea, chocolate, or tions using a developed pharmacokinetic food-effect cola drinks per day); history of alcohol dependence or drug abuse model and an already available pharmacokinetic/phar- in the last 5 years, or daily consumption of alcohol >40 g/day for macodynamic model [15]. men or >24 g/day for women; intake of any medication (except 1242 Int Arch Allergy Immunol 2022;183:1241–1250 Coimbra/Puntes/Gich/Martínez/Molina/ DOI: 10.1159/000524856 Antonijoan/Campo/Labeaga Color version available online Day-28 Day 1 Day 4 Day 12 Day 15 Day 22 Informed Wash out period consent at least 7 days 24 Bilastine 20 mg Bilastine 20 mg 12 once daily 12 once daily Randomization Healthy volunteers (fasted) (fasted) male & Safety female follow-up 18–45 years Bilastine 20 mg Bilastine 20 mg 12 once daily once daily 12 (fed) (fed) P1 treatment Wash out P2 treatment Follow-up (4 days) (1 week) (4 days) (1 week) Fig. 1. Study design scheme. acetaminophen [paracetamol] for short-term symptomatic treat- ing of day 2) and 48 h (morning of day 3) for subsequent doses and ment) within 2 weeks prior to taking the study medication, includ- monitoring and were then hospitalized again by 7 p.m. on day 3 ing over-the-counter products (including natural food supple- until 12 h after the fourth dose (day 4). Participants returned for ments, vitamins, and medicinal plant products); positive test re- clinical and safety evaluation 24 h after the fourth dose (day 5). sults for hepatitis B surface antigen, hepatitis C virus antibody, or On day 1 and day 4 of each crossover treatment period, skin human immunodeficiency virus; positive results for abuse drugs reactivity and itching sensation were evaluated, and blood samples in urine test or ethanol in breath test; background or clinical evi- were collected. The safety and tolerability of bilastine were also as- dence of chronic disease; rare hereditary problems of galactose in- sessed, including systolic and diastolic blood pressure, heart rate, tolerance, Lapp lactase deficiency, or glucose-galactose malab- ECG, and recording of adverse events. sorption; pregnant or breast-feeding women; smokers (use of any On day −1, all participants were randomized to one of two ex- tobacco product, including smokeless tobacco, nicotine patches, traction groups (group A or group B), which determined the time electronic cigarettes, etc.) within 6 months prior to the study med- points for blood sampling in each crossover period. Blood collec- ication intake; participation in another clinical drug trial during tion and plasma preparation procedures were approved by the an- the previous 3 months; blood donation within 4 weeks of inclusion alytical laboratory before starting the study. The extraction of in the study; mental or legal incapacity at screening; unwillingness blood samples for the determination of bilastine plasma concen- or inability to follow the procedures outlined in the protocol; his- trations was performed on all volunteers. Five samples were col- tory of difficulty in swallowing; positive dermographism or any lected from each subject on days 1 and 4 of each crossover period. other condition that, in the investigator’s opinion, may have jeop- In group A, samples were collected at baseline (predose) and +0.5, ardized the trial execution. +2, +6, and +12 h post-bilastine administration; in group B, sam- ples were collected at baseline (predose) and +1, +4, +9, and +24 h Fasting and Fed Conditions post-bilastine administration. A cannula was placed in the forearm Subjects in the fed arm of the study received a moderate-fat to permit repeated sampling. Drug plasma concentrations were breakfast 30 min before each bilastine dose. This comprised whole determined under Good Laboratory Practices by Anapharm Eu- milk (200 mL), white sugar (7 g), bread (40 g), toast (34 g), olive rope S.L. oil (10 mL), and ham (30 g) (approximately 480 kcal [144 kcal as Skin reactivity test and subjective evaluation of itching were fat], 15.83% protein, 54.17% carbohydrate, and 30.0% fat). Fruit or conducted at baseline (predose) and +0.5, +1, +2, +4, +6, +9, +12, fruit juices were not allowed. and +24 h after the first and last bilastine doses in each experimen- Subjects in the fasting arm of the study received the daily bilas- tal period. The skin reactivity test involved intradermal injection tine dose after a minimum of 10 h since the last food intake. On of 0.05 mL of a histamine solution (100 mg/mL) in the ventral days 1 and 4, all subjects received a snack 4 h after bilastine admin- forearm. Each ventral forearm (right and left) was divided into istration, lunch 6 h post-medication, and another snack 10 h post- four zones based on proximity to the main body mass (proximal medication. Water was not permitted from 1 h before until 2 h and distal) and to the midline of the body (external vs. internal). after administration of bilastine. Each histamine injection was performed in a different zone, ran- domly assigned, leaving a minimum distance of 2.5 cm between Pharmacokinetic and Pharmacodynamic Evaluations different evaluations. The application was performed by inserting Recruited subjects attended the clinic by 7 p.m. the day prior to the needle (tuberculin syringe) tip at a 45° angle and moving it for- the first treatment day (day −1) and remained hospitalized until 12 wards and upwards. The wheal and flare surfaces induced were h after the first bilastine dose (day 1). They returned at 24 h (morn- measured 15 min after histamine injection, drawing the contours Lack of Clinical Relevance of Bilastine- Int Arch Allergy Immunol 2022;183:1241–1250 1243 Food Interaction in Healthy Volunteers DOI: 10.1159/000524856 Table 1. Demographic details and baseline vital signs of randomized subjects (n = 24) Parameter Mean SD Median Minimum Maximum Age, years 27.29 4.89 26 19 40 Body weight, kg 66.52 10.14 63.25 52.00 91.00 Height, cm 169.29 8.57 168.50 152.00 182.00 BMI: Quetelet’s index, kg/m2 23.18 1.97 22.60 20.50 27.70 Systolic BP, mm Hg 118.21 12.19 117 100 139 Diastolic BP, mm Hg 62.04 6.63 10.69 51 75 Heart rate, bpm 69.96 10.02 69.50 52 92 Temperature, ºC 35.94 0.43 36.05 35.30 36.70 BMI, body mass index; BP, blood pressure; bpm, beats per minute; SD, standard deviation. with a permanent marker pen onto a transparent film, and quan- tative variables, the number and percentage of patients with non- tifying the surface area using Visitrak SystemTM. The left and right missing data per category were the default frequency tabulation. arms were used alternately for successive evaluations. Each of the variables obtained in the objective skin reactivity eval- The intradermal injection of histamine induces a wheal and uations were evaluated by means of two-way analysis of variance flare response. In this study, wheal and flare surface areas were (ANOVA) of repeated measures, considering the factors of treat- measured on days 1 and 4 in each group and during each crossover ment and time. The analysis was performed in two different ways: period (fasting and fed conditions). The primary endpoint was the • Expressing the data as percentage reduction with respect to change from baseline in the mean area under the curve (AUC) by baseline values, to compare AUC0–24 h of day 1 and day 4 under time over 24 h (AUC0–24 h) of the wheal and flare surface areas on fasting and fed conditions; days 1 and 4 under fasting and fed conditions. • Expressing the data as direct values, in order to obtain informa- The efficacy of bilastine was assessed as the ability to reduce tion on the possible effect of the time course. wheal and flare areas (percentage of reduction in these areas) ver- The four AUCs for each individual (days 1 and 4, fasting and sus baseline values at each time point. The curves were built with fed) were evaluated by means of two-way ANOVA of repeated the percentage of reduction of wheal and flare areas by time, both measures, considering day and food. This was used to evaluate before (baseline curve) and after bilastine administration, and the whether the change between day 1 and day 4 was similar with and mean change in AUC was calculated as the main outcome. without food. The itching sensation was evaluated 5 min after each histamine The second analysis involved a three-way ANOVA; the factors application using a visual analog scale. This consisted of a 100-mm being time, day, and food. When statistically significant differenc- horizontal line on which subjects marked a vertical line at the point es were detected in a time factor, a detailed analysis was performed corresponding to their subjective itching sensation. The left end of evaluating the differences between groups at each evaluation time the line corresponded to “no itching” and the right end to “very and the differences between evaluation times after each group, us- much itching.” The recorded score was the distance in millimeters ing a simple-main-effects omnibus test and pairwise comparisons. from the left end to the subjects’ mark. For all statistical analyses, the level of significance was set at 5% (alpha value 0.05), two-sided. Safety Assessment All adverse events occurring after the first study medication intake and within a week after the last dose were considered treat- ment-emergent adverse events (TEAEs). The investigator assessed Results the severity of any adverse event and likely causality. Biochemical and hematological laboratory tests were conducted and ECG and vital signs recorded at initial screening and the end of the study (24 Study Population h after the last bilastine dose of the second crossover period). Among the 41 subjects screened for this trial, 29 met the selection criteria. Seven subjects were excluded for Statistics personal reasons, three for positive dermographism, and The study sample size was calculated considering a variation coefficient of 25% for the primary endpoint and a significance lev- two for altered laboratory tests. Twenty-four subjects (12 el of 5%. A sample size of 22 subjects provided a power of 80% for men and 12 women), all Caucasian, were randomized and detecting a minimum difference between treatments of 15%. Be- 23 completed the study. One subject withdrew from the cause of the high risk of dropouts as a result of the prolonged study study after the first treatment period, for personal rea- duration, it was decided to increase the sample size to 24 subjects. sons. Demographic details and baseline vital signs for the Statistical analysis and data management were performed us- ing IBM-SPSS (version 22.0). The default summary statistics for 24 randomized subjects are presented in Table 1. None of quantitative variables were the number of observations, mean, the randomized subjects were smokers. With regard to standard deviation, median, minimum, and maximum. For quali- alcohol consumption, 13 subjects did not drink at all and 1244 Int Arch Allergy Immunol 2022;183:1241–1250 Coimbra/Puntes/Gich/Martínez/Molina/ DOI: 10.1159/000524856 Antonijoan/Campo/Labeaga Color version available online 300 300 250 250 200 200 Bilastine, ng/mL Bilastine, ng/mL 150 150 100 100 50 50 0 0 0 2 4 6 8 10 12 14 16 18 20 22 24 0 2 4 6 8 10 12 14 16 18 20 22 24 a Time after treatment, h b Time after treatment, h Fig. 2. Bilastine plasma concentrations (mean ± standard deviation) on day 1 in fasting (grey line) and fed (blue line) subjects (a) and on day 4 in fasting (red line) and fed (green line) subjects (b). the remaining 11 subjects consumed a maximum of 17.5 this delay in onset of action of bilastine in the fed group g alcohol/day (mean 6.15 g/day). Regarding the con- was brief, and the profiles of wheal inhibition in fasting sumption of xanthines (tea, coffee, chocolate, etc.), 20 and fed subjects on day 1 were broadly the same (Fig. 3a), subjects consumed xanthines daily (mean 6 units/week). with no statistically significant differences between both The only concomitant medication used during the study groups from 2 h after bilastine administration and on- was acetaminophen for a headache in one subject and na- wards. Peak inhibition, which indicates the maximum ef- sal congestion in another. fect of bilastine, was 75.2% and occurred at 4 h under fasting conditions, compared with 75.1% at 6 h under fed Pharmacokinetic Evaluation conditions. In both groups, the percentage inhibition at In this study, moderately fatty food had a significant 24 h, compared with baseline, remained statistically sig- effect on the pharmacokinetics of oral bilastine 20 mg. On nificant: 41.5% ± 12.1 fasting (p < 0.001) versus 40.3% ± day 1, the mean maximum plasma concentration (Cmax) 15.4 fed (p < 0.001). of bilastine was reduced by 34.27% with food, from 183.13 On day 4, there was no statistically significant differ- ± 70.34 ng/mL (fasting) to 120.38 ± 41.25 ng/mL (fed) ence between the percentage of wheal area inhibition (Fig. 2a). The mean plasma AUC0–24 h of bilastine was re- from baseline at any time point under fasting versus fed duced by 32.72%, from 1,037.23 (fasting) to 697.82 ng×h/ conditions (Fig. 3b). Peak inhibition was 73.3% at 12 h mL (fed), and the mean time to Cmax was extended from postdose under fasting conditions and 76.6% at 9 h post- 1 h to 2 h postdose. Similarly, on day 4, the mean Cmax and dose under fed conditions. plasma AUC0–24 h of bilastine were reduced by food, from ANOVA evaluation (1-, 2-, and 3-way) failed to iden- 189.46 ± 77.31 (fasting) to 126.78 ± 23.51 ng/mL (fed; tify any statistically significant effect of food on the per- 33.08% reduction), and from 1,088.21 (fasting) to 774.05 centage inhibition of wheal area in the skin reactivity test. ng×h/mL (fed; 28.87% reduction), respectively, while the The two-way ANOVA (day/food) applied to the mean time to Cmax was extended from 1 to 2 h postdose (Fig. 2b). AUC of percentages of reduction revealed a statistically significant effect of the day factor (p = 0.004) but not the Pharmacodynamic Evaluation food factor (p = 0.415) nor the interaction day × food fac- Skin Reactivity Test: Wheal Area tor (p = 0.196). The percentage inhibition of wheal area (compared with baseline) was statistically significantly greater in Skin Reactivity Test: Flare Area fasting subjects than fed subjects at 30 min (p < 0.05) and The profiles of percentage inhibition of flare area from 1 h (p < 0.001) after the first dose of bilastine. However, baseline were substantially the same under fasting and fed Lack of Clinical Relevance of Bilastine- Int Arch Allergy Immunol 2022;183:1241–1250 1245 Food Interaction in Healthy Volunteers DOI: 10.1159/000524856 Color version available online 100 100 Day 1 (fasting) Day 4 (fasting) 90 90 Inhibition versus baseline value, % Inhibition versus baseline value, % Day 1 (fed) Day 4 (fed) 80 80 70 70 *** 60 60 50 50 40 40 30 30 20 20 * 10 10 0 0 –10 –10 0 2 4 6 8 10 12 14 16 18 20 22 24 0 2 4 6 8 10 12 14 16 18 20 22 24 a Time after treatment, h b Time after treatment, h Fig. 3. Percentage wheal inhibition from baseline to 24 h after the first dose of bilastine (day 1), fasting (grey line) or fed (blue line), (a) and the last dose of bilastine (day 4), fasting (red line) or fed (green line) (b). Statistically significant differences between fasting and fed conditions on day 1. *p < 0.05 and ***p < 0.001. Color version available online 100 100 90 90 Inhibition versus baseline value, % Inhibition versus baseline value, % 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 Day 1 (fasting) 10 Day 4 (fasting) 0 Day 1 (fed) 0 Day 4 (fed) –10 –10 0 2 4 6 8 10 12 14 16 18 20 22 24 0 2 4 6 8 10 12 14 16 18 20 22 24 a Time after treatment, h b Time after treatment, h Fig. 4. Percentage flare inhibition versus baseline to 24 h after the first dose of bilastine (day 1), fasting (grey line) and fed (blue line), (a) and the last dose of bilastine (day 4), fasting (red line) or fed (green line) (b). conditions, on both day 1 (Fig. 4a) and day 4 (Fig. 4b). AUC of percentages of reduction revealed a statistically The mean maximum effect of bilastine ranged from significant effect of the day factor (p < 0.001) but not the 83.3% to 84.2% and occurred between 4- and 6-h post- food factor (p = 0.933). The interaction day × food factor dose in subjects in both groups (fasting and fed) and on was statistically significant (p = 0.025). both days (days 1 and 4). This antihistamine effect was well maintained at 24 h postdose on both days. Skin Reactivity Test: Subjective Assessment of Itching ANOVA evaluation (1-, 2-, and 3-way) failed to iden- Compared with baseline values, there were statistically tify any statistically significant effect of food on the per- significant reductions (p < 0.01) in itching, under both fed centage inhibition of flare area in the skin reactivity test. and fasting conditions, from 2 to 12 h postdose on day 1. The two-way ANOVA (day/food) applied to the mean On day 4, the reductions were statistically significant at 1246 Int Arch Allergy Immunol 2022;183:1241–1250 Coimbra/Puntes/Gich/Martínez/Molina/ DOI: 10.1159/000524856 Antonijoan/Campo/Labeaga Color version available online 24 20 16 VAS, mm 12 8 Fig. 5. Subjective assessment of itching on a visual analog scale (VAS; 0 = no itching, 4 100 = worst itching), mean ± standard de- viation, over a 24-h period after oral bilas- tine 20 mg, in fasting subjects on day 1 0 (grey line), fed subjects on day 1 (blue line), 0 2 4 6 8 10 12 14 16 18 20 22 24 fasting subjects on day 4 (red line) and fed Time after treatment, h subjects on day 4 (green line). all postdose time points from 0.5 to 24 h under both con- Discussion ditions (Fig. 5). Food had no statistically significant effect on itching This study compared the pharmacokinetic and phar- sensation, as determined by ANOVA evaluation (1-, 2-, macodynamic profiles of oral bilastine 20 mg per day un- or 3-way). The two-way ANOVA (day/food) applied to der fed and fasting conditions in healthy volunteers. the mean AUC of percentages of reduction revealed a sta- Overall, the pharmacokinetic difference observed be- tistically significant effect of the day factor (p = 0.011) but tween both conditions (an AUC0–24 h reduction of about not the food factor (p = 0.448) nor the interaction day × 33% with fed vs. fasting on days 1 and 4 [steady state]) food factor (p = 0.850). only led to a short delay in the onset of action to 1-h post- administration with respect to wheal inhibition on the Safety first day of treatment. No difference was found in flare Five TEAEs were recorded in five different subjects inhibition or itching sensation. during the study: mild dyspnea in one subject on day 1 in Previous studies have evaluated the pharmacokinetics the fasting group; mild nasal congestion in one subject on of bilastine coadministered with or without food, obtain- day 4 in the fasting group; mild vomiting in one subject ing similar results to the present study. A reduction of on day 1 in the fed group; and headache in two subjects 30% and 25% in bioavailability was observed when bilas- (1 mild, 1 moderate) on day 1 in the fed group. Acetamin- tine was taken with high-fat and low-fat food, respective- ophen was administered for the cases of moderate head- ly, relative to fasting conditions [16]. ache and nasal congestion. The case of nasal congestion In this study, the pharmacodynamic profile was evalu- was considered unrelated to bilastine administration, ated as the wheal and flare response after an intradermal while the other 4 cases were considered possibly related. injection of histamine. Four previous wheal and flare All TEAEs resolved without consequences. clinical studies have been performed in healthy Cauca- No clinically significant changes were observed in lab- sian or Japanese volunteers after administration of bilas- oratory tests (hematology and biochemistry) carried out tine 20 mg under fasting conditions [5, 17–19]. In two of during the study. Changes observed in vital signs (sys- these studies, the wheal and flare response was induced tolic and diastolic blood pressure and heart rate) did not by histamine using the skin prick-test method [5, 17], show any clinically relevant abnormalities, and all param- and, in the other two studies, the wheal and flare response eters remained within the normal range. No clinically sig- was induced by intradermal injection of histamine 5 μg nificant changes were observed in ECG data recorded [18, 19]. In all of these studies, no remarkable differences during the study, neither did physical examinations show were seen regarding onset of action, maximum effect, and any clinically important changes. duration of action. When the wheal and flare pharmaco- Lack of Clinical Relevance of Bilastine- Int Arch Allergy Immunol 2022;183:1241–1250 1247 Food Interaction in Healthy Volunteers DOI: 10.1159/000524856 dynamic effect was assessed in addition to the 24-h phar- ertheless, if rapid relief of symptoms is needed, taking the macokinetic profile in healthy volunteers, a hysteresis first dose without food may be better than taking it with phenomenon was observed [5, 17]. That means bilastine food. remains highly effective even when its plasma concentra- Fexofenadine and bilastine are quite similar in some tion is very low. In other words, the marginal decrease in pharmacological aspects, including alterations in their efficacy is not in line with the much faster decline in plas- pharmacokinetic profile when administered with food. ma concentrations. Recently, the long duration of anti- Similar to bilastine, fexofenadine plasma AUC and Cmax histaminic effect with bilastine, albeit at low plasma con- are reduced by 17% and 11%, respectively, for a capsule centrations, has been shown to be related to its long resi- formulation, and by 24% and 25%, respectively, for a tab- dence time at the human histamine H1 receptor [20]. This let formulation, when the drug is administered 30 min could explain why, in the current study, although the after a high-fat breakfast versus a 10-h fast [24]. In addi- AUC is decreased by around 30% when bilastine is coad- tion, fexofenadine and bilastine are non-brain-penetrat- ministered with food, the pharmacodynamic effect is ing antihistamines and zwitterions, display similar bind- only slightly altered in the first hour on day 1 but remains ing to H1-receptors, have similar acid-base dissociation similar during the remaining days of treatment, indepen- constants, have larger molecular weights than other non- dent of the fasting or fed condition. sedating antihistamines, and exhibit the hysteresis phe- The methodology used in this study is well document- nomenon [1, 25, 26]. However, in the case of fexofena- ed, and the study design (crossover, young volunteers) dine, drug-food interactions are not reflected with a was chosen to minimize interindividual variability. In warning in its SmPC; therefore, taking the current study fact, baseline values obtained for wheal and flare areas did results into consideration, one can argue that maybe the not differ between both treatment sequences, showing same should also apply to bilastine. similar conditions for each treatment period. Wheal and The effects of food on the pharmacokinetic profiles of flare results are normally considered with caution be- other second-generation H1-antihistamines are variable. cause some data suggest that histamine challenge tests do The plasma AUC for cetirizine appears to be unaffected not necessarily correlate with clinical responses [21]. by food [27], while that for ebastine [28] and rupatadine However, at the same time, some authors describe the [29] may be increased. For desloratadine, in one early wheal and flare response as the “best indicator we have of study in healthy volunteers, food had no significant im- the effectiveness of H1 antihistamines in clinical practice” pact on the drug´s pharmacokinetic profile [30]. How- [22]. In fact, a recent study demonstrated that efficacy in ever, plasma AUC and Cmax were reduced by over 30% chronic spontaneous urticaria could be predicted by when food was coadministered in most subjects in a Chi- >75% inhibition of the histamine wheal at 24 h after ad- nese study, in which almost all subjects (97.8%) were des- ministration of an antihistamine [23]. loratadine-extensive metabolizers [31]. Prior to the current study, a pharmacokinetic-phar- None of the previously mentioned studies of the inter- macodynamic modeling study of the antihistaminic ac- action of food with other second-generation antihista- tivity of bilastine was performed, extracting data from 12 mines measured pharmacodynamic activity. Thus, the different clinical trials [15]. Simulations performed present study makes an important contribution to knowl- showed that the pharmacodynamics of bilastine remained edge about the clinical relevance of food-drug pharmaco- unchanged despite the decreased bioavailability with kinetic interactions, at least for bilastine. Although the food. The present study corroborates these findings at current study was not designed to evaluate safety and tol- steady state since no differences in wheal and flare AUC0– erability, no serious adverse events were recorded during 24 h between the fed and fasting conditions were observed drug administration and bilastine was well-tolerated, on day 4. Only a small difference in the reduction of wheal with no relevant changes in vital signs, hematology, or area by bilastine was observed in the first hour on day 1 biochemistry, as previously shown in other studies [2, 3]. of treatment. Although the bilastine European Summary of Product Characteristics (SmPC) advises that bilastine should be taken without food (i.e., 2 h before or 1 h after Conclusions food) [10], this advice was based on evidence from previ- ous in vitro and in vivo pharmacokinetic studies [16]. The The pharmacokinetic interaction of bilastine with results of this study suggest that interaction between bi- food does not imply a significant reduction of its periph- lastine and food is not clinically relevant as a whole. Nev- eral antihistaminic efficacy. Despite a slight delay in onset 1248 Int Arch Allergy Immunol 2022;183:1241–1250 Coimbra/Puntes/Gich/Martínez/Molina/ DOI: 10.1159/000524856 Antonijoan/Campo/Labeaga of action on the first treatment day, the global clinical ef- Conflict of Interest Statement ficacy of bilastine is not affected by coadministration with Jimena Coimbra, Montserrat Puntes, Ignasi Gich, Joan Mar- food. tínez, Pol Molina, and Rosa Antonijoan; they are part of the re- search team (CIM. Hospital Sant Pau). Cristina Campo and Luis Labeaga are employees of FAES. Acknowledgments Medical writing support, under the guidance of the authors, Funding Sources was provided by David P. Figgitt, PhD, ISMPP CMPPTM, and Kath- erine A. Lyseng-Williamson, BSc. Pharm, Content Ed Net, with This study was sponsored by FAES FARMA S. A. funding from FAES FARMA S. A., Spain. Author Contributions Statement of Ethics Rosa Antonijoan and Jimena Coimbra participated in the de- This study (EudraCT: 2018-000913-19) was conducted follow- sign of the trial. Jimena Coimbra, Montserrat Puntes, Joan Mar- ing the international recommendations for clinical research gath- tínez, and Pol Molina conducted the research and investigation ered in the last revision of the Declaration of Helsinki and accord- process. Ignasi Gich contributed to data analysis. Jimena Coimbra ing to the Guidelines for Good Clinical Practice (GCP) and the and Rosa Antonijoan revised the manuscript. Luis Labeaga and current applicable Spanish and European legislation. Independent Cristina Campo designed the trial and contributed to the writing Ethics Committee approval and Spanish Agency authorization and revision of the paper. were obtained. 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