Role of Bilastine in Allergic Rhinitis: A Narrative Review.

Allergic rhinitis (AR) is considered a trivial disease and is often self-treated with over-the-counter drugs and home remedies. However, AR is a contributing risk factor for asthma associated with complications, including chronic cough, eosinophilic esophagitis, and otitis media with effusion. In AR, inflammation is primarily mediated by histamines. Guidelines advise using second-generation oral H1 antihistamines as the primary treatment for AR. Second-generation H1 antihistamines strongly prefer the H1 receptor, limiting their ability to enter the central nervous system. Thus, they have minimal adverse effects. Among these H1 antihistamines, bilastine is highly specific for H1 receptors with a slight affinity for other receptors. It has a rapid and prolonged action, which reduces the need for frequent dosing and has better compliance. In the long term, bilastine is well-tolerated with minimal adverse effects. It is not associated with drug interactions, so dosage adjustment is unnecessary. Bilastine does not penetrate the brain and is nonsedating at 80 mg once daily. The low possibility of drug-drug interactions and pharmacokinetics of bilastine makes it suitable for elderly patients, even with compromised hepatic and renal function, without dose adjustment. This review comprehensively discusses the guidelines and the role of bilastine in treating AR. How to cite this article: Tiwaskar M, Vora A, Tewary K, et al. Role of Bilastine in Allergic Rhinitis: A Narrative Review. J Assoc Physicians India 2023;71(11):58-61.

A simple and sensitive LC-MS/MS method for determination of doxylamine in human plasma and its application in a bioequivalence study in healthy Chinese volunteers.

A simple, rapid, sensitive and specific LC-MS/MS method was developed and validated for the quantitative determination of doxylamine in human plasma, using isotope doxylamine-d5 as internal standard (IS). The detection was conducted on a QTRAP 5500 tandem mass spectrometer coupled with electrospray ionization (ESI) source in positive ion mode. Quantification was achieved by positive electrospray ionization containing multiple reaction monitoring (MRM) transitions of m/z 271.0→182.0 for doxylamine and m/z 276.2→187.3 for IS. The mobile phase A was methanol, and mobile phase B was 20 mM ammonium acetate (0.2 % formic acid) in water, using a gradient elution procedure at a flow rate of 0.6 mL/min. The method was validated with a sensitivity of 0.500 ng/mL and a linear concentration range of 0.500-200 ng/mL. The inter-batch precision (%CV) was less than 5.4 %, and the accuracy deviation (%RE) ranged from - 10.6 % to 3.7 %; the inter-batch precision (%CV) was less than 6.6 %, and the accuracy deviation (%RE) was ranged from - 2.7 % to 0.1 %. The selectivity, sensitivity, extraction recovery, matrix effect, carryover, dilution reliability, stability and other characteristics were within the acceptable range. This validated method was successfully applied to a bioequivalence study that orally administered 25 mg of doxylamine succinate tablets in 60 healthy Chinese volunteers.

Antihistamine use during breastfeeding with focus on breast milk transfer and safety in humans: A systematic literature review.

Current data on use of antihistamines during breastfeeding and risks to the breastfed infant are insufficient. The aim of this systematic review was to provide an overview of studies measuring the levels of antihistamines in human breast milk, estimating the exposure for breastfed infants and/or reporting possible adverse effects on the breastfed infant. An additional aim was to review the antihistamine product labels available in the European Union (EU) and the United States. We searched seven online databases and identified seven human lactation studies that included 25 mother-infant pairs covering cetirizine, clemastine, ebastine, epinastine, loratadine, terfenadine and triprolidine. In addition, one study investigated the impact of chlorpheniramine or promethazine on prolactin levels among 17 women, and one study investigated possible adverse drug reactions in 85 breastfed infants exposed to various antihistamines. The relative infant dose was below 5% for all antihistamines, ranging from 0.3% for terfenadine to 4.5% for clemastine. Most product labels of the 10 antihistamines with available information in both the EU and the United States reported lack of evidence and recommended to avoid use during breastfeeding. The knowledge gap on antihistamines and lactation is extensive, and further human studies are warranted to ensure optimal treatment of breastfeeding women with allergy.

Application of a dual mechanistic approach to support bilastine dose selection for older adults.

The objective of this study was to evaluate bilastine dosing recommendations in older adults and overcome the limitation of insufficient data from phase I studies in this underrepresented population. This was achieved by integrating bilastine physicochemical, in vitro and in vivo data in young adults and the effect of aging in the pharmacology by means of two alternative approaches: a physiologically-based pharmacokinetic (PBPK) model and a semi-mechanistic population pharmacokinetic (Senescence) model. Intestinal apical efflux and basolateral influx transporters were needed in the PBPK model to capture the observations from young adults after single i.v. (10 mg) and p.o. (20 mg) doses, supporting the hypothesis of involvement of gut transporters on secretion. The model was then used to extrapolate the pharmacokinetics (PKs) to elderly subjects considering their specific physiology. Additionally, the Senescence model was develop starting from a published population PK) model, previously applied for pediatrics, and incorporating declining functions on different physiological systems and changes in body composition with aging. Both models were qualified using observed data in a small group of young elderlies (N = 16, mean age = 68.69 years). The PBPK model was further used to evaluate the dose in older subjects (mean age = 80 years) via simulation. The PBPK model supported the hypothesis that basolateral influx and apical efflux transporters are involved in bilastine PK. Both, PBPK and Senescence models indicated that a 20 mg q.d. dose is safe and effective for geriatrics of any age. This approach provides an alternative to generate supplementary data to inform dosing recommendations in under-represented groups in clinical trials.

Development of an improved method to estimate the days of continuous drug ingestion, based on the micro-segmental hair analysis.

To prove drug-related crimes, it is important to estimate the date on which a specific drug was ingested. Previously, we developed a method, "micro-segmental hair analysis," to estimate the day of ingestion of a single-dose drug by segmenting a hair strand into 0.4-mm segments, which correspond to daily hair growth. In this study, the method was improved to estimate the days of continuous drug ingestion. The subjects ingested four hay-fever medicines (fexofenadine, epinastine, cetirizine, and loratadine) continuously (1-18 days) and chlorpheniramine as a single dose at intervals of several weeks as an internal temporal marker (ITM). The hair strands of the subjects were collected and subjected to a micro-segmental analysis. The distribution curves of each hay-fever medicine in a hair strand had broad peaks reflecting the number of days of drug ingestion. The positions on the curves corresponding to the first and final ingestion days of hay-fever medicines were identified using the ITM. The positions were near the hair segments on both ends of full width at half maximum (W2 ) of the broad peak. When the first and final days of continuous ingestion were estimated using W2 , independent of peak shape, the absolute average error from the actual ingestion days was approximately 2 days. Overall, we established a method to estimate the days of both single-dose and continuous drug ingestions. Furthermore, the method would be useful to investigate drug ingestion history in various scenes such as drug-related crimes and therapeutic drug monitoring.

The Role of Alcohol Dehydrogenase in Drug Metabolism: Beyond Ethanol Oxidation.

Alcohol dehydrogenases (ADHs) are most known for their roles in oxidation and elimination of ethanol. Although less known, ADHs also play a critical role in the metabolism of a number of drugs and metabolites that contain alcohol functional groups, such as abacavir (HIV/AIDS), hydroxyzine (antihistamine), and ethambutol (antituberculosis). ADHs consist of 7 gene family numbers and several genetic polymorphic forms. ADHs are cytosolic enzymes that are most abundantly found in the liver, although also present in other tissues including gastrointestinal tract and adipose. Marked species differences exist for ADHs including genes, proteins, enzymatic activity, and tissue distribution. The active site of ADHs is relatively small and cylindrical in shape. This results in somewhat narrow substrate specificity. Secondary alcohols are generally poor substrates for ADHs. In vitro-in vivo correlations for ADHs have not been established, partly due to insufficient clinical data. Fomepizole (4-methylpyrazole) is a nonspecific ADH inhibitor currently being used as an antidote for the treatment of methanol and ethylene glycol poisoning. Fomepizole also has the potential to treat intoxication of other substances of abuse by inhibiting ADHs to prevent formation of toxic metabolites. ADHs are inducible through farnesoid X receptor (FXR) and other transcription factors. Drug-drug interactions have been observed in the clinic for ADHs between ethanol and therapeutic drugs, and between fomepizole and ADH substrates. Future research in this area will provide additional insights about this class of complex, yet fascinating enzymes.

In Silico Analysis, Synthesis, and Biological Evaluation of Triazole Derivatives as H1 Receptor Antagonist.

INTRODUCTION: Histamine, a biological amine, is considered as a principal mediator of many pathological processes regulating several essential events in allergies and autoimmune diseases. Numerous derivatives have been developed that strive with histamine at the H1 receptor and prevent binding of histamine at the H1 receptor, thereby preventing allergic reactions. Molecules containing a triazole ring fused with six-membered ring systems are found to possess broad applications in the field of medicine and industry. The present study is an attempt to characterize the impact of the nature of the substituent introduced at 5 positions of the-4H-1,2,4-triazole-3-thiol on their capacities to bind with the H1 receptor. METHODS: Molecular docking (PDB ID: 3RZE) revealed that synthesized derivatives and target proteins were actively involved in binding with Tyr-108, Thr-112, Ala-216, and Phe-432 subunits. A pharmacophore model, new 5-(4-substituted phenyl)-4-(phenylamino)-4-H-1,2,4-triazole-3- thiols (5a-5h) were designed and evaluated for H1-blocking activity using isolated segments from the guinea pig ileum. RESULTS: According to in silico analysis, all the compounds have a topological polar surface area (TPSA) less than 140 Å squared, so they tend to easily penetrate cell membranes. The results show that most of the compounds are non-inhibitors of CYP450 substrates that play a fundamental role in drug metabolism. Compounds 5d (50.53±12.03), 5h (50.62±12.33) and 7a (55.07±12.41) are more active than others. CONCLUSION: Finally, these derivatives were screened for H1 receptor antagonist activity using guinea pig ileum, taking chlorpheniramine maleate as a standard. Most of the compounds were found to possess better antihistamine activity.

Bioavailability of Triprolidine as a Single Agent or in Combination With Pseudoephedrine: A Randomized, Open-Label Crossover Study in Healthy Volunteers.

Antihistamines have been in clinical use for more than 70 years to treat allergic and nonallergic symptoms including relief from cold and flu symptoms. Despite their widespread use, pharmacokinetic (PK) data are sparse for older, first-generation antihistamines. This phase 1 single-center open-label, randomized, single-dose, 3-way crossover trial evaluated the PK profiles of 2 doses of film-coated triprolidine caplets (2.5 and 5 mg) compared with a reference combination tablet (triprolidine 2.5 mg + pseudoephedrine 60 mg) in 24 healthy adults. Blood samples were collected predose and at specified intervals across a 24-hour period after administration, and triprolidine was quantified using liquid chromatography-tandem mass spectrometry. Maximum plasma concentration of triprolidine for the 2.5 mg and dose-normalized 5 mg single-agent tablets were comparable (8.4 versus 7.1 ng/mL, respectively) and higher for the combination tablet (9.5 ng/mL). PK parameters, including time to maximum plasma concentration (∼1.5 hours) and elimination half-life (∼4 hours), were comparable between the 3 treatment arms. The safety profile of this sedating antihistamine was as expected; however, adverse effects were reported in a markedly higher proportion of women than men. There were no significant sex differences in any of the measured PK parameters.

Improvement of solubility and dissolution of ebastine by fabricating phosphatidylcholine/ bile salt bilosomes.

Although ebastine (EBT) can impede histamine-induced skin allergic reaction and persuade long acting selective H1 receptor antagonistic effects but its poor water solubility circumscribed its clinical application. The main objective of this research work was to improve the aqueous solubility and oral bioavailability of EBT by preparing EBT-loaded bilosomes (EBT-PC-SDC-BS). A thin film hydration method was used to prepare ebastine loaded bilosomes. The prepared-formulations were optimized considering size, morphology and entrapment efficiency. The SEM images revealed regular and spherical shape of bilosomes. Average size of the prepared EBT-PC-SDC-BS was 665.8 nm and zeta potential was around-32.9 mV with 89.05 % average entrapment efficiency (EE).Importantly, the solubility of EBT in water was amplified up to 17.9 µg/ml compared to pure drug (2 µg/mL) reflecting a highest solubility increase of 751 %. In vitro drug release results of prepared EBT-PC-SDC-BS exhibited improved release behavior. Finally, it is established from the results that the EBT-PC-SDC-BS could function as a favorable nano-carrier system to improve the solubility as well as dissolution of EBT.

Ebastine in the treatment of allergic rhinitis and urticaria: 30 years of clinical studies and real-world experience

Histamine, acting predominantly via the H1-receptor, is an important mediator of the symptoms of allergy. H1-antihistamines, which stabilize the receptor in its inactive form, are the treatment of choice for some chronic allergic conditions. Ebastine is a well-established secondgeneration oral H1-antihistamine that is administered once daily at a dose of 10-20 mg and is available both as a standard tablet and as a fast-dissolving tablet that disintegrates in the mouth. Ebastine has been shown to relieve symptoms in patients with allergic rhinitis or urticaria in multiple clinical trials. In addition to its antihistamine effects, the drug has modulating effects on the allergic inflammatory process, thus potentially explaining its beneficial effect on nasal obstruction in some patients. Ebastine is generally well tolerated at recommended doses and is one of the lowest-risk antihistamines with respect to adverse cognitive/psychomotor effects, as confirmed by decades of pharmacovigilance. New long-term data confirm its efficacy and tolerability during up to 1 year of treatment in patients with chronic urticaria

La histamina, que actúa predominantemente a través del receptor H1, es un mediador importante de los síntomas de alergia, y los antihistamínicos H1, que estabilizan el receptor en su forma inactiva, son el tratamiento de elección para algunas afecciones alérgicas crónicas. La ebastina es un antihistamínico H1 oral de segunda generación bien establecido. Se administra una vez al día en una dosis de 10 a 20 mg y está disponible como comprimido estándar y también como comprimido de disolución rápida que se desintegra en la boca. La ebastina ha demostrado en numerosos ensayos clínicos ser eficaz para aliviar los síntomas de pacientes con rinitis alérgica o urticaria. La ebastina tiene efectos moduladores del proceso inflamatorio alérgico además de sus efectos antihistamínicos, lo que pueden ayudar a explicar el efecto beneficioso que tiene sobre la obstrucción nasal en algunos pacientes. La ebastina es generalmente bien tolerada a las dosis recomendadas y es uno de los antihistamínicos de menor riesgo con respecto a los efectos adversos cognitivos/psicomotores, confirmado después de décadas de farmacovigilancia. Los nuevos datos a largo plazo confirman su eficacia y tolerabilidad hasta un año de tratamiento en pacientes con urticaria crónica

Pharmacokinetics of hydroxyzine and cetirizine following oral administration of hydroxyzine to exercised Thoroughbred horses.

Hydroxyzine is a first-generation antihistamine and cetirizine, a second-generation antihistamine and active metabolite of hydroxyzine. Hydroxyzine is commonly used in performance horses and as such its use in closely regulated; however, there are no published studies suitable for establishing appropriate regulatory recommendations. In the current study, 12 exercised Thoroughbred research horses received a single oral administration of 500 mg of hydroxyzine. Blood and urine samples were collected prior to and up to 96 hr postdrug administration and concentrations of hydroxyzine and cetirizine determined using liquid chromatography-tandem mass spectrometry. A joint parent/metabolite population 2-compartment pharmacokinetic model with first-order absorption and elimination was utilized to describe the pharmacokinetics of both compounds. Serum hydroxyzine and cetirizine concentrations were above the limit of quantitation (0.1 ng/ml) of the assay at 96 hr (the last time point sampled). The terminal half-life was 7.41 and 7.13 hr for hydroxyzine and cetirizine, respectively. Findings from this study suggest that a prolonged withdrawal time should be observed if this compound is used in performance administered to performance horses and is classified as prohibited substance by the applicable regulatory body.

Probe dependency in the determination of ligand binding kinetics at a prototypical G protein-coupled receptor.

Drug-target binding kinetics are suggested to be important parameters for the prediction of in vivo drug-efficacy. For G protein-coupled receptors (GPCRs), the binding kinetics of ligands are typically determined using association binding experiments in competition with radiolabelled probes, followed by analysis with the widely used competitive binding kinetics theory developed by Motulsky and Mahan. Despite this, the influence of the radioligand binding kinetics on the kinetic parameters derived for the ligands tested is often overlooked. To address this, binding rate constants for a series of histamine H1 receptor (H1R) antagonists were determined using radioligands with either slow (low koff) or fast (high koff) dissociation characteristics. A correlation was observed between the probe-specific datasets for the kinetic binding affinities, association rate constants and dissociation rate constants. However, the magnitude and accuracy of the binding rate constant-values was highly dependent on the used radioligand probe. Further analysis using recently developed fluorescent binding methods corroborates the finding that the Motulsky-Mahan methodology is limited by the employed assay conditions. The presented data suggest that kinetic parameters of GPCR ligands depend largely on the characteristics of the probe used and results should therefore be viewed within the experimental context and limitations of the applied methodology.

In vitro and in vivo performance of epinastine hydrochloride-releasing contact lenses.

A number of drug-releasing contact lenses are currently being studied to address issues inherent in eye drops as a drug delivery method. In this study, we developed epinastine hydrochloride-releasing daily soft contact lenses for treatment of allergic conjunctivitis and examined their in vitro and in vivo performance. Preformed soft contact lenses with/without ionic functional groups were soaked in a solution of epinastine hydrochloride in phosphate-buffered saline to prepare epinastine hydrochloride-releasing soft contact lenses. Among these contact lenses with different ionicities, anionic lenses demonstrated the maximum, relatively linear epinastine hydrochloride release, in vitro. The amount of epinastine hydrochloride release was directly proportional to the concentration of the epinastine hydrochloride solution used to prepare the contact lens. The epinastine hydrochloride-releasing anionic soft contact lens also demonstrated prolonged drug release and significantly greater efficacy compared with epinastine hydrochloride eye drops 12 h after treatment, in vivo. Further studies are required to determine the appropriate amount of epinastine hydrochloride to be contained in the anionic soft contact lenses.

Simple HPLC Method for Quantitative Determination of Carbinoxamine in Human Plasma: Application in Pharmacokinetic Studies and Therapeutic Drug Monitoring.

A sensitive, specific and cost-effective HPLC method was developed for quantitative determination of carbinoxamine in human plasma using liquid chromatography with ultraviolet detection. A simple liquid-liquid extraction by ethyl acetate was used to extract carbinoxamine from human plasma. Satisfactory separation was achieved by a mobile phase consisting of 20 mM ammonium dihydrogen orthophosphate containing 0.01% triethyl amine (pH adjusted to 3 by using phosphoric acid) and acetonitrile in ratio of (75:25, v/v) at a flow rate of 0.9 mL/min on Hypersil® BDS C18 column (250×4.6 mm, 5 µm) column. The UV detector was set at 260 nm. The developed method was validated in human plasma with a lower limit of quantitation of 5 ng/mL for carbinoxamine. Linearity was demonstrated over the concentration range 5-200 ng/mL. The observed within- and between-day assay precision ranged from 1.902 to 14.90%; accuracy varied between 98.87 and 108.0%. This method can be used suitably for pharmacokinetic studies and in therapeutic drug monitoring in patients treated with carbinoxamine.

Falso positivo a morfina en orina por reactividad cruzada con alimemazina / False positive result to morphine in urine due to cross-reactivity to alimemazine

La alimemazina (Variargil(R)) es un antihistamínico anti-H1 reversible inespecífico que atraviesa la barrera hematoencefálica. Actúa como anticolinérgico. Su forma de presentación es en gotas en suspensión oral. Su uso clínico está extendido a rinitis alérgica estacional, angioedema y urticaria leve a partir de los 2 años de edad, conjuntivitis alérgica e insomnio de conciliación en la infancia. Presenta una farmacocinética muy variable, somnolencia excesiva conocida como «heavy hangover» y efecto de rebote tras su retirada. No está autorizado su uso en menores de 2 años. Presentamos el caso de un paciente de 19 meses que acude a Urgencias por referir somnolencia y falta de respuesta a estímulos tras la administración de alimemazina por dificultad para conciliar el sueño

Alimemazine (Variargil(R)) is a non-specific reversible anti-H1 antihistamine that crosses the blood-brain barrier. It acts as anticholinergic drug. It is marketed in drop form (oral suspension). It is used to relieve seasonal allergic rhinitis, angioedema, mild urticaria, allergic conjunctivitis, and for difficulty in falling asleep in children. It has a very variable pharmacokinetic, excessive "heavy hangover drowsiness" and rebound effect after withdrawal. It is not authorised for children under 2 years of age. The case is presented of a patient seen in the emergency room due to drowsiness and lack of response to stimuli after administration of alimemazine due to difficulties in falling asleep

Determination of d-amphetamine and diphenhydramine in beagle dog plasma by a 96-well formatted liquid-liquid extraction and capillary zone electrophoresis with field-amplified sample stacking.

This paper describes a method for quantification of d-amphetamine and diphenhydramine in beagle dog plasma by organic solvent field-amplified sample stacking (FASS)-capillary zone electrophoresis (CZE), using amlodipine as the internal standard. The separation was carried out at 25 °C in a 40.2 cm × 75 µm fused-silica capillary with an applied voltage of 20 kV using 25 mM phosphate-18.75 mM borate (pH 3.5). The detection wavelength was 200 nm. Clean-up and preconcentration of plasma biosamples were developed by 96-well formatted liquid- liquid extraction (LLE). In this study, the peak areas of d-amphetamine, diphenhydramine and amlodipine in the plasma sample increased by the factor of 48, 67 and 43 compared to the CZE without sample stacking. The method was suitably validated with respect to stability, specificity, linearity, lower limit of quantitation, accuracy, precision and extraction recovery. The calibration graph was linear from 2 to 500 ng/ml for d-amphetamine and 2-5000 ng/ml for diphenhydramine. All the validation data were within the required limits. Compared with the LC/MS/MS method that we previously established, there was no significant difference between the two methods in validation characteristics, except the LLOQs. The developed method was successfully applied to the evaluation of pharmacokinetic study of the Quick-Acting Anti-Motion Capsules (QAAMC) in beagle dogs.

A Phase I Study of the Pharmacokinetics and Pharmacodynamics of Intranasal Doxylamine in Subjects with Chronic Intermittent Sleep Impairment.

INTRODUCTION: Doxylamine tablets are approved as an over-the-counter sleep aid. We developed a doxylamine succinate intranasal metered-dose delivery system with the expectation of a more rapid onset of action with reduced side-effect potential compared with the oral tablet. METHODS: This phase I study randomized 24 adults with chronic intermittent sleep impairment to receive either single doses of intranasal doxylamine succinate 3.2, 6.3, or 12.7 mg or doxylamine succinate 25-mg oral tablet. Doxylamine pharmacokinetics were assessed using noncompartmental methods; pharmacodynamics were evaluated using the Karolinska Sleepiness Scale (KSS) and numerous psychomotor tests. Adverse events (AEs) were monitored. RESULTS: None of the intranasal dose levels produced a mean maximum plasma concentration (Cmax) above the 50 ng/mL target level or a time to maximum concentration shorter than that of the oral tablet. At the highest intranasal dose, Cmax and area under the doxylamine concentration-time curve were approximately 25% of the values achieved with the oral dose. Variation in most pharmacokinetic parameters was higher with intranasal compared with oral dosing. A relationship between plasma doxylamine concentration and KSS change from baseline was evident for the 25-mg tablet and, to a lesser extent, for the 12.7-mg intranasal dose. Changes from baseline in psychomotor parameters did not show a relationship to intranasal dose, and did not distinguish between intranasal versus oral dosing. The most common AEs with intranasal dosing were nasal congestion, nasal dryness, and frontal headache. CONCLUSION: The nasal spray did not increase doxylamine absorption or systemic bioavailability compared with the oral tablet.

Brompheniramine and Chlorpheniramine Pharmacokinetics Following Single-Dose Oral Administration in Children Aged 2 to 17 Years.

Two pediatric studies characterized brompheniramine and chlorpheniramine pharmacokinetics in a total of 72 subjects, aged 2 to 17 years. A single age-/weight-based oral dose, ranging from 1 to 4 mg, was administered with 2 to 6 oz of water at least 2 hours after a light breakfast. Plasma samples were obtained before and for 72 hours after dosing and analyzed using high-pressure liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods; relationships with age were assessed using linear regression. Results indicated that for brompheniramine and chlorpheniramine, Cmax was similar across age groups, although it tended to occur earlier in the youngest group. AUC was ∼15% to 30% higher in the oldest age group. As expected, CLo and Vz /F increased with age; however, following allometric scaling, no age-related differences existed. Because the increase with age for both parameters was similar, no age-related differences in t1/2,z existed (∼15 hours). Overall, the single doses were well tolerated. Sedation was the most common reported AE and appeared to be more prevalent in the 2- to 5-year-old group. Overall, these results indicate that an age/weight dosing nomogram using a 4-fold range of doses achieves similar Cmax and AUC.

Model Informed Pediatric Development Applied to Bilastine: Ontogenic PK Model Development, Dose Selection for First Time in Children and PK Study Design.

PURPOSE: Bilastine is an H1 antagonist whose pharmacokinetics (PK) and pharmacodynamics (PD) have been resolved in adults with a therapeutic oral dose of 20 mg/day. Bilastine has favorable characteristics for use in pediatrics but the PK/PD and the optimal dose in children had yet to be clinically explored. The purpose is to: (1) Develop an ontogenic predictive model of bilastine PK linked to the PD in adults by integrating current knowledge; (2) Use the model to design a PK study in children; (3) Confirm the selected dose and the study design through the evaluation of model predictability in the first recruited children; (4) Consider for inclusion the group of younger children (< 6 years). METHODS: A semi-mechanistic approach was applied to predict bilastine PK in children assuming the same PD as described in adults. The model was used to simulate the time evolution of plasma levels and wheal and flare effects after several doses and design an adaptive PK trial in children that was then confirmed using data from the first recruits by comparing observations with model predictions. RESULTS: PK/PD simulations supported the selection of 10 mg/day in 2 to <12 year olds. Results from the first interim analysis confirmed the model predictions and design hence trial continuation. CONCLUSION: The model successfully predicted bilastine PK in pediatrics and optimally assisted the selection of the dose and sampling scheme for the trial in children. The selected dose was considered suitable for younger children and the forthcoming safety study in children aged 2 to <12 years.

Identification of selective 8-(piperidin-4-yloxy)quinoline sulfone and sulfonamide histamine H1 receptor antagonists for use in allergic rhinitis.

A series of potent, selective and long-acting quinoline-based sulfonamide human H1 histamine receptor antagonists, designed for once-daily intranasal administration for the treatment of rhinitis were developed. Sulfonamide 33b had a slightly lower affinity for the H1 receptor than azelastine, had low oral bioavailability in the rat and dog, and was turned over to five major metabolites. Furthermore, 33b had longer duration of action than azelastine in guinea pigs, lower rat brain-penetration, and did not cause time dependent inhibition of CYP2D6 or CYP3A4. The clinical dose in humans is expected to be low (approximately 0.5mg per day) based on the clinical dose used for azelastine and a comparison of efficacy data from animal models for 33b and azelastine.