Spectroscopic interaction studies of H2 receptor antagonists with levocetirizine.

Patients with allergic rhinitis may also suffer abdominal pain, gastritis or peptic ulcer. In this condition patient may use levocetirizine with famotidine or ranitidine. These drugs have potential to interact with another drug and form complex. The aim of the present study is to evaluate the possible drug drug interaction with each other which may cause increase or decrease of therapeutic effects. For this purpose, validity of Beer Lambert law was checked, lone availability of famotidine (20gm), ranitidine (150gm) and levocetirizine (5mg) were studied in pH simulated to gastric juice (pH 1), pH 4, pH 7.4 and in pH 9 and finally percent availabilities of these drugs were calculated with the help of simultaneous equation. Results showed high percentage of levocetirizine in all pH as 300.32%, 514.41%, 173.38% and 220.68% in presence of famotidine but very low availability of famotidine as 5.36%, 35.38%, 51.87% and 10.89% in presence of levocetirizine. In the case of levocetirizine and ranitidine interaction, zero percent levocetirizine was available at pH 1and 9, 56.28% in pH 4 and 191.1% in pH 7.4. On the other hand, ranitidine was available as 95.36%, 127.93%, 41.47% and 144.3%. These results showed that percentage of all drugs were altered in presence of each other due to drug-drug interaction. This may be due to the charge transfer binding capabilities of the drugs which resulted in significantly changed availability of famotidine, ranitidine as well as levocetirizine.

Chiral Transplacental Pharmacokinetics of Fexofenadine: Impact of P-Glycoprotein Inhibitor Fluoxetine Using the Human Placental Perfusion Model.

PURPOSE: Fexofenadine is a well-identified in vivo probe substrate of P-glycoprotein (P-gp) and/or organic anion transporting polypeptide (OATP). This work aimed to investigate the transplacental pharmacokinetics of fexofenadine enantiomers with and without the selective P-gp inhibitor fluoxetine. METHODS: The chiral transplacental pharmacokinetics of fexofenadine-fluoxetine interaction was determined using the ex vivo human placenta perfusion model (n = 4). In the Control period, racemic fexofenadine (75 ng of each enantiomer/ml) was added in the maternal circuit. In the Interaction period, racemic fluoxetine (50 ng of each enantiomer/mL) and racemic fexofenadine (75 ng of each enantiomer/mL) were added to the maternal circulation. In both periods, maternal and fetal perfusate samples were taken over 90 min. RESULTS: The (S)-(-)- and (R)-(+)-fexofenadine fetal-to-maternal ratio values in Control and Interaction periods were similar (~0.18). The placental transfer rates were similar between (S)-(-)- and (R)-(+)-fexofenadine in both Control (0.0024 vs 0.0019 min-1) and Interaction (0.0019 vs 0.0021 min-1) periods. In both Control and Interaction periods, the enantiomeric fexofenadine ratios [R-(+)/S-(-)] were approximately 1. CONCLUSIONS: Our study showed a low extent, slow rate of non-enantioselective placental transfer of fexofenadine enantiomers, indicating a limited fetal fexofenadine exposure mediated by placental P-gp and/or OATP2B1. The fluoxetine interaction did not affect the non-enantioselective transplacental transfer of fexofenadine. The ex vivo placental perfusion model accurately predicts in vivo placental transfer of fexofenadine enantiomers with remarkably similar values (~0.17), and thus estimates the limited fetal exposure.

A Review of Different Analytical Techniques for Fexofenadine Hydrochloride and Montelukast Sodium in Different Matrices.

Fexofenadine hydrochloride is an antihistamine agent used for the treatment of allergic disorders like rhinitis. It is a second generation antihistamine. Montelukast sodium is an anti-asthmatic agent and leukotriene receptor antagonist used in the treatment of respiratory disorders. This article exemplifies the reported analytical methods like electrometric methods, ultraviolet spectroscopy, mass spectroscopy, thin layer chromatography, high performance liquid chromatography, high performance thin layer chromatography and tandem spectroscopy for determination of fexofenadine HCl and montelukast sodium in dosage form and in biological matrices. This review covers almost all the analytical methods for fexofenadine hydrochloride and montelukast sodium form 1968-2018 years. Complete analytical validation parameters reported are discussed in this review for both analytes. Among various analytical methods, HPLC and UV-visible spectrophotometry were found to be the most extensively used methods by the researchers.

A Randomized Study on the Bioequivalence of Desloratadine in Healthy Chinese Subjects and the Association of Different Metabolic Phenotypes With UGT2B10 and CYP2C8 Genotypes.

BACKGROUND: Desloratadine is a drug with a phenotypic polymorphism in metabolism and has been approved for use in many countries to treat allergic diseases. CYP2C8 and UGT2B10 are metabolic enzymes, which may be involved in the metabolism of desloratadine. OBJECTIVE: This study aimed to demonstrate bioequivalence between the test product (desloratadine tablet) and the reference product AERIUS (5mg), both orally administered. And the role of UGT2B10 and CYP2C8 genotypes in healthy Chinese subjects with different Desloratadine metabolic phenotypes was examined. METHODS: It was a randomized, open-label, and four-sequence, single-dose crossover study conducted on 56 healthy Chinese subjects. The pharmacokinetics (PK) and safety of the test and reference Desloratadine products were compared. UGT2B10 and CYP2C8 genotypes were determined by the TaqMan assay using genomic DNA. Multiple linear regression was applied to analyze the correlation between genotypes and the metabolic ratio. RESULTS: The mean serum concentration-time curves of desloratadine and 3-OH-desloratadine were similar between the test product and the reference product. For the PK similarity comparison, the 90% CIs for the geometric mean ratios of Cmax, AUC0-t, and AUC0-∞ of desloratadine and 3-OH-desloratadine of test and reference product were completely within 80-125%. None of all 56 subjects had serious adverse events. Only 2 subjects were poor-metabolizers in 56 healthy subjects. There was no significant correlation between investigated genotypes of CYP2C8 and UGT2B10 and the metabolic ratio. CONCLUSION: The test desloratadine tablet was bioequivalent to the reference product. No direct relationship between CYP2C8 and UGT2B10 genotypes and desloratadine metabolic ratio was identified.

Chiral Discrimination of P-glycoprotein in Parturient Women: Effect of Fluoxetine on Maternal-Fetal Fexofenadine Pharmacokinetics.

BACKGROUND AND OBJECTIVE: Fluoxetine, antidepressant widely-used during pregnancy, is a selective inhibitor for P-glycoprotein (P-gp). Fexofenadine, an in vivo P-gp probe, is an antihistamine drug for seasonal allergic rhinitis and chronic urticaria treatment during pregnancy and it is available as a racemic mixture. This study evaluated the chiral discrimination of P-gp investigating the effect of fluoxetine on maternal-fetal pharmacokinetics of fexofenadine. METHODS: Healthy parturient women received either a single oral dose of 60 mg racemic fexofenadine (Control group; n = 8) or a single oral dose of 40 mg racemic fluoxetine 3 h before a single oral dose of 60 mg racemic fexofenadine (Interaction group; n = 8). Maternal blood and urine samples were collected up to 48 h after fexofenadine administration. At delivery, maternal-placental-fetal blood samples were collected. RESULTS: The maternal pharmacokinetics of fexofenadine was enantioselective (AUC0-∞R-(+)/S-(-) ~ 1.5) in both control and interaction groups. Fluoxetine increased AUC0-∞ (267.7 vs 376.1 ng.h/mL) and decreased oral total clearance (105.1 vs 74.4 L/h) only of S-(-)-fexofenadine, whereas the renal clearance were reduced for both enantiomers, suggesting that the intestinal P-gp-mediated transport of S-(-)-fexofenadine is influenced by fluoxetine to a greater extent that the R-(+)-fexofenadine. However, the transplacental transfer of fexofenadine is low (~16%), non-enantioselective and non-influenced by fluoxetine. CONCLUSIONS: A single oral dose of 40 mg fluoxetine inhibited the intestinal P-gp mediated transport of S-(-)-fexofenadine to a greater extent than R-(+)-fexofenadine in parturient women. However, the placental P-gp did not discriminate fexofenadine enantiomers and was not inhibited by fluoxetine.

Bacterial metabolism rescues the inhibition of intestinal drug absorption by food and drug additives.

Food and drug products contain diverse and abundant small-molecule additives (excipients) with unclear impacts on human physiology, drug safety, and response. Here, we evaluate their potential impact on intestinal drug absorption. By screening 136 unique compounds for inhibition of the key intestinal transporter OATP2B1 we identified and validated 24 potent OATP2B1 inhibitors, characterized by higher molecular weight and hydrophobicity compared to poor or noninhibitors. OATP2B1 inhibitors were also enriched for dyes, including 8 azo (R-N=N-R') dyes. Pharmacokinetic studies in mice confirmed that FD&C Red No. 40, a common azo dye excipient and a potent inhibitor of OATP2B1, decreased the plasma level of the OATP2B1 substrate fexofenadine, suggesting that FD&C Red No. 40 has the potential to block drug absorption through OATP2B1 inhibition in vivo. However, the gut microbiomes of multiple unrelated healthy individuals as well as diverse human gut bacterial isolates were capable of inactivating the identified azo dye excipients, producing metabolites that no longer inhibit OATP2B1 transport. These results support a beneficial role for the microbiome in limiting the unintended effects of food and drug additives in the intestine and provide a framework for the data-driven selection of excipients. Furthermore, the ubiquity and genetic diversity of gut bacterial azoreductases coupled to experiments in conventionally raised and gnotobiotic mice suggest that variations in gut microbial community structure may be less important to consider relative to the high concentrations of azo dyes in food products, which have the potential to saturate gut bacterial enzymatic activity.

Levocetirizine Oral Disintegrating Tablet: A Randomized Open-Label Crossover Bioequivalence Study in Healthy Japanese Volunteers.

Levocetirizine is classified as a second-generation antihistamine. Levocetirizine is available for the treatment of allergic disorders such as allergic rhinitis and chronic idiopathic urticaria. This was a single-center, single-dose, open-label, randomized, 2-way crossover study in healthy Japanese male subjects consisting of 2 parts. Part 1 compared the bioavailability of levocetirizine oral disintegrating tablet (ODT) and levocetirizine immediate-release tablet (IRT) taken with water in the fasted state in 24 subjects; all subjects completed this part of the trial. In part 2, the bioavailability of levocetirizine ODT without water was compared with that of levocetirizine IRT with water in the fasted state in 48 subjects; 47 subjects completed this part of the trial. Bioequivalence was demonstrated between levocetirizine IRT 5 mg and ODT 5 mg. The safety profiles were generally similar between levocetirizine ODT and levocetirizine IRT, with no serious adverse events, deaths, or adverse events leading to withdrawal reported during the study.

Development of medicated chewing gum of taste masked levocetirizine dihydrochloride using different gum bases: in vitro and in vivo evaluation.

Objective: The aim of this study was to develop medicated chewing gum (MCG) formulation for taste-masked levocetirizine dihydrochloride (LCZ) that can provide fast drug release into the salivary fluid.Methods: Taste-masked LCZ was first prepared by two methods: cyclodextrin complexation using Kleptose or Captisol and formation of drug resin complex using Kyron T-154 or Kyron T-314 to overcome poor LCZ palatability. MCGs were then prepared using the taste-masked drug, gum base (Artica-T, Chicle, or Health In Gum (HIG), plasticizer (glycerol or soy lecithin at 6 or 8% of the final gum weight). The developed MCGs were evaluated for physical properties, content uniformity, and drug release. Best release MCGs were evaluated thermally to investigate the plasticizer effectiveness and for ex vivo chew out study to confirm adequate drug release. Drug bioavailability was determined for selected formula compared to commercial tablets.Results: Based on taste-masking efficiency, drug/Kleptose complex (1:3 molar ratio) was chosen for incorporation into chewing gums. Physical properties and drug release showed that gum base type, plasticizer type, and level affected not only physical properties but also drug release from MCGs. Thermal study showed decreased glass transition temperature (Tg) with increased plasticizer level. Chew out study confirmed almost complete drug release after a few minutes of chewing. Pharmacokinetic results showed shorter tmax (0.585 vs. 1.375 h) and higher Cmax (0.113 vs. 0.0765 µg/mL) for MCGs than conventional tablets.Conclusion: Results provided evidence that MCGs could be a better alternative to conventional tablet formulations with improved bioavailability and enhanced palatability.

Pharmacokinetics and safety of bilastine in children aged 6 to 11 years with allergic rhinoconjunctivitis or chronic urticaria.

Bilastine, a second-generation antihistamine, is approved in Europe for the treatment of allergic rhinoconjunctivitis and urticaria in adults and children aged ≥ 6 years. Pharmacokinetic data for children aged 6-11 years were extracted post hoc from a study in which children (2-11 years) with allergic rhinoconjunctivitis or urticaria received oral bilastine (10 mg/day). Maximum plasma concentration (Cmax) and area under the plasma concentration curve (AUC) data were compared with adult pharmacokinetic data from seven clinical studies (bilastine 20 mg/day). Safety data for children aged 6-11 years were extracted post hoc from a phase III randomized controlled trial of children (2-11 years) with allergic rhinoconjunctivitis or chronic urticaria receiving once-daily bilastine 10 mg or placebo for 12 weeks. Exposure and Cmax values were similar for children (6-11 years) and adults: median pediatric/adult ratios for AUC0-24 and Cmax were 0.93 and 0.91, respectively. There was no significant difference in the incidence of treatment-emergent adverse in children (6-11 years) receiving bilastine 10 mg or placebo.Conclusion: Pharmacokinetic and safety analyses in children aged 6-11 years support the suitability of the pediatric dose of bilastine 10 mg and confirm that the safety profiles of bilastine and placebo are similar.What is Known:• Bilastine, a second-generation antihistamine, is approved in Europe for the treatment of allergic rhinoconjunctivitis and urticaria in adults (20 mg/day) and children aged ≥ 6 years (10 mg/day).• An ontogenic model based on adult data and pharmacokinetic/pharmacodynamic simulations supported the selection of a bilastine dose of 10 mg/day in children aged 2-11 years. Bilastine 10 mg/day was shown to have a safety profile similar to that of placebo in a large phase III randomized clinical trial in children aged 2-11 years.What is New:• As bilastine is approved in Europe for children aged ≥6 years, the current study reports the results of two post hoc analyses of pharmacokinetic and safety data in children aged 6-11 years.• Analysis of pharmacokinetic and safety data in children aged 6-11 years supports the suitability of the pediatric dose of bilastine 10 mg and confirms that its safety profile is similar to that of placebo.

Bioequivalence Evaluation of Three Pediatric Oral Formulations of Bilastine in Healthy Subjects: Results from a Randomized, Open Label, Crossover Study.

BACKGROUND AND OBJECTIVE: Bilastine is a non-sedating H1 antihistamine indicated for the treatment of allergic rhinoconjunctivitis and urticaria. The aim of this trial was to assess the bioequivalence of three novel pediatric oral formulations of bilastine. METHODS: An open label, randomized, four-treatment-period, four-sequence, crossover, single-center study was conducted in 23 healthy volunteers. Each subject received four single doses of bilastine under fasting conditions: a 10-mg orodispersible tablet (DT1), a 10-mg oral solution (SOL), a 10-mg orodispersible tablet without water (DT2dry), and a 10-mg orodispersible tablet with water (DT2water, reference formulation). Blood samples were collected during 72 h with a washout period of at least 7 days. Bilastine maximum plasma concentration (Cmax) and area under the plasma concentration-time curve between 0 to t time (AUC0-t) were calculated to assess bioequivalence. Tolerability was evaluated throughout the study. RESULTS: The three oral pediatric formulations tested were bioequivalent to the reference formulation as determined by the ratio test/reference of the geometric mean and their 90% confidence intervals (between 0.80 and 1.25) for the Cmax, AUC0-t and AUC0-∞. Bilastine was well tolerated when administered indistinctly as an orodispersible tablet or as an oral solution. CONCLUSION: The three oral pediatric formulations tested were found to be bioequivalent to the reference formulation. All formulations were well tolerated. TRIAL REGISTRATION: Spanish Clinical Studies Registry (REEC) number 2014-000786-41.

The Effect Of Food On The Pharmacokinetic Properties And Bioequivalence Of Two Formulations Of Levocetirizine Dihydrochloride In Healthy Chinese Volunteers.

PURPOSE: The aim of this study is to assess the bioequivalence of a new generic formulation and the branded formulation of levocetirizine dihydrochloride in healthy Chinese volunteers under fasting and fed conditions, and food-intake effect on the pharmacokinetic properties is also evaluated. PATIENTS AND METHODS: Volunteers were randomly allocated into two groups to receive a single oral dose of generic formulation and branded formulation under fasting or fed conditions, respectively. Blood samples were collected at designated time points. Plasma concentrations of levocetirizine were determined by UFLC-MS/MS. Safety evaluations were carried out through the study. The main pharmacokinetic parameters of the two formulations of levocetirizine were calculated using non-compartmental analysis incorporated in WinNonlin® 7.0 software. RESULTS: Forty-nine volunteers were enrolled; 46 completed the studies. Under fasting and fed conditions, the 90% confidence intervals for the geometric mean of generic/branded ratios were in the range of 94.75-107.24% and 99.98-114.69% for the maximum observed concentration, and 97.13-102.50% and 98.36-103.98% for the area under the concentration-time curve. As a result of food intake before administration, the reduced rate and extent of absorption of levocetirizine were observed. Both formulations were generally well tolerated, with no serious adverse reactions reported. CONCLUSION: The two formulations demonstrated essentially identical pharmacokinetic profiles and were all well within the FDA/CFDA bioequivalence standards. Meanwhile, food intake can delay the absorption rate and reduced the bioavailability of levocetirizine in healthy Chinese volunteers.

Brain histamine H1 receptor occupancy after oral administration of desloratadine and loratadine.

Some histamine H1 receptor (H1R) antagonists induce adverse sedative reactions caused by blockade of histamine transmission in the brain. Desloratadine is a second-generation antihistamine for treatment of allergic disorders. Its binding to brain H1Rs, which is the basis of sedative property of antihistamines, has not been examined previously in the human brain by positron emission tomography (PET). We examined brain H1R binding potential ratio (BPR), H1R occupancy (H1RO), and subjective sleepiness after oral desloratadine administration in comparison to loratadine. Eight healthy male volunteers underwent PET imaging with [11C]-doxepin, a PET tracer for H1Rs, after a single oral administration of desloratadine (5 mg), loratadine (10 mg), or placebo in a double-blind crossover study. BPR and H1RO in the cerebral cortex were calculated, and plasma concentrations of loratadine and desloratadine were measured. Subjective sleepiness was quantified by the Line Analogue Rating Scale (LARS) and the Stanford Sleepiness Scale (SSS). BPR was significantly lower after loratadine administration than after placebo (0.504 ± 0.074 vs 0.584 ± 0.059 [mean ± SD], P < 0.05), but BPR after desloratadine administration was not significantly different from BPR after placebo (0.546 ± 0.084 vs 0.584 ± 0.059, P = 0.250). The plasma concentration of loratadine was negatively correlated with BPR in subjects receiving loratadine, but that of desloratadine was not correlated with BPR. Brain H1ROs after desloratadine and loratadine administration were 6.47 ± 10.5% and 13.8 ± 7.00%, respectively (P = 0.103). Subjective sleepiness did not significantly differ among subjects receiving the two antihistamines and placebo. At therapeutic doses, desloratadine did not bind significantly to brain H1Rs and did not induce any significant sedation.

Pharmacokinetics and pharmacodynamics of olopatadine following administration via nasogastric tube to healthy horses.

OBJECTIVE: To investigate the pharmacokinetics and antihistaminic effects (pharmacodynamics) of olopatadine in a small population of healthy horses after administration via nasogastric tube. ANIMALS: 4 healthy adult Thoroughbreds. PROCEDURES: Olopatadine (0.1 mg/kg, once) was administered via nasogastric tube. Blood samples were collected at predetermined time points for pharmacokinetic analyses of the drug in plasma. Olopatadine effects were investigated by measurement of cutaneous wheals induced by ID histamine injection (0.1 mL [10 µg]/injection) at predetermined time points. Inhibition effect ratios were calculated on the basis of measured wheal size (area) after versus before olopatadine administration. RESULTS: Mean ± SD maximum plasma olopatadine concentration was 48.8 ± 11.0 ng/mL approximately 1.5 hours after administration. Median terminal half-life was 6.11 hours. Mean ± SD maximal effect was 88.2 ± 4.9% inhibition approximately 3.5 hours after drug delivery, and the inhibition effect remained > 80% for 12.5 hours after treatment. No signs of adverse clinical effects were observed. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested olopatadine may have a strong, long-term inhibitory effect against histamine-induced wheals in the skin of horses. Clinical research with a larger number of horses is warranted.

Model-informed pediatric development applied to bilastine: Analysis of the clinical PK data and confirmation of the dose selected for the target population.

Bilastine is a non-sedating second-generation H1 antihistamine approved for treatment of allergic rhinoconjunctivitis (AR) and urticaria (U) in adults at the oral (p.o.) dose of 20 mg once daily (OD). Optimal attributes can be anticipated for its clinical use in pediatrics due to its favorable safety and tolerability and age-independent PD profile. The aim of this work was to characterize bilastine PK in children through population modeling of data from a limited sampling confirmatory clinical trial in children with AR or U. The objective was also to ascertain whether the proposed dose (10 mg/day) in the target pediatric subset aged 2-<12 years matches the systemic exposure seen in adults at the 20 mg/day dose. A popPK model characterizing bilastine PK behavior in children aged from 4 to <12 years treated with 10 mg oral bilastine daily was successfully developed and qualified. No relationship was found between bilastine PK and age or weight; stopping rules pre-stablished to finalize the trial, i.e., model completeness and no dependence of exposure on decreasing age, were thus fulfilled. On a second step, the popPK model in children was linked to the PD model in adults assuming the same PD as described in adults and used to compare the PD outcome between both populations. Finally, an allometric scaling method and a physiological approximation were used to evaluate the suitability of the selected dose in the youngest children, showing that children from 2 years were deemed to belong to the same population as well. The achievement of comparable PK (i.e., within the range) to that observed in adults after the therapeutic dose of 20 mg, together with the achievement of similar PD and additional integrative analysis, served to confirm the validity of the 10 mg daily dose for the target pediatric subset (2 to <12 years).

Comparison of the pharmacokinetics and tolerability of montelukast/levocetirizine administered as a fixed-dose combination and as separate tablets.

OBJECTIVE: A novel fixed-dose combination (FDC) capsule of 10/5 mg of montelukast/levocetirizine may lead to better compliance than two separate tablets taken together. The aim of this study was to evaluate the pharmacokinetics (PK) and tolerability of an FDC of montelukast and levocetirizine compared to separate tablets. MATERIALS AND METHODS: A randomized, open-label, single-dose, two-sequence, two-period, crossover study was conducted with healthy male subjects. In each period, either an FDC or separate tablets were administered orally, and serial blood samples were collected for PK analysis for up to 34 hours after dosing. PK parameters were calculated using noncompartmental methods. The 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of the maximum plasma concentration (Cmax) and the area under the curve to the last measurable concentration (AUClast) for the two interventions were estimated. Tolerability assessments were performed for all the subjects who received the drug at least once. RESULTS: The PK profiles of the two interventions were comparable. For montelukast, the GMRs and 90% CIs for the Cmax and AUClast were 0.9800 (0.8903 - 1.0787) and 1.0706 (0.9968 - 1.1498), respectively. The corresponding values for levocetirizine were 0.9195 (0.8660 - 0.9763) and 1.0375 (1.0123 - 1.0634), respectively. Both interventions were well tolerated. CONCLUSION: The PK and tolerability profiles of montelukast and levocetirizine after a single oral administration were comparable between the FDC and separate tablets. For patients with allergic rhinitis who require a combination treatment, the FDC of montelukast and levocetirizine will be a convenient therapeutic option.
.

A Novel Surfactant-free Lipid-based Formulation for Improving Oral Bioavailability of Loratadine Using Colloidal Silicon Dioxide as Emulsifier and Solid Carrier.

BACKGROUND: The purpose of this study was to develop an innovative surfactant-free lipidbased formulation (LF) for improving oral bioavailability of loratadine based on using solid particles colloidal silicon dioxide (CSD) as emulsifier and solid carrier. METHODS: Loratadine was dissolved in oil solution with the aid of co-solvent and LF formulations were prepared by a simple adsorption and milling technique. The LF Powder was evaluated in terms of angle of repose and X-ray powder diffraction. After dispersing and emulsifying in water, the particle size and morphology were also characterized. In vitro dissolution and pharmacokinetic behavior in vivo were also studied. RESULTS: Orthogonal design indicated that the amount of CSD in formulations had a major and significant influence on emulsification. The optimal formulation showed LF with good flowability and without crystallization or deposition of loratadine in it. CONCLUSION: After dispersing in water, an emulsion with the mean droplet size of 1.2µm was obtained. Although the dissolution of drug from LF was slower in vitro in acidic aqueous solution, pharmacokinetic studies in vivo showed that the bioavailability of loratadine increased 2.49-fold by CF compared to a commercial tablet.

Predictive Performance of Physiologically Based Pharmacokinetic (PBPK) Modeling of Drugs Extensively Metabolized by Major Cytochrome P450s in Children.

The accuracy of physiologically based pharmacokinetic (PBPK) model prediction in children, especially those younger than 2 years old, has not been systematically evaluated. The aim of this study was to characterize the pediatric predictive performance of the PBPK approach for 10 drugs extensively metabolized by CYP1A2 (theophylline), CYP2C8 (desloratidine, montelukast), CYP2C9 (diclofenac), CYP2C19 (esomeprazole, lansoprazole), CYP2D6 (tramadol), and CYP3A4 (itraconazole, ondansetron, sufentanil). Model performance in children was evaluated by comparing simulated plasma concentration-time profiles with observed clinical results for each drug and age group. PBPK models reasonably predicted the pharmacokinetics of desloratadine, diclofenac, itraconazole, lansoprazole, montelukast, ondansetron, sufentanil, theophylline, and tramadol across all age groups. Collectively, 58 out of 67 predictions were within 2-fold and 43 out of 67 predictions within 1.5-fold of observed values. Developed PBPK models can reasonably predict exposure in children age 1 month and older for an array of predominantly CYP metabolized drugs.

The influence of piperine on the pharmacokinetics of fexofenadine, a P-glycoprotein substrate, in healthy volunteers.

PURPOSE: Piperine (PIP) has been found to inhibit P-glycoprotein (P-gp) function in rats, suggesting that it may have the potential to modulate P-gp-mediated drug efflux in humans. The aim of this study was to evaluate the effect of PIP on the pharmacokinetics of fexofenadine (FEX), a P-gp substrate, in healthy volunteers. METHODS: An open-label, two-period, sequential study involving 12 healthy volunteers was conducted. A single oral dose of FEX 120 mg was given to volunteers during the control phase and after the treatment phase. A once-daily oral dose of PIP 20 mg was given to volunteers during the treatment phase (10 days). Blood samples were collected at predefined time intervals, and plasma samples containing FEX were analyzed by liquid chromatography-tandem mass spectrometry. RESULTS: Treatment with PIP significantly increased maximum plasma concentration of FEX [406.9 (control) vs. 767 ng/mL (treatment)] and area under the plasma concentration-time curve [3403.7 (control) vs. 5724.7 ng.h/mL (treatment)] when compared to the control phase. In contrast, PIP treatment significantly decreased apparent oral clearance of FEX [35.4 (control) vs. 20.7 L/h (treatment)] as compared to the control. There was no significant change observed in the half life and renal clearance of FEX between the treatment phase and control phase. CONCLUSIONS: The results suggest that altered pharmacokinetics and enhanced bioavailability of FEX might be attributed to PIP-mediated inhibition of P-gp drug efflux. Therefore, intake of PIP or dietary supplements containing PIP may potentially enhance the absorption or bioavailability of P-gp substrate drugs in addition to FEX.

Pharmacokinetics, Pharmacodynamics and Population Pharmacokinetic/Pharmacodynamic Modelling of Bilastine, a Second-Generation Antihistamine, in Healthy Japanese Subjects.

BACKGROUND AND OBJECTIVES: Bilastine is a novel second-generation antihistamine for the symptomatic treatment of allergic rhinitis and urticaria. The objective of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of bilastine following single and multiple oral doses in healthy Japanese subjects. The pharmacokinetic and pharmacodynamic profiles were compared with those reported in Caucasian subjects. METHODS: In a single-blind, randomized, placebo-controlled, parallel-group, single- and multiple-ascending dose study, bilastine tablets were administered at single doses of 10, 20, and 50 mg (Part I), and once daily for 14 days at 20 and 50 mg (Part II). RESULTS: After single oral doses, maximum plasma concentrations (C max) were reached at 1.0-1.5 h postdose. Plasma exposure [C max and area under the plasma concentration-time curve (AUC)] increased dose-proportionally at single doses of 10-50 mg. In repeated-dose administration, no remarkable differences were observed between Day 1 and Day 14 for C max or AUC. For inhibitory effects on wheal and flare response, bilastine 20 and 50 mg showed significant inhibition from 1.5 h after administration as compared with placebo, and the significant effect persisted for 24 h after administration. The rates of adverse events (AEs) were comparable between bilastine and placebo in both Part I and Part II. In addition, no dose- or administration period-dependent tendency of increase in rate of AEs or worsening of severity was observed. CONCLUSION: Bilastine exhibits similar single- and multiple-dose pharmacokinetic and pharmacodynamic characteristics in healthy Japanese subjects compared with those observed in Caucasian subjects in previous studies.

Pharmacokinetics, Safety, and Tolerability of Once-Daily Intranasal Fluticasone Furoate and Levocabastine Administered Alone or Simultaneously as fluticasone Furoate/Levocabastine Fixed-Dose Combination.

PURPOSE: The purpose of this study was to investigate potential systemic pharmacokinetic interactions between intranasal fluticasone furoate (FF) and levocabastine (LEVO) when delivered simultaneously via a metered atomizing spray pump. METHODS: This was a randomized, open-label, crossover study. Healthy male and female subjects (n = 30) received once-daily repeat doses of FF/LEVO (100/200 µg) as a fixed-dose combination (FDC), FF (110 µg), or LEVO (200 µg) for 7 days. FF and LEVO plasma pharmacokinetics (0-24 hours) were measured on day 7, with safety assessments over the study duration. RESULTS: Systemic exposure to LEVO was similar when administered as FF/LEVO FDC or LEVO alone. Following FF/LEVO FDC or FF alone, the majority (>99%) of FF concentrations were nonquantifiable, that is, below the lower limit of quantification of 10 pg/mL. All treatments were well tolerated, and adverse event incidence was similar across the treatment groups. CONCLUSIONS: These results suggest that in healthy subjects, for LEVO, there is no pharmacokinetic interaction with FF when delivered as FF/LEVO FDC. As the majority of data were below the assay sensitivity for FF, any potential differences in the bioavailability of FF when delivered alone or as FF/LEVO FDC could not be established. There was no clinically relevant impact on safety/tolerability when FF/LEVO was coadministered.