Rapid and sensitive method for simultaneous determination of citalopram with antihistamines by liquid chromatography.

A highly sensitive liquid chromatographic method with UV detection has been developed for simultaneous determination of citalopram, levocetirizine and loratadine in bulk drug, pharmaceutical formulation and human serum at 230nm employing 80:20 v/v methanol-water as mobile phase with pH3.5, adjusting flow rate of 1.0mL.min-1. Separation was achieved on Shimadzu Shim-pack CLC-ODS (M) 25M column within the linear range of 0.4-12.5, 0.8-25 and 0.8-25µg.mL-1 with R2 >0.998 and detection limit 7.75, 3.35 and 10.26ng.mL-1respectively. ICH guidelines were followed for validation showing 0.22-1.76, 0.06-1.83 and 0.22-2.11% RSD. The recovery of analytes in tablets and serum was found to be in acceptable range. The method was fruitfully employed for the determination of studied analyte in pharmaceutical formulation and human serum.

Developing a High-performance Liquid Chromatography Method for Simultaneous Determination of Loratadine and its Metabolite Desloratadine in Human Plasma.

BACKGROUND: Allergic diseases are considered as the major burden on public health with increased prevalence globally. Histamine H1-receptor antagonists are the foremost commonly used drugs in the treatment of allergic disorders. The target drug in this study, loratadine, belongs to this class of drugs and its biometabolite desloratadine which is also a non-sedating H1 receptor antagonist with anti-histaminic activity being 2.5 to 4 times greater than loratadine. This study aimed to develop and validate a novel isocratic Reversed-phase High-Performance Liquid Chromatography (RP-HPLC) method for rapid and simultaneous separation and determination of loratadine and its metabolite, desloratadine in human plasma. METHODS: The drug extraction method from plasma was based on protein precipitation technique. The separation was carried out on a Thermo Scientific BDS Hypersil C18 column (5µm, 250 x 4.60 mm) in a mobile phase of MeOH: 0.025M KH2PO4 adjusted to pH 3.50 using orthophosphoric acid (85: 15, v/v) at an ambient temperature. The flow rate was maintained at 1 mL/min and maximum absorption was measured using the PDA detector at 248 nm. RESULTS: The retention times of loratadine and desloratadine in plasma samples were recorded to be 4.10 and 5.08 minutes, respectively, indicating a short analysis time. Limits of detection were found to be 1.80 and 1.97 ng/mL for loratadine and desloratadine, respectively, showing a high degree of sensitivity of the method. The method was then validated according to FDA guidelines for the determination of the two analytes in human plasma. CONCLUSION: The results obtained indicate that the proposed method is rapid, sensitive in the nanogram range, accurate, selective, robust and reproducible compared to other reported methods.

Effect of taste masking technology on fast dissolving oral film: dissolution rate and bioavailability.

Fast dissolving oral film is a stamp-style, drug-loaded polymer film with rapid disintegration and dissolution. This new kind of drug delivery system requires effective taste masking technology. Suspension intermediate and liposome intermediate were prepared, respectively, for the formulation of two kinds of fast dissolving oral films with the aim of studying the effect of taste masking technology on the bioavailability of oral films. Loratadine was selected as the model drug. The surface pH of the films was close to neutral, avoiding oral mucosal irritation or side effects. The thickness of a 2 cm × 2 cm suspension oral film containing 10 mg of loratadine was 100 µm. Electron microscope analysis showed that liposomes were spherical before and after re-dissolution, and drugs with obvious bitterness could be masked by the encapsulation of liposomes. Dissolution of the two films was superior to that of the commercial tablets. Rat pharmacokinetic experiments showed that the oral bioavailability of the suspension film was significantly higher than that of the commercial tablets, and the relative bioavailability of the suspension film was 175%. Liposomal film produced a certain amount of improvement in bioavailability, but lower than that of the suspension film.

D-Optimal mixture design optimization of an HPLC method for simultaneous determination of commonly used antihistaminic parent molecules and their active metabolites in human serum and urine.

This study describes a specific, precise, sensitive and accurate method for simultaneous determination of hydroxyzine, loratadine, terfenadine, rupatadine and their main active metabolites cetirizine, desloratadine and fexofenadine, in serum and urine using meclizine as an internal standard. Solid-phase extraction method for sample clean-up and preconcentration of analytes was carried out using Phenomenex Strata-X-C and Strata X polymeric cartridges. Chromatographic analysis was performed on a Phenomenex cyano (150 × 4.6 mm i.d., 5 µm) analytical column. A D-optimal mixture design methodology was used to evaluate the effect of changes in mobile phase compositions on dependent variables and optimization of the response of interest. The mixture design experiments were performed and results were analyzed. The region of ideal mobile phase composition consisting of acetonitrile-methanol-ammonium acetate buffer (40 mm; pH 3.8 adjusted with acetic acid): 18:36:46% v/v/v was identified by a graphical optimization technique using an overlay plot. While using this optimized condition all analytes were baseline resolved in <10 min. Solvent mixtures were delivered at 1.5 mL/min flow rate and analytes peaks were detected at 222 nm. The proposed bioanalytical method was validated according to US Food and Drug Administration guidelines. The proposed method was sensitive with detection limits of 0.06-0.15 µg/mL in serum and urine samples. Relative standard deviation for inter- and intra-day precision data was found to be <7%. The proposed method may find application in the determination of selected antihistaminic drugs in biological fluids.

LC-ESI-MS/MS estimation of loratadine-loaded self-nanoemulsifying drug delivery systems in rat plasma: Pharmacokinetic evaluation and computer simulations by GastroPlus™.

A rapid, sensitive, and accurate bioanalytical method was established for the quantitation and pharmacokinetic investigation of loratadine (LTD) in rat plasma by liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS/MS) using loratadine-d5 as internal standard (ISTD). The analyte and ISTD were extracted by solid-phase extraction and chromatographic separation was achieved on Gemini NX- Reverse Phase C18 (50 × 4.6mm; 5 µ) using mobile phase mixture of 5mM ammonium formate buffer in water (pH 3.5 ± 0.1 with formic acid), and acetonitrile (20:80 v/v), at a flow rate of 0.400 mL/min with injection volume of 10 µL. LTD and ISTD were detected at m/z 383.3 → 337.4 and 388.4 → 337.3 with retention time of 2.62 and 2.59 min, respectively. High sensitivity (1.0 ng/mL) was achieved using small volume of rat plasma (20 µL) and the method was validated over a linearity range of 1.05-405.41 ng/mL with high correlation coefficient (r = 0.9998). The extraction method displayed a mean process efficiency of 63.25 and 65.47% for LTD and ISTD, respectively. The validated method when successfully applied for quantification of LTD in rat plasma revealed enhanced bioavailability of orally administered LTD-loaded self-nanoemulsifying drug delivery system (SNEDDS) (Cmax, 466.65 ± 18.94 ng/mL and AUC0-t 633.00 ± 12.44 ng-h/mL) over LTD-suspension (Cmax, 104.75 ± 2.87 ng/mL and AUC0-t 287.00 ± 9.11 ng-h/mL). The in vivo-in silico prediction by the GastroPlus™ software showed good prediction accuracy for LTD-SNEDDS (fold error < 2). The Loo-Reigelman method (2-compartment) presented best model-fitting indicating adequate in vitro-in vivo correlations. Conclusively, the developed sensitive analytical method displayed enhanced systemic availability of LTD-SNEDDS, and the in vivo in silico approach revealed sufficiently good GI simulation.

HPTLC Method for the Determination of Paracetamol, Pseudoephedrine and Loratidine in Tablets and Human Plasma.

A sensitive, accurate and selective high performance thin layer chromatography (HPTLC) method was developed and validated for the simultaneous determination of paracetamol (PAR), its toxic impurity 4-aminophenol (4-AP), pseudoephedrine HCl (PSH) and loratidine (LOR). The proposed chromatographic method has been developed using HPTLC aluminum plates precoated with silica gel 60 F254 using acetone-hexane-ammonia (4:5:0.1, by volume) as a developing system followed by densitometric measurement at 254 nm for PAR, 4-AP and LOR, while PSH was scanned at 208 nm. System suitability testing parameters were calculated to ascertain the quality performance of the developed chromatographic method. The method was validated with respect to USP guidelines regarding accuracy, precision and specificity. The method was successfully applied for the determination of PAR, PSH and LOR in ATSHI(®) tablets. The three drugs were also determined in plasma by applying the proposed method in the ranges of 0.5-6 µg/band, 1.6-12 µg/band and 0.4-2 µg/band for PAR, PSH and LOR, respectively. The results obtained by the proposed method were compared with those obtained by a reported HPLC method, and there was no significance difference between both methods regarding accuracy and precision.

[Determination of Desloratadine and Its Metabolite 3-OH Desloratadine in Human Plasma by LC-MS/MS].

OBJECTIVE: To develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of desloratadine and its metabolite 3-OH desloratadine in human plasma. METHODS: 24 healthy male volunteers received a single oral dose of 5 mg desloratadine tablets in a randomized crossover bioequivalence study with two preparations of tablets. Serial plasma samples were taken and analyzed by the LC-MS/MS method. The pharmacokinetic parameters of the two preparations were calculated and compared statistically to evaluate their bioequivalence using Winnonlin 6. 3. RESULTS: The calibration curves of desloratadine and 3-OH desloratadine were both linear over the concentration range of 0. 050-6. 0 ng/mL, with intra-batch and inter-batch relative standard deviations less than 15%. The 90% confidence intervals (CIs) of peak concentration (Cmax) area under the curve (AUC)0t and AUC0-∞ of desloratadine and 3-OH desloratadine all resided within the bioequivalence limit 80%-125%. No significant difference in peak time (Tmax) was demonstrated between the two preparations. CONCLUSION: The LC-MS/MS method can be used for simultaneous determination of desloratadine and 3-OH desloratadine in human plasma, which has been successfully applied-to a bioequivalence study.

LC-MS/MS bioanalysis of loratadine (Claritin) in dried blood spot (DBS) samples collected by subjects in a clinical research study.

A high-performance liquid chromatography-tandem mass spectrometric (LC-MS/MS) method has been developed and validated for the quantitative analysis of loratadine, an H1 histamine antagonist, in human dried blood spot (DBS) samples following a single self-administered 10 or 20mg oral dose. The samples were produced by spotting approximately 30µl of whole blood onto PE-226 cards. Two 3-mm discs were cut from the DBS samples and extracted using aqueous methanol containing the internal standard. After transfer and drying of the resulting sample extract, the reconstituted residues were chromatographed using a Waters XSelect C18 column and isocratic elution for MS/MS detection. The possible impact due to hematocrit, volume of blood sample spotted, storage temperature, and humidity, on the accuracy of measured DBS results were investigated. The results showed that only spotted blood volume might have an impact; a small volume (10µl) tended to give a larger negative bias in the measured value than the large volume ones (≥20µl). The current method was fully validated over a dynamic range of 0.200-20.0ng/ml with correlation coefficients (r(2)) for three validation batches equal to or better than 0.990. The intra-day accuracy and precision at the LLOQ were -11.5 to 0.0% bias and 6.4 to 8.9% CV, respectively. For the other QC samples (0.600, 3.00, 10.0 and 15.0ng/ml), the precision ranged from 4.2 to 9.8% CV and from 6.3 to 8.1% CV, respectively, in the intra-day and inter-day evaluations; the accuracy ranged from -1.7 to 10.0% and 2.7 to 5.3% bias, respectively, in the intra-day and inter-day batches. Loratadine is stable in the DBS samples for at least 271 days at ambient temperature in a desiccator, for at least 24h at 60°C and under 80% relative humidity, followed by re-conditioning at ambient temperature in a desiccator. The current methodology has been applied to determine the loratadine levels in DBS samples collected by subjects in a clinical research study to evaluate pharmacokinetic sampling in point-of-care setting.

Simultaneous determination of desloratadine and montelukast sodium using second-derivative synchronous fluorescence spectrometry enhanced by an organized medium with applications to tablets and human plasma.

A rapid, simple, and sensitive second-derivative synchronous fluorimetric method has been developed and validated for the simultaneous analysis of a binary mixture of desloratadine (DSL) and montelukast sodium (MKT) in their co-formulated tablets. The method is based on measurement of the synchronous fluorescence intensities of the two drugs in McIlvaine's buffer, pH 2.3, in the presence of carboxy methyl cellulose sodium (CMC) as a fluorescence enhancer at a constant wavelength difference (Δλ) of 160 nm. The presence of CMC enhanced the synchronous fluorescence intensity of DSL by 216% and that of MKT by 28%. A linear dependence of the concentration on the amplitude of the second derivative synchronous fluorescence spectra was achieved over the ranges of 0.10-2.00 and 0.20-2.00 µg/mL with limits of detection of 0.02 and 0.03, and limits of quantification of 0.05 and 0.10 µg/mL for DSL and MKT, respectively. The proposed method was successfully applied for the determination of the studied compounds in laboratory-prepared mixtures and tablets. The results were in good agreement with those obtained with the comparison method. The high sensitivity attained by the proposed method allowed the determination of MKT in spiked human plasma with average % recovery of 100.11 ± 2.44 (n = 3).

Molecularly imprinted nano particles combined with miniaturized homogenous liquid-liquid extraction for the selective extraction of loratadine in plasma and urine samples followed by high performance liquid chromatography-photo diode array detection.

In this work a molecularly imprinted polymer was developed as a selective sorbent for extraction of loratadine (as a model) in complex matrices followed by miniaturized homogeneous liquid-liquid extraction (MHLLE) for the first time. The molecularly imprinted polymer (MIP) which is based on loratadine as the template was synthesized successfully by precipitation polymerization and was used as a selective sorbent. This technique was applied for preconcentration, sample preparation, and determination of loratadine using high performance liquid chromatography-photo diode array detection (HPLC-PDA). Optimization of various parameters affecting molecular imprinted solid phase extraction (MISPE), such as pH of adsorption, composition and volume of eluent, adsorption and desorption times were investigated. Besides, in the subsequent stage (MHLLE) the type and volume of extraction solvent, sodium hydroxide amount, surfactant concentration, and extraction time were investigated and optimized. Under the optimal condition, maximum enrichment capacity and Langmuir constant were 91mgg(-1) and 0.014Lmg(-1), respectively. Furthermore, enrichment factor and extraction recovery of MIP-MHLLE method were 30 and 90%, respectively. The LOD of the proposed method was 0.2µgL(-1) and a linear dynamic range of 1-1000µgL(-1) was obtained with correlation coefficient of greater than 0.998. The present method was applied for extraction and determination of loratadine in plasma and urine samples in µgL(-1) levels and satisfactory results were achieved (RSD <8% based on three replicate measurements).

Prevalence of desloratadine poor metabolizer phenotype in healthy Jordanian males.

PURPOSE: To study the prevalence of desloratadine slow metabolizer phenotype among a group of healthy Jordanian male volunteers. METHODS: A total of 62 healthy Jordanian male volunteers were included in this study. A single 5 mg desloratadine oral tablet was given and blood samples were taken to determine the desloratadine and 3-hydroxydesloratadine (3-OH-desloratadine) concentrations using a specific liquid chromatography-mass spectrometric method (LC/MS/MS). The determination of pharmacokinetic parameters of all the individuals was determined by using Kinetica® program version 4.1. Poor metabolizers or slow metabolizers of desloratadine were determined as individuals having a 3-OH-desloratadine to desloratadine exposure ratio lower than 10% or a desloratadine half-life ≥ 50 h. RESULTS: Among the 62 volunteers who participated in the study there were only two volunteers who were labeled as desloratadine slow metabolizers, giving a prevalence of 3.2%. The maximum plasma concentrations (C(max)) were similar in the extensive and slow metabolizers groups but a longer time (t(max)) was needed to achieve this concentration in one of the volunteers who was a desloratadine slow metabolizer. CONCLUSION: The incidence of the poor metabolizer phenotype of desloratadine in the Jordanian population studied is similar to certain ethnic groups (e.g. Asian, Caucasians and Hispanic); however, it is lower than other populations (e.g. American Indians and Black).

[Comparative pharmacokinetics of antigrippin-maximum administered in capsules and powder for preparing solutions].

Comparative pharmacokinetics of anti-influenza drug composition Antigrippin-maximum administered in capsules and a powder for preparing solutions has been studied after single administraton in a group of 18 healthy volunteers. Both preparations [manufactured by the Antiviral Research and Production Corporation (St Petersbutg) contain 6 active components, including paracetamol, rimantadine, loratadine, ascorbic acid, calcium gluconate, and rutoside in equal amounts. The concentrations of unchanged paracetamol, rimantadine, and loratadine in the blood plasma were degtermined by HPLC with mass-spectrometric and UV detection. The pharmacokinetic parameters of allindicated active components exhibited no detectable distinctions, except for the time to attaining maximum concentration ofparacetamol and the value of the maximum concentration of loratadine.

Investigation of endogenous blood plasma phospholipids, cholesterol and glycerides that contribute to matrix effects in bioanalysis by liquid chromatography/mass spectrometry.

Matrix effects caused by compounds endogenous to the biological sample are a primary challenge in quantitative LC/MS/MS bioanalysis. Many approaches have been developed to minimize matrix effects such as optimization of sample extraction procedures and use of isotopically labeled internal standards. Unexpected matrix components may still remain undetected, however, because of the selective mass transitions monitored during MS/MS analysis. Glycerophosphocholines are the major phospholipids in plasma that have been widely shown to cause significant matrix effects on electrospray ionization efficiencies for target analytes. The purpose of this work was to investigate potential matrix effects resulting from different endogenous lipid classes, including phospholipids, acylglycerols and cholesterols, in order to establish a library for the relative presence of these components in biological sample extracts obtained by commonly used sample preparation techniques. Thirteen compounds were selected which were representatives of eight phospholipids classes, mono, di, triacylglycerols, cholesterol and cholesterol esters. Post-column infusion experiments were carried out to compare relative ion suppression effects of these compounds. Chlorpheniramine and loratadine were selected as model test analytes. A Concentration Normalized Suppression Factor (%CNSF) was defined to allow comparison of ion suppression effects resulting from different endogenous lipids according to their typical concentrations in human plasma and erythrocytes. A simple LC/MS/MS method was developed to monitor these endogenous components in sample extracts and their extraction recoveries from a plasma pool were compared using protein precipitation, liquid-liquid extraction, supported-liquid extraction, solid phase extraction and Hybrid SPE-precipitation methods. Endogenous lipid components other than GPChos, such as cholesterols and triacylglycerols, may result in significant matrix effects and should be monitored during method development. No single extraction procedure was efficient in removing all of the various lipid components. Use of the results presented here, along with a consideration of analyte chemical structure, the type of matrix and the type of sample preparation procedure, may help a bioanalytical scientist to better anticipate and minimize matrix effects in developing LC/MS/MS-based methods.

Effects of prednisolone on the pharmacokinetics of loratadine after oral and intravenous administration of loratadine in rats.

The present study aims to investigate the effects of prednisolone on the pharmacokinetics of orally and intravenously administered loratadine in rats. A single dose of loratadine was administered orally (4 mg/kg) and intravenously (1 mg/kg) in the presence or absence of prednisolone (0.2 or 0.8 mg/kg). Compared to the oral control group, prednisolone (0.2 mg/kg, p < 0.05; 0.8 mg/kg, p < 0.01) significantly increased the area under the plasma concentrationtime curve of orally administered loratadine by 54.0-96.4%. After oral administration, the peak plasma concentration of loratadine was significantly (0.2 mg/kg, p < 0.05; 0.8 mg/kg, p < 0.01) increased by 20.9-65.3% in the presence of prednisolone. Consequently, the relative bioavailability of loratadine was increased by 1.54- to 1.96-fold. Compared to the intravenous control group, the presence of prednisolone significantly (0.8 mg/kg, p < 0.05) increased the area under the plasma concentration-time curve of loratadine. Prednisolone enhanced the oral bioavailability of loratadine in this study. The enhanced bioavailability of loratadine may be due to inhibition both cytochrome P450 3A4-mediated metabolism and the efflux pump P-glycoprotein (P-gp) in the intestine and/or liver by the presence of prednisolone.

A new open tubular capillary microextraction and sweeping for the analysis of super low concentration of hydrophobic compounds.

A sample pre-concentration method based on the in-line coupling of in-tube solid-phase microextraction and electrophoretic sweeping was developed for the analysis of hydrophobic compounds. The sample pre-concentration and electrophoretic separation processes were simply and sequentially carried out with a (35%-phenyl)-methylpolysiloxane-coated capillary. The developed method was validated and applied to enrich and separate several pharmaceuticals including loratadine, indomethacin, ibuprofen and doxazosin. Several parameters of microextration were investigated such as temperature, pH and eluant. And the concentration of microemulsion that influences separation efficiency and microextraction efficiency were also studied. Central composite design was applied for the optimization of sampling flow rate and sampling time that interact in a very complex way with each other. The precision, sensitivity and recovery of the method were investigated. Under the optimal conditions, the maximum enrichment factors for loratadine, indomethacin, ibuprofen and doxazosin in aqueous solutions are 1355, 571, 523 and 318, respectively. In addition, the developed method was applied to determine loratadine in rabbit blood sample.

A retrospective, open-label analysis of the population pharmacokinetics of a single 10-mg dose of loratadine in healthy white Jordanian male volunteers.

BACKGROUND: Loratadine is a long-acting tricyclic antihistamine with selective peripheral histamine H(1)-receptor antagonist activity. Loratadine 10-mg tablets have been reported to be rapidly absorbed after once-daily administration for 10 days in healthy adult subjects, with a T(max) of 1.3 hours for loratadine and 2.5 hours for its major active metabolite, descarboethoxyloratadine. The t(1/2) in normal adult subjects has been reported to be 8.4 hours (range, 3-20 hours) for loratadine and 28 hours for its metabolite. OBJECTIVE: The aim of this study was to determine the population pharmacokinetics of loratadine after oral administration. METHODS: A retrospective analysis was conducted of prior noncompartmental analysis results from healthy white Jordanian male subjects who participated in 2 pharmacokinetic studies. After a 10-hour overnight fast, a single 10-mg loratadine tablet was administered orally followed by 240 mL of water. Blood samples were collected before dosing and at 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 96 hours after dosing. Mean and population plasma level profiles were examined. The calculated primary and secondary pharmacokinetic parameters were V(d)/F, k(e), absorption rate constant, lag time, distribution rate constant, redistribution rate constant, T(max), and C(max). RESULTS: A total of 72 healthy male subjects with a mean (SD) age of 23 (3.57) years participated in the 2 studies. The analytical method was linear over the concentration range from 0.10 to 20.00 ng/mL (r > 0.999). The lower limit of quantitation was 0.1 ng/mL with 95% accuracy. Precision, expressed as %CV, was 7.44%. Intraday accuracy ranged from 91.9% to 97.2% at high and low quality control levels, respectively. Interday accuracy ranged from 93.57% (%CV, 4.35%) to 98.78% (%CV, 5.78%), respectively. Population ke, t(1/2), absorption rate constant, and absorption t(1/2) were 0.19 hour(-1), 3.65 hours, 1.31 hours(-1), and 0.53 hour, respectively. Distribution rate constant, redistribution rate constant, and lag time were 0.31 hour(-1), 0.02 hour(-1), and 0.32 hour, respectively. The noncompartmental estimate for C(max) was 3.02 ng/mL, which occurred at 1.30 hours, with a t(1/2) of 5 hours and a k(e) of 0.14 hour(-1). No adverse events were recorded during the study. CONCLUSION: The population t(1/2) for loratadine was 3.65 hours in this group of healthy white Jordanian male volunteers, shorter than that observed in previous research.

LC-MS-ESI for the determination of loratadine and descarboethoxyloratadine in human plasma.

A rapid, sensitive, and accurate liquid chromatography-tandem mass spectrometry assay for simultaneous determination of loratadine (L) and its active metabolite, descarboethoxyloratadine (DCL), in human plasma is developed using desipramine as internal standard (IS). The analytes and IS are separated on a Betabasic cyano (100 mm x 2.1 mm, 5 microm) column and detected by tandem mass spectrometry with a turbo ion spray interface operating in positive ion and multiple reaction monitoring acquisition mode. The total chromatographic runtime is 3.0 min with retention time for L, DCL, and IS at 0.82, 1.58, and 1.97 min, respectively. The method is validated over a dynamic linear range of 0.05-15.00 ng/mL for both L and DCL with a correlation coefficient of r(2) 0.9984 and 0.9979, respectively. The intra-batch and inter-batch precision (%CV) across five levels (LLOQ, LQC, MQC, HQC, and ULOQ) is less than 9%. The method is successfully applied to a bioequivalence study of 10 mg loratadine tablet formulation in 28 healthy Indian male subjects under fasted condition.

Simultaneous determination of rupatadine and its metabolite desloratadine in human plasma by a sensitive LC-MS/MS method: application to the pharmacokinetic study in healthy Chinese volunteers.

A sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed for simultaneous determination of rupatadine and its metabolite desloratadine in human plasma. After the addition of diphenhydramine, the internal standard (IS), plasma samples were extracted with a mixture of methyl tert-butyl ether and n-hexane (1:1, v/v). The analysis was performed on a Ultimate AQ-C18 (4.6mm x 100mm, 5microm) column using a mobile phase consisting of a 80/20 mixture of methanol/water containing 0.0005% formic acid pumped at 0.3mlmin(-1). The analytes and the IS were detected in positive ionization mode and monitoring their precursor-->product ion combinations of m/z 416-->309, 311-->259, and 256-->167, respectively, in multiple reaction monitoring mode. The linear ranges of the assay were 0.1-50 and 0.1-20ngml(-1) for rupatadine and desloratadine, respectively. The lower limits of reliable quantification for both rupatadine and desloratadine were 0.1ngml(-1), which offered high sensitivity and selectivity. The within- and between-run precision was less than 7.2%. The accuracy ranged from -9.2% to +6.4% and -7.2% to +7.2% for rupatadine and desloratadine in quality control samples at three levels, respectively. The method has been successfully applied to a pharmacokinetic study of rupatadine and its major metabolite after oral administration of 10, 20 and 40mg rupatadine tablets to healthy Chinese volunteers.

Pharmacokinetic and safety profile of rupatadine when coadministered with azithromycin at steady-state levels: a randomized, open-label, two-way, crossover, Phase I study.

BACKGROUND: Rupatadine is an oral active antihistamine and platelet-activating factor antagonist indicated for the management of allergic rhinitis and chronic urticaria in Europe. OBJECTIVE: The purpose of this study was to describe the effect of the concomitant administration of azithromycin and rupatadine on the pharmacokinetics of rupatadine and its metabolites after repeated doses. METHODS: This was a multiple-dose, randomized, open-label, 2-way, crossover, Phase I study in which healthy male and female volunteers received rupatadine 10 mg once a day for 6 days either alone or with azithromycin 500 mg on day 2 and 250 mg from day 3 to day 6. Treatments were administered after a fasting period of 10 hours with 240 mL of water, and fasting conditions were kept until 3 hours postmedication. A washout period of at least 21 days between the 2 active periods was observed. Blood samples were collected and plasma concentrations of rupatadine and its metabolites desloratadine and 3-hydroxydesloratadine were determined by liquid chromatography tandem mass spectrometry. Tolerability was based on the recording of adverse events (AEs), physical examination, electrocardiograms, and laboratory screen controls at baseline and the final study visit. RESULTS: Twenty-four healthy volunteers (15 males, 9 females; mean [SD] age, 25.67 [5.58] years; weight, 65.96 [8.57] kg) completed the study. Except for maximum observed concentration during a dosing interval (Cmax,ss) of 3-hydroxydesloratadine, on average, there were no statistically significant differences in mean plasma concentrations in any of the main pharmacokinetic parameters of rupatadine, desloratadine, and 3-hydroxydesloratadine when administered in combination with azithromycin or alone. The Cmax,ss ratio was 111 (90% CI, 91-136) and area under the plasma concentration-time curve during a dosing interval (AUC0-tau) ratio had a value of 103 (90% CI, 91-117). The corresponding ratios for the rupatadine metabolites were 109 (90% CI, 100-120) for Cmax,ss and 103 (90% CI, 96-110) for AUC0-tau for desloratadine and 109 (90% CI, 103-115) for Cmax,ss and 104 (90% CI, 100-108) for AUC0-tau for 3-hydroxydesloratadine. Point estimates for Cmax,ss ratios using paired data were 111% for rupatadine, 109% for desloratadine, and 109% for 3-hydroxydesloratadine. The 90% CIs were included in the interval 80% to 125% for desloratadine and 3-hydroxydesloratadine, whereas 90% CI for rupatadine was shifted to the right of the interval used for comparing bioavailability of the drugs. A total of 5 subjects reported 9 AEs; 5 of these were thought to be related to the drug administration and all were categorized as mild or moderate. The reported AEs were somnolence (1/24 in the rupatadine group and 1/24 in the rupatadine plus azithromycin group), diarrhea (1/24 in the rupatadine plus azithromycin group), and gastric discomfort (2/24 in the rupatadine plus azithromycin group). Four AEs were considered not to be related (2 episodes of headache, 1 anemia, 1 cheilitis). All were resolved spontaneously. No serious AEs were reported. CONCLUSIONS: The results of this study in these healthy volunteers found no significant differences in pharmacokinetic parameters other than Cmax,ss of 3-hydroxydesloratadine between rupatadine 10 mg administered alone or with azithromycin 500 mg on day 2 and 250 mg from day 3 to day 6. The administration of rupatadine compared with rupatadine plus azithromycin met the regulatory definition of bioequivalence in terms of exposure and rate parameters; however, Cmax,ss of rupatadine was outside the conventional confidence interval.

Antihistaminic effects of rupatadine and PKPD modelling.

Rupatadine is a new oral antihistaminic agent used for the management of allergic inflammatory conditions, such as rhinitis and chronic urticaria. The aim of the present study was to develop a population pharmacokinetic/pharmacodynamic (PKPD) model for the description of the effect of rupatadine and one of its active metabolites, desloratadine, on the histamine-induced flare reaction and to predict the response to treatment after repeated administrations of rupatadine. Both rupatadine and desloratadine were characterized by two-compartmental kinetics. For both compounds, covariates sex and weight had a significant effect on several parameters. The pharmacodynamics were described by an indirect model for the inhibition of flare formation that accounted for the contribution of both rupatadine and desloratadine to the antihistaminic effect. The final PKPD model adequately described the original data. The simulated response after repeated once-daily administrations of 10 mg rupatadine showed a significant and maintained antihistaminic effect over time, between two consecutive dosing intervals.