Applying Biopharmaceutical Classification System criteria to predict the potential effect of Cremophor® RH 40 on fexofenadine bioavailability at higher doses.

Aim: To study the impact of various permeability enhancers on fexofenadine bioavailability. Furthermore, to predict the potential effect of Cremophor® RH 40 on fexofenadine pharmacokinetics at higher doses using Biopharmaceutical Classification System criteria. Experimental methods: The effect of the dose increase (60-360 mg) on the dissolution and permeability behavior of fexofenadine-Cremophor RH 40 formulations was studied in humans. The Biopharmaceutical Classification System criteria of the drug was determined. Results & conclusion: Cremophor RH 40 improved the dissolution and bioavailability of fexofenadine. The pharmacokinetics increased linearly with the dose increase. Absorption number (An) was significantly increased after addition of Cremophor RH 40 in comparison to an unprocessed drug. Similar An values were observed throughout the same dose range. The dose number (D0) values were <1 whereas, all the dissolution number (Dn) values were >1 at the same dose level.

Effect of pineapple juice on the pharmacokinetics of celecoxib and montelukast in humans.

Aim: To study the influence of pineapple juice on the pharmacokinetics of celecoxib and montelukast in humans. Experimental methods: The research comprised two separate arms. Each arm was randomized, two-crossover periods separated by a 2-week washout period. Subjects received a single dose of celecoxib or montelukast after pretreatment with either water or pineapple juice for 4 days before the study beginning. Results & conclusion: Pineapple juice enhanced the systemic exposure of both drugs without any noticeable adverse effects. For celecoxib, Cmax and AUC0-∞ were increased significantly by 40 and 60%, respectively. Cl/F was decreased by 45% without affecting its t1/2. For montelukast, Cmax and AUC0-∞ were significantly increased by 21 and 48%, respectively, along with 25% decrease in clearance and 13% increase in t1/2.

Validation of a liquid chromatography method for the simultaneous determination of several nonsteroidal anti-inflammatory drugs in human plasma for therapeutic drug monitoring.

BACKGROUND: Diflunisal, naproxen, ketoprofen, etodolac, mefenamic acid, rofecoxib, and celecoxib are nonsteroidal anti-inflammatory drugs, which have analgesics, antipyretics, and anti-inflammatory activities. The aim of this work was to develop and validate a simple assay that could be implemented in most laboratories for the purpose of clinical and toxicological screening, pharmacokinetic studies, and in therapeutic drug monitoring. METHODS: A new and simple high-performance liquid chromatography assay was developed and validated for the simultaneous determination of the above-mentioned drugs in small samples of human plasma (0.25 mL). After protein precipitation with acetonitrile, satisfactory separation was achieved on a Hypersil BDS C18 column (250 × 4.6 mm, 5 m) using a mobile phase comprising 20 mmol/L ammonium phosphate buffer (pH = 3) and acetonitrile at a ratio of 35:65, vol/vol; the elution was isocratic at ambient temperature with a flow rate of 1 mL/min. The UV detector was set at 265 nm. RESULTS: The method was validated according to the recommendations of the Food and Drug Administration, including assessment of linearity, selectivity, precision, accuracy, and stability in human plasma. The use of betamethasone dipropionate as internal standard improved accuracy and precision. Response was linear over the calibration ranges. The limits of quantification were 0.2 g/mL for diflunisal and naproxen, 0.05 g/mL for ketoprofen, 0.1 g/mL for etodolac and mefenamic acid, and 0.02 g/mL for celecoxib and rofecoxib. The percent coefficient of variation for the QCs and the limit of quantification were within 10%, and the accuracies ranged between 96% and 106% for all the analytes. Mean drug recovery values were in the range of 95%-98% and 90.0% for all analytes and internal standard, respectively. All the analytes were stable in frozen plasma over a period of 3 months at -80°C. CONCLUSIONS: This assay method was valid within a wide range of plasma concentrations and may be proposed as a suitable method for pharmacokinetic studies, therapeutic drug monitoring implementation, and routine clinical applications and suitable for special populations of patients who receive a combination of these drugs.

Pharmacokinetics and comparative bioavailability of domperidone suspension and tablet formulations in healthy adult subjects.

Domperidone is a dopamine antagonist with a unique gastroprokinetic and antiemetic properties. This study was conducted to evaluate the pharmacokinetics (PKs) and comparative bioavailability of suspension (reference) and tablet (test) formulations of domperidone. In vivo study was established according to a single-center, randomized, single-dose, laboratory-blinded, two way, cross-over study with a washout period of 1 week. Under fasting conditions, 26 healthy Egyptian male volunteers were randomly allocated to receive a single oral dose of either 20 mL domperidone or two tablets (each contains 10 mg domperidone) of marketed suspension and tablet formulations. Plasma samples were obtained over a 24-hour interval and analyzed for domperidone by reversed phase liquid chromatography with fluorescence detection. The 90% confidence intervals for the ratio of log transformed values of Cmax , AUC0-t , and AUCt-∞ of the two treatments were within the acceptable range (0.8-1.25) for bioequivalence. From PK perspectives, in this small study in healthy Egyptian adult male volunteers, a single 20 mg dose of the tablet formulation was bioequivalent to a single 20 mg dose of the suspension formulation based on the US FDA's regulatory definition. No adverse events occurred or were reported during the study and both formulations were well tolerated.

Pharmacokinetics and comparative bioavailability of allopurinol formulations in healthy subjects.

Allopurinol is the most commonly used urate-lowering therapy in gout. This study was undertaken to evaluate the pharmacokinetics and relative bioavailability of two brands of allopurinol tablets. The in vivo study was established according to a single-center, randomized, single-dose, laboratory-blinded, Two Way, Cross-Over Study with a washout period of 1 week. Under fasting conditions, 24 healthy male volunteers were randomly allocated to receive a single oral dose (200 mg) of either test and reference formulations. Plasma samples were obtained over a 6-hour interval and analyzed for allopurinol by reversed phase liquid chromatography with ultraviolet detection. The 90% confidence intervals for the ratio of log transformed values of Cmax , AUC0-t , and AUCt-∞ of the two treatments were within the acceptable range (0.8-1.25) for bioequivalence. From PK perspectives, the two allopurinol formulations were considered bioequivalent, based on the rate and extent of absorption. No adverse events occurred or were reported after a single 200-mg allopurinol and both formulations were well tolerated.

Piroxicam immediate release formulations: A fasting randomized open-label crossover bioequivalence study in healthy volunteers.

Piroxicam is a NSAID with analgesic and antipyretic properties, used for the treatment of rheumatoid diseases. The aim of this study was to evaluate the bioequivalence of two brands of piroxicam capsules (20 mg) in 24 Egyptian volunteers. The in vivo study was established according to a single-center, randomized, single-dose, laboratory-blinded, 2-period, 2-sequence, crossover study with a washout period of 3 weeks. Under fasting conditions, 24 healthy male volunteers were randomly selected to receive a single oral dose of one capsule (20 mg) of either test or reference product. Plasma samples were obtained over a 144-hour interval and analyzed for piroxicam by HPLC with UV detection. The pharmacokinetic parameters Cmax , tmax , AUC0-t , AUC0-∞ , Vd /F, Cl/F, and t1/2 were determined from plasma concentration-time profiles. The 90% confidence intervals for the ratio of log transformed values of Cmax , AUC0-t , and AUC0-∞ of the two treatments were within the acceptable range (0.8-1.25) for bioequivalence. From PK perspectives, the two piroxicam formulations were considered bioequivalent, based on the rate and extent of absorption. No adverse events occurred or were reported after a single 20-mg piroxicam and both formulations were well-tolerated.

A new and simple HPLC method for determination of etamsylate in human plasma and its application to pharmacokinetic study in healthy adult male volunteers.

A new and simple HPLC assay method was developed and validated for the determination of etamsylate in human plasma. After protein precipitation with 6% perchloric acid, satisfactory separation was achieved on a HyPURITY C18 column (250 mm × 4.6 mm, 5 µm) using a mobile phase comprising 20 mM sodium dihydrogen phosphate-2 hydrate (pH was adjusted to 3.5 by phosphoric acid) and acetonitrile at a ratio of 95:5 v/v. The elution was isocratic at ambient temperature with a flow rate of 0.75 ml/min. Allopurinol was used as internal standard. The calibration curve was linear over the range from 0.25 to 20 µg/ml (r (2) = 0.999). The limit of quantification for etamsylate in plasma was 0.25 µg/ml. The within day coefficient of variance (%CV) ranged from 3.9% to 10.2%, whereas the between-day %CV ranged from 3.1% to 8.7%. The assay method has been successfully used to estimate the pharmacokinetics of etamsylate after oral administration of a 500 mg tablet under fasting conditions to 24 healthy Egyptian human male volunteers. Various pharmacokinetic parameters including AUC0- t , AUC0-∞, C max, T max, t 1/2, MRT, Cl/F, and Vd/F were determined from plasma concentration-time profile of etamsylate.

Dose Linearity of Glimepiride in Healthy Human Egyptian Volunteers.

The present study was adopted to evaluate the pharmacokinetics and dose linearity of glimepiride after administration of single oral doses of 1-6 mg glimepiride in an open-label, five-way crossover study. Twenty-four healthy male Egyptian volunteers were given 1, 2, 3, 4, and 6 mg of glimepiride on five occasions, and blood samples were collected over 24 hours. Plasma glimepiride concentrations were assayed by a validated reversed-phase high-performance liquid chromatography method with UV detection and the data were evaluated by non-compartmental methods to determine pharmacokinetic parameters. The mean elimination half-lives (t1/2 ) did not vary with the dose. The peak plasma levels (Cmax ) and area under the plasma level versus time curve (AUC) data showed dose-proportional response. The time to peak plasma concentration (tmax ), mean residence time, oral clearance (Cl/F) and apparent volume of distribution (Vd /F) were all similar regardless of the administered dose (P > .05). The 90% confidence intervals of the ratios of dose-adjusted log transformed values of Cmax , AUC0-t , AUC0-∞ , t1/2 , and tmax fell within the range of 80-125%. These findings suggest that glimepiride disposition is linear over the dose range studied healthy human Egyptian volunteers.