Patient-friendly extemporaneous formulation of bisoprolol: application to stability and bioavailability studies.

Community and hospital pharmacists always face the challenge to prepare oral liquid extemporaneous formulations to fit the needs of a specific patient population when commercial forms or the required strength is unavailable. This study was performed to prepare a stable patient-friendly oral liquid extemporaneous formulation of bisoprolol. Eight different extemporaneous formulations were prepared using various suspending agent(s). The in vitro dissolution of all extemporaneous formulations was examined. A comprehensive accelerated stability study was carried out to evaluate the adequate beyond-use date of the most optimized extemporaneous formulation. A validated ultra-performance liquid chromatography method was used for the analysis and quantification of bisoprolol in the accelerated stability and bioavailability studies. A group of eight healthy volunteers was enrolled in a two-way cross-over experimental design to study the bioavailability of the most optimized extemporaneous formulation. The pharmacokinetic parameters of bisoprolol were estimated. Extemporaneous suspension containing 0.5% w/v xanthan gum was easily prepared with a simple, natural, safe, sugar-free excipients. It achieved the best dissolution behavior among other extemporaneous suspensions. It was an easily pourable viscous suspension with no sedimentation. At least 98% of the initial concentration of bisoprolol remained throughout the 6-month study period in the selected suspension regardless of the storage conditions. There was no perceptible change in color, odor, or taste, and no noticeable microbial growth was observed in any sample. The selected formulation was bioequivalent to the commercial tablet in terms of the rate and extent of absorption. This research may be of great help during development of appropriate extemporaneous formulation of bisoprolol fumarate. The simple preparation method could be utilized to draw up a standard operating procedure (SOP) easy to use by different types of pharmacy settings.

Towards novel nano-based vaccine platforms for SARS-CoV-2 and its variants of concern: Advances, challenges and limitations.

Vaccination is the most effective tool available for fighting the spread of COVID-19. Recently, emerging variants of SARS-CoV-2 have led to growing concerns about increased transmissibility and decreased vaccine effectiveness. Currently, many vaccines are approved for emergency use and more are under development. This review highlights the ongoing advances in the design and development of different nano-based vaccine platforms. The challenges, limitations, and ethical consideration imposed by these nanocarriers are also discussed. Further, the effectiveness of the leading vaccine candidates against all SARS-CoV-2 variants of concern are highlighted. The review also focuses on the possibility of using an alternative non-invasive routes of vaccine administration using micro and nanotechnologies to enhance vaccination compliance and coverage.

Regen-Cov and Covid-19, Update on the Drug Profile and Fda Status: A Mini-Review and Bibliometric Study.

COVID-19 is caused by coronavirus (SARS-CoV-2) is a worldwide health crisis. This severe acute respiratory syndrome was declared an outbreak after the first case was reported in Wuhan, the capital city of Hubei Province in China. On March 11th, 2020, the World Health Organization (WHO) declared it as a pandemic. The pharmaceutical treatment of COVID-19 has garnered significant critical attention due to the unavailability of medications to treat COVID-19. Recently, researchers have shown an increased interest in the monoclonal antibody drugs to treat COVID-19 especially REGEN-COV (casirivimab and imde-vimab). This review aims to highlight the relation between the drug and COVID-19 and the recently updated information on the monoclonal antibody REGEN-COV from the U.S. Food and Drug Administration and other authorities. It is also designed to focus on the bibliometric data of REGEN-COV for the last three years (2020, 2021, and 2021) in PubMed and Google Scholar.

Development of Cyclodextrin-Functionalized Transethoniosomes of 6-Gingerol: Statistical Optimization, In Vitro Characterization and Assessment of Cytotoxic and Anti-Inflammatory Effects.

The poor solubility and stability of 6-gingerol (6-G) could hamper its clinical applications. The aim of the current study was to develop a novel ultra-deformable cyclodextrin-functionalized transethoniosomes (CD-TENs) as a promising delivery system for 6-G. Transethoniosomes (TENs) are flexible niosomes (NVs) due to their content of ethanol and edge activators (EAs). CD-functionalized nanoparticles could improve drug solubility and stability compared to the corresponding nanovesicles. 6-G-loaded ethoniosomes (ENs) were formulated by the ethanol injection technique in the presence and absence of EA and CD to explore the impact of the studied independent variables on entrapment efficiency (EE%) and % 6-G released after 24 h (Q24h). According to the desirability criteria, F8 (CD-functionalized transethoniosomal formula) was selected as the optimized formulation. F8 demonstrated higher EE%, permeation, deformability and stability than the corresponding TENs, ENs and NVs. Additionally, F8 showed higher cytotoxic and anti-inflammatory activity than pure 6-G. The synergism between complexation with CD and novel ultra-deformable nanovesicles (TENs) in the form of CD-TENs can be a promising drug delivery carrier for 6-G.

Logic of Selecting Suitable Dissolution Parameters in New Drug Formulations Based on A BCS Approach.

Since the biopharmaceutical quality of generic drug formulations depends on the quality of the reference products and also information about the in-vitro release performance of drugs under different conditions is scarce in the literature, a dissolution study of four reference tablets was performed. Each drug was representative of one Class of the Biopharmaceutical Classification System. The in-vitro release performance of propranolol-HCl, carbamazepine, ranitidine-HCl, and metronidazole was evaluated using a USP basket and paddle apparatus at different agitation rates (50, 75, and 100 rpm) with two doses of each drug. In all experiments, pharmacopeial dissolution media was used and the samples were taken with automatic equipment at specific times up to 60 min, except for propranolol-HCl, for which the samples were taken up to 30 min. The dissolution profiles were compared by model-independent, model-dependent, and ANOVA-based comparisons. The three methods of data comparison showed that low vs. high doses were significantly different (P < 0.05), which may influence cases in which biowaivers of propranolol-HCl and ranitidine-HCl are requested. Additionally, the results showed that despite different hydrodynamic environments produced by the basket and paddle apparatus, under certain conditions, both types of equipment generated comparable in-vitro results. Variables such as the dose, agitation rate, and type of dissolution apparatus are important factors to consider in designing dissolution tests for drug products. This information can be used to test a new dosage when there is no pharmacopeial method available to perform a dissolution study. Further researches on the in-vitro release performance of reference drug products are required.

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.

Hydrogel-based matrices for controlled drug delivery of etamsylate: Prediction of in-vivo plasma profiles.

OBJECTIVES: To design oral controlled release (CR) hydrogel matrix tablets of etamsylate using various hydrophilic polymers. Additionally, to predict plasma concentration-time profiles of etamsylate released from different CR matrices. METHODS: Characterization of the in-vitro release rate was performed by various model dependent and model independent approaches. A simple numerical convolution strategy was adopted to predict the in-vivo performance of all matrices from their in-vitro percent released data. The statistical analysis was conducted utilizing a student t-test and ANOVA. RESULTS: The release of etamsylate from all matrices showed a deviation from Fickian transport mechanism except; F2 followed Case II release whereas, F9 and F11 obeyed Fickian diffusion. CR hydrogel based-matrices (F4 and F11) demonstrated the maximum drug retardation and satisfied the USP release limits. Concentration-time profiles of etamsylate were predicted successfully from the in-vitro release data of all prepared matrices. Pharmacokinetic parameters of etamsylate CR hydrogel matrices were significantly changed with comparison to reference product except F1. CONCLUSION: The designed (F2-F11) matrices had the capability to extend the plasma level of etamsylate for an adequate time. However, F4 and F11 were considered the most ideal formulations for once daily application of etamsylate. The prediction of in-vivo pharmacokinetics of etamsylate was very useful to assess the rationality of the designed matrices for the practical application in humans.

Tablet splitting: is it worthwhile? Analysis of drug content and weight uniformity for half tablets of 16 commonly used medications in the outpatient setting.

BACKGROUND: Tablet splitting is a well-established medical practice in clinical settings for multiple reasons, including cost savings and ease of swallowing. However, it does not necessarily result in weight-uniform half tablets. OBJECTIVES: To (a) investigate the effect of tablet characteristics on weight and content uniformity of half tablets, resulting from splitting 16 commonly used medications in the outpatient setting and (b) provide recommendations for safe tablet-splitting prescribing practices. METHODS: Ten random tablets from each of the selected medications were weighed and split by 5 volunteers (2 men and 3 women aged 25-44 years) using a knife. The selected medications were mirtazapine 30 mg, bromazepam 3 mg, oxcarbazepin 150 mg, sertraline 50 mg, carvedilol 25 mg, bisoprolol fumarate 10 mg, losartan 50 mg, digoxin 0.25 mg, amiodarone HCl 200 mg, metformin HCl 1,000 mg, glimepiride 4 mg, montelukast 10 mg, ibuprofen 600 mg, celecoxib 200 mg, meloxicam 15 mg, and sildenafil citrate 50 mg. The resulting half tablets were evaluated for weight and drug content uniformity in accordance with proxy United States Pharmacopeia (USP) specification (95%-105% for digoxin and 90%-110% for the other 15 drugs). Weight and drug content uniformity were assessed by comparing weight or drug content of the half tablets with one-half of the mean weight or drug content for all whole tablets in the sample. The percentages by which the weight and drug content of each whole tablet or half tablet differed from sample mean values were calculated. Other relevant physical characteristics of the 16 products were measured. RESULTS: A total of 52 of 320 half tablets (16.2%) and 48 of 320 half tablets (15.0%) fell outside of the proxy USP specification for weight and drug content, respectively. Bromazepam, carvedilol, bisoprolol, losartan, digoxin, and meloxicam half tablets failed the weight and content uniformity test; however, the half tablets for the rest of the medications passed the test. Mean percent weight loss after splitting was less than 1.5% for all drugs. Bromazepam, carvedilol, and digoxin showed the highest powdering loss during the tablet-splitting process. CONCLUSIONS: Tablet splitting could be safer and easier when drug- and patient-specific criteria have been met. Tablet size, shape, and hardness may also play a role in the decision to split a tablet or not. Tablets containing drugs with a wide therapeutic index and long half-life might be more suitable candidates for division. Dose variation exceeded a proxy USP specification for more than one-third of sampled half tablets of bromazepam, carvedilol, bisoprolol, and digoxin. Drug content variation in half tablets appeared to be attributed to weight variation due to fragment or powder loss during the splitting process.

Modeling of the pharmacokinetic/pharmacodynamic interaction between irbesartan and hydrochlorothiazide in normotensive subjects.

PURPOSE: To investigate the pharmacokinetic/pharmacodynamic (PK/PD) interaction between irbesartan (IRB) and hydrochlorothiazide (HCT) in normotensive subjects. METHODS: A three-way crossover study was used. Serial drug concentrations and drug effects, including systolic and diastolic blood pressure and heart rate were monitored after administration of irbesartan and hydrochlorothiazide alone and in combination. The data were fitted to a PK/PD model and the parameters for irbesartan and hydrochlorothiazide when administered alone and in combination were compared. RESULTS: The plasma profiles for irbesartan and hydrochlorothiazide followed the two-compartment model after a single dose. The PK parameters of irbesartan were not affected by hydrochlorothiazide; however irbesartan decreased the hydrochlorothiazide AUC by 25% and increased its clearance by 25%. There were no significant changes in heart rate after each drug alone or in combination. Irbesartan plus hydrochlorothiazide had a greater blood pressure lowering effect compared with irbesartan alone, despite the unchanged irbesartan PK. The relationship between irbesartan plasma concentration and its effects plotted in chronological order showed anticlockwise hysteresis. The PD parameter estimates for the effect of irbesartan on systolic blood pressure, when administered with hydrochlorothiazide were significantly different from those when irbesartan was administered alone. This was manifested by a 25% increase in Emax , and a 40% decrease in EC50 , suggesting a synergistic blood pressure lowering effect for the combination. While parameter estimates for the effect of irbesartan on diastolic blood pressure were changed by hydrochlorothiazide, the differences were only significant for EC50 . CONCLUSION: A limited potential for clinically significant interactions between irbesartan and hydrochlorothiazide at the given doses were observed; therefore, no dosage adjustments were recommended for either drug when used together. (ClinicalTrials.gov Identifier NCT01858610)

Single-dose linezolid pharmacokinetics in critically ill patients with impaired renal function especially chronic hemodialysis patients.

BACKGROUND AND OBJECTIVE: Renal failure patients were treated with linezolid (LZD) for proven or suspected infections by multi-resistant Gram-positive cocci. The aim of this study was to determine if dose adjustment of LZD is needed as a function of renal impairment or not, especially that a significant component of LZD is eliminated unchanged in urine. METHODS: The single dose pharmacokinetics of LZD was investigated. Eighteen non-infected male subjects with various degrees of renal impairment ranged from normal to severe chronic impairment were enrolled, including end-stage renal disease (ESRD) patients maintained on hemodialysis (HD). LZD was administered as a single oral 600 mg dose, and blood samples were drawn at different times and analysed by a validated HPLC assay method. Plasma profiles were evaluated by non-compartmental and compartmental approaches. RESULTS AND DISCUSSION: A similar rate and extent of LZD absorption and elimination and comparable body exposure was observed in both healthy subjects and acute renal failure patients. The extent of LZD exposure was significantly increased by 3-fold in ESRD patients in their off-dialysis day. Furthermore, the t1/2 and MRT values were significantly increased by ~5- and 3-fold, respectively. The Vd /F values of LZD did not change with renal function. A significant decrease in CL/F by ~3-fold was observed in ESRD patients in their off-dialysis day however, CL/F was significantly increased by ~4-fold during HD. Approximately half of the administered LZD dose was removed during the HD session in these selected cohorts of ESRD patients. LZD was generally well tolerated. CONCLUSIONS: The dose of LZD did not need to be adjusted for patients with acute renal dysfunction or ESRD on HD. One of the twice-daily doses should be administered after the dialysis session because almost half of the LZD dose was substantially removed by HD. During the first three dialysis sessions of the treatment course, to avoid potentially ineffective therapy, a supplemental dose of LZD might be given if necessary or the dose of LZD should be administered 4 h before the beginning of the HD session. This was to keep LZD levels above the MIC for the organism causing the infection being treated.

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.

In vitro dissolution and in vivo bioequivalence evaluation of two brands of trimetazidine tablets.

Trimetazidine is an effective anti-anginal agent and anti-ischaemic effect. The objective of this study was to assess the in vitro dissolution and to evaluate the bioavailability of two brands of trimetazidine dihydrochloride tablets. Prior to the in vivo PKs study, an in vitro comparative dissolution test was performed for 2 oral brands of trimetazidine dihydrochloride tablets (20 mg). In vivo PKs study was evaluated in 24 healthy male volunteers after a single dose oral administration in an open, randomized, two-way crossover study with a washout period of 1 week. After an overnight fast, human volunteers were randomly allocated to receive a single dose of either test or reference product. Blood samples were collected over a 24-hour period following drug administration and plasma was analyzed for trimetazidine concentrations using a validated high-performance liquid chromatography assay method. The PK parameters Cmax , AUC0-t , AUC0-∞ , tmax , 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 AUCt-∞ of the test product over those of reference were within the acceptable range (0.8-1.25) for bioequivalence. As a result, the 2 trimetazidine formulations are considered bioequivalent and thus could be prescribed interchangeably in the medical practice based on its PK effect and biopharmaceutical performance.

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.

Simultaneous quantification of linezolid, tinidazole, norfloxacin, moxifloxacin, levofloxacin, and gatifloxacin in human plasma for therapeutic drug monitoring and pharmacokinetic studies in human volunteers.

BACKGROUND: Linezolid may be administered in combination with norfloxacin, gatifloxacin, levofloxacin, moxifloxacin, and tinidazole for the treatment of various infections, such as urinary and respiratory tract infections, to improve the efficacy of the treatment or to reduce the duration of therapy. Knowledge of the antibiotic plasma concentrations combined with bacterial susceptibility evaluated in terms of minimum inhibitory concentration would optimize treatment efficacy while limiting the risk of dose-related adverse effects and avoiding suboptimal concentrations. METHODS: A new high-performance liquid chromatography assay method was developed and validated for determination of the above-mentioned drugs in small samples of human plasma. After protein precipitation with acetonitrile:methanol (1:1, vol/vol), satisfactory separation was achieved on a Hypersil BDS C18 column (250 × 4.6 mm, 5 µm) using a mobile phase comprising 20 mM sodium dihydrogen phosphate-2 hydrate (pH = 3.2) and acetonitrile at a ratio of 75:25, vol/vol; the elution was isocratic at ambient temperature with a flow rate of 1.5 mL/min. The ultraviolet detector was set at 260 nm. The validated method was applied to assay real plasma samples used for pharmacokinetic studies and therapeutic drug monitoring of the selected drugs. RESULTS: The assay method described was found to be rapid, sensitive, reproducible, precise, and accurate. Linearity was demonstrated over the concentration ranges as follows: 0.1-30 µg/mL for linezolid and tinidazole; 0.05-5 µg/mL for norfloxacin; and 0.1-10 µg/mL for moxifloxacin, levofloxacin, and gatifloxacin (mean r = 0.9999, n = 12). The observed within- and between-day assay precisions were within 12.5%, whereas accuracy ranged between 92.0% and 112% for all the analytes. The lower limit of quantification was 0.1 µg/mL for all the analytes except norfloxacin which was 0.05 µg/mL. 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, especially for some populations of patients who receive a combination of these drugs.

Pharmacokinetic interactions of valsartan and hydrochlorothiazide: an open-label, randomized, 4-period crossover study in healthy Egyptian male volunteers.

BACKGROUND: Co-administration of valsartan (VAL) and hydrochlorothiazide (HCT) has been used to regulate blood pressure. Compliance with a multiple medication regimen can be difficult for some patients; therefore, a combination of VAL + HCT tablets may be a suitable alternative. OBJECTIVE: This study was conducted to compare the rate and extent of absorption of VAL and HCT after oral administration as a fixed-dose combination (FDC) tablet and concomitant administration of the individual drugs under fasting conditions in healthy Egyptian subjects. The study was extended to investigate any potential interaction between VAL and HCT. METHODS: This study was conducted as an open-label, randomized study with 2 parts (parts I and II), with each part consisting of 4 single-dose treatment periods with a crossover design and 2-week washout periods. Blood samples were collected up to 48 hours postdose, and plasma was analyzed for VAL and HCT concentrations by using HPLC. The pharmacokinetic properties of each drug after co-administration of VAL and HCT were compared with those of each drug administered alone. Tolerability was assessed by physical examination and verbally questioning subjects regarding their well-being and any feelings of discomfort. All events reported by the subjects were recorded in adverse-event forms. RESULTS: Forty-eight healthy subjects were enrolled (24 in each part), and all subjects completed the study. None of the participants showed any sign of adverse drug reactions during or after the completion of the study. Statistical analysis confirmed that the 90% CIs for AUC and Cmax of VAL/HCT FDC and VAL + HCT were within the commonly accepted bioequivalence range of 0.8 to 1.25. As a result, from an in vivo pharmacokinetic perspective, 1 FDC tablet could be considered interchangeable in medical practice with the 2 individual reference tablets. However, the 90% CIs between VAL alone and when administered with HCT, either as FDC or concomitantly, indicated the presence of an interaction between VAL and HCT, which would significantly decrease the systemic exposure and intensity of VAL absorption. The co-administration of HCT with VAL decreased the AUC and Cmax of HCT nonsignificantly compared with administration of HCT alone. CONCLUSIONS: Both VAL/HCT FDC and VAL + HCT were well tolerated. The safety/efficacy profile of VAL + HCT co-administration therapy could be extended to the VAL/HCT FDC tablet. The interaction of HCT with other angiotensin-receptor blockers should be investigated to determine whether this interaction is limited to VAL or if other angiotensin-receptor blockers have the same pharmacokinetic interactions. Further studies are necessary to determine the role of efflux and influx transporters on VAL and HCT disposition and pharmacokinetics.

Therapeutic drug monitoring and pharmacokinetic compartmental analysis of sulpiride double-peak absorption profile after oral administration to human volunteers.

BACKGROUND: The pharmacokinetics of oral drugs that exhibit double peaks cannot be described adequately by using conventional compartmental models. OBJECTIVE: The aim of this study was to describe the double-peak plasma pharmacokinetic profile of sulpiride after oral administration to healthy volunteers based on physiological and biopharmaceutical considerations. METHODS: A single 100 mg dose of sulpiride was given to 16 healthy volunteers. Blood samples were drawn at different times and analysed by a validated HPLC assay method. Plasma profiles were evaluated by non-compartmental and compartmental approaches. RESULTS: The non-compartmental parameters determined were k (0.079±0.008 h(-1)), t1/2 (9.0±2.9 h), Vd /F (330.5±87.3 L), Cl/F (38.2±9.8 L/h) and AUC0→∞ (1402.5±404.7 ng.h/mL). The compartmental analysis was described appropriately using a two-compartment body model, with first order absorption from two different sites in the gut. The parameters determined were k21 (0.68±0.2 h(-1)), ka1 (0.7±0.27 h(-1)), ka2 (2.7±1.8 h(-1)) Vc/F (45.1±15.7 L), α (33.3±1.5 h(-1)), ß (0.11±0.03 h(-1)) and time for the beginning of the absorption from the second site (4.4±2.1 h). CONCLUSION: The developed analytical method was suitable for use in pharmacokinetic studies and therapeutic drug monitoring implementation. Sulpiride was well tolerated by the patients without any serious adverse events being observed. The double peaks in the serum concentration-time profiles could be due to differential rates of absorption along the gastrointestinal tract. The discontinuous absorption model with two sites of absorption was adequate to describe the double-peak of the sulpiride plasma profile. ClinicalTrials. gov identifiers: NCT01777685.