Generic Preparation Research Articles

Bioequivalence of generic and branded amoxicillin capsules in healthy human volunteers.

CONTEXT:The Medical Council of India urges doctors to prescribe generic drugs as far as possible. The Indian Medical Association had responded earlier saying that it requires guarantees on the quality of generic forms of drugs. Although no published scientific reports are available on the issue of therapeutic inequivalence, unconfirmed clinician accounts and newspaper reports of therapeutic inequivalence exist.AIM:This study was planned to ascertain whether bioequivalence of branded and generic amoxicillin capsule is comparable.SETTINGS AND DESIGN:An open-label, randomized, single-dose, two-treatment, two-sequence, two-period crossover oral bioequivalence study was conducted in 12 healthy, adult human subjects under fasting condition.MATERIALS AND METHODS:Serum samples, collected at 8 time points, were analyzed by a validated ultraviolet spectrophotometer method. Pharmacokinetic (PK) parameters such as area under the curve (AUC)0–t, AUC0–∞, Cmax, and Tmax were determined along with time above minimum inhibitory concentration (MIC).STATISTICAL ANALYSIS USED:The log-transformed PK parameters (Cmax, AUC0–t, AUC0–∞) were analyzed using a Two One-Sided Test ANOVA in SAS for each parameter. Tmax and MIC were analyzed by Wilcoxon rank-sum test in GraphPad Prism.RESULTS:Geometric mean ratio of Cmax fell within bioequivalence criteria. The upper and lower confidence limits of both AUC0–t and AUC0–∞ geometric mean ratio fell below bioequivalence criteria. Time above MIC of generic preparation was significantly lower than that of branded version.CONCLUSIONS:The generic capsule was not bioequivalent to the branded amoxicillin capsule.

Comparison of acute side effect profile of zoledronic acid – Innovator versus generic preparation

BackgroundZoledronic acid is a bisphosphonate that has been approved for the treatment and prevention of glucocorticoid-induced osteoporosis, post-menopausal and male osteoporosis. The infusion is given intravenous annually. It is an antiresorptive agent with high affinity for mineralized bone and particularly for areas of high bone turnover. ObjectiveComparison of acute side effects of innovator and generic zoledronic acid infusion. MethodRetrospective data of 222 patients who were prescribed zoledronic acid (innovator or generic) over a 3-year period were recorded for any adverse effect. A total of 154 (69.37%) patients received zoledronic acid (innovator) infusion and the 68 patients received generic zoledronic acid infusion. ResultsThe indications of using the infusion were rheumatoid arthritis (58%), lupus (24%), systemic sclerosis (5.4%) and others (12.6%). The commonest adverse effect in both groups was musculoskeletal. The 30% of patients with rheumatoid arthritis experienced worsening of joint pains after the infusion which lasted maximally 48h. Transient low grade fever was seen in 21% in the innovator group versus 56% in generic group (p=0.0001). High grade fever (38°C or more) was less common and was seen in 6.5% in innovator group and 20.6% in generic group (p=0.002). Reinfusion was associated with 30% lesser side effects as compared to first infusion. ConclusionThe frequency of side effects was more common in generic (55.88%) than the innovator group (35.06%). Musculoskeletal and gastrointestinal symptoms were common after infusion; therefore, we would recommend paracetamol and anti-emetic agents to be added empirically for 48h of therapy.

The prospects for the use of gliclazide in current therapy of type 2 diabetes mellitus

The article discusses aspects for the use of sulfonylurea derivative – gliclazide in the current treatment of type 2 diabetes mellitus. Domestic generic preparation of gliclazide with modified release – Diaglizid MR has proven efficacy and safety, is bioequivalent to the original formulation and can be recommended for the treatment of type 2 diabetes mellitus

Simultaneous Detection of 46 Veterinary Drug Residues in Animal Meat by UHPLC

A novel UHPLC–MS/MS approach, using multi-period multiple-reaction monitoring (mpMRM), was developed for the detection of 46 veterinary drugs including representative beta-agonists, quinolones, sulfonamides, tetracyclines in food of animal origin samples. A simple procedure based on protein precipitation associated with ultrafiltration was employed to realize a generic sample preparation for food of animal origin. In particular, multi-period multiple-reaction monitoring (mpMRM) was developed as a MS scan mode for veterinary drugs to meet the requirements of qualitative and quantitative detection of multiple veterinary drug residues and improve sensitivity and reliability in this method. Furthermore, the method was fully validated for all 46 drugs, and the specificity, linearity, limit of detection, limit of quantification, accuracy and precision results are good. Using the developed method, 30 pork samples and 20 beef samples were analysed, and the result is consistent with that using GB methods (National standard method of the People’s Republic of China) but using less time, which demonstrates that our developed method is not only accurate and reliable, but also greatly improves the cost-effectiveness of the analytical procedures. This approach not only is much more effective than the traditional sample preparation method, but also provides data on four classes of veterinary drugs in one analytical run, which enabled high-throughput and efficiency. The obtained results proved the usefulness of the method as applied in the field of residue analysis.

A multi-centre, phase IV study to evaluate the steady-state plasma concentration and serum bactericidal activity of a generic teicoplanin preparation

Introduction: Teicoplanin is an effective treatment option against methicillin-resistant, Gram-positive bacteria, like Staphylococcus aureus. It is a glycopeptide antibiotic, produced through microbial fermentation, a process resulting in variations in the N-acyl side chain. Concerns that these variations may affect the pharmacokinetic profile and the clinical efficacy of generic teicoplanin preparations have been raised.Method: To address this issue, a multi-centre observational study was conducted to evaluate steady-state peak and trough serum concentrations, and the serum bactericidal activity (SBA) and safety of a generic teicoplanin preparation in critically ill patients. Additionally, the composition of the generic teicoplanin was compared to that of the innovator drug to assess differences in the composition.Results: Following pre-determined loading and maintenance dose schedules, the mean peak and trough teicoplanin serum concentrations were 20.98 mg/l and 10.38 mg/l, respectively. A statistically...

Determining canine skin concentrations of terbinafine to guide the treatment of Malassezia dermatitis.

Terbinafine (TBF) is known to concentrate and persist in human skin. Its use is increasing in veterinary medicine, but there are limited data concerning its tissue concentration and efficacy in dogs. (i) Describe TBF accumulation in canine skin; (ii) Integrate pharmacokinetic data with historical minimum inhibitory concentration (MIC) results for Malassezia pachydermatis to verify the currently used dosage of TBF for the treatment of Malassezia dermatitis. Ten healthy, client-owned dogs. Dogs were given TBF (generic preparation, 250 mg tablets) 30 mg/kg per os (p.o.) once daily for 21 days. Serum, sebum and stratum corneum (SC) samples were collected on days 1, 5, 7, 11, 14, 21, 28 and 35. High-pressure liquid chromatography was used to determine drug concentrations in samples. Relevant (mean ± standard deviation) parameters for TBF in serum, paw SC, thorax SC and sebum, respectively, were: maximum concentration (Cmax , μg/mL) 23.59 ± 10.41, 0.31 ± 0.26, 0.30 ± 0.32 and 0.48 ± 0.25; half-life (t1/2 , d) 4.49 ± 2.24, 6.34 ± 5.33, 4.64 ± 3.27 and 5.12 ± 3.33; time to maximum concentration (Tmax , d) 10.40 ± 6.98, 13.20 ± 5.16, 11.90 ± 8.62 and 10.60 ± 3.69. These results suggest that TBF does not achieve high concentrations in canine SC or sebum compared to serum. The mean Cmax of all skin tissues (paw SC, thorax SC and sebum) barely exceeded the reported Malassezia MIC90, of 0.25 μg/mL, which indicates that doses higher than 30 mg/kg p.o. once daily may be necessary.

Quantitative targeted and retrospective data analysis of relevant pesticides, antibiotics and mycotoxins in bakery products by liquid chromatography-single-stage Orbitrap mass spectrometry

In addition to ‘traditional’ multi-residue and multi-contaminant multiple reaction monitoring (MRM) mass spectrometric techniques devoted to quantifying a list of targeted compounds, the global food industry requires non-targeted methods capable of detecting other possible potentially hazardous compounds. Ultra-high-performance liquid chromatography combined with a single-stage Orbitrap high-resolution mass spectrometer (UHPLC-HRMS Exactive™-Orbitrap Technology) was successfully exploited for the complete selective and quantitative determination of 33 target compounds within three major cross categories (pesticides, antibiotics and mycotoxins) in bakery matrices (specifically milk, wheat flour and mini-cakes). Resolution was set at 50 000 full width at half maximum (FWHM) to achieve the right compromise between an adequate scan speed and selectivity, allowing for the limitations related to the necessary generic sample preparation approach. An exact mass with tolerance of 5 ppm and minimum peak threshold of 10 000 units were fixed as the main identification conditions, including retention time and isotopic pattern as additional criteria devoted to greatly reducing the risk of false-positive findings. The full validation for all the target analytes was performed: linearity, intermediate repeatability and recovery (28 analytes within 70–120%) were positively assessed; furthermore, limits of quantification between 5 and 100 µg kg−1 (with most of the analytes having a limit of detection below 6 µg kg−1) indicate good performance, which is compatible with almost all the regulatory needs. Naturally contaminated and fortified mini-cakes, prepared through combined use of industrial and pilot plant production lines, were analysed at two different concentration levels, obtaining good overall quantitative results and providing preliminary indications of the potential of full-scan HRMS cluster analysis. The effectiveness of this analytical approach was also tested in terms of the formulation of hypotheses for the identification of other analytes not initially targeted which can have toxicological implications (e.g. 3-acetyl-deoxynivalenol and deoxynivalenol-3-glucoside), opening a window on retrospective investigation perspectives in food safety laboratories.

Revealing local variations in nanoparticle size distributions in supported catalysts: a generic TEM specimen preparation method.

The specimen preparation method is crucial for how much information can be gained from transmission electron microscopy (TEM) studies of supported nanoparticle catalysts. The aim of this work is to develop a method that allows for observation of size and location of nanoparticles deposited on a porous oxide support material. A bimetallic Pt-Pd/Al(2)O(3) catalyst in powder form was embedded in acrylic resin and lift-out specimens were extracted using combined focused ion beam/scanning electron microscopy (FIB/SEM). These specimens allow for a cross-section view across individual oxide support particles, including the unaltered near surface region of these particles. A site-dependent size distribution of Pt-Pd nanoparticles was revealed along the radial direction of the support particles by scanning transmission electron microscopy (STEM) imaging. The developed specimen preparation method enables obtaining information about the spatial distribution of nanoparticles in complex support structures which commonly is a challenge in heterogeneous catalysis.

Universal Route to Polycyclic Aromatic Hydrocarbon Analysis in Foodstuff: Two-Dimensional Heart-Cut Liquid Chromatography-Gas Chromatography-Mass Spectrometry.

Analysis of polycyclic aromatic hydrocarbons (PAHs) in complex foodstuff is associated with complicated and work-intensive sample preparation. Chromatographic interference has to be faced in many situations. The scope of the current work was the development of a highly efficient two-dimensional heart-cut LC-LC-GC-MS method. Detection was performed with a time-of-flight mass spectrometer (TOF-MS) to allow for a comprehensive evaluation of the obtained data in terms of cleanup efficiency. Additionally, routine detection was performed with single quadrupole MS. An easy and quick generic sample preparation protocol was realized as a first step. During method development, focus was given to optimizing HPLC cleanup for complex foodstuff. Silica-, polymeric-, and carbon-based HPLC phases were tested. Coupling of silica gel to π-electron acceptor modified silica gel showed the best cleanup properties. A four rotary valve configuration allowed the usage of a single binary HPLC pump. Screening of several fatty and nonfatty food matrices showed the absence of unwanted matrix compounds in the cleaned-up PAH fraction down to the low picogram range using TOF-MS. Limits of quantitation (LOQ) were below 0.1 μg/kg for all EU priority PAHs. Recovery rates ranged from 82 to 111%. Validation data fully complied with EU Regulation 836/2011. Sample preparation was possible in 20 min. Interlacing of HPLC and GC allowed an average method runtime of 40 min per sample.

Impact of Conversion From Advagraf to Twice-Daily Generic Tacrolimus in Kidney Transplant Recipients: A Single-Center Study

BackgroundThe conversion of twice-daily (Prograf) to once-daily tacrolimus (Advagraf) as well as from Prograf to a generic tacrolimus preparation was proved to be safe in kidney transplant patients. There are no published studies comparing the clinical outcomes of patients who were receiving Advagraf and were switched to generic preparations of tacrolimus. ObjectivesTo evaluate the impact, safety profile, side effects, and renal graft function after the conversion of Advagraf to a generic preparation of tacrolimus. Population and MethodsThis prospective study was conducted over a 9-month period. The conversion to twice-daily generic tacrolimus was performed on a 1 mg:1 mg basis, total daily dose. We included 123 kidney transplant recipients (55% male). The mean (± SD) age was 49.9 ± 12 years. There were 100 (81%) Caucasian patients; the mean (± SD) time from transplantation to conversion was 4.6 ± 4.4 years. ResultsA significant increase in blood levels (18%; P = .000) was reported. There was a necessary tacrolimus dose reduction of 17% (P = .000) and ≥3 blood trough levels to adjust the initial tacrolimus blood levels. The mean serum creatinine remained stable before conversion, at months 1 and 6 (1.40, 1.43, and 1.46 mg/dL, respectively). Significant adverse effects were reported in 9% of our patients. There were no episodes of acute rejection or graft loss during the study. ConclusionsThe conversion proved to be safe. A drug reduction was necessary to ensure stable renal function and good tolerability.

Determination of selected veterinary antimicrobials in poultry excreta by UHPLC-MS/MS, for application in Salmonella control programs.

The most important source of Salmonella spp. infection in humans is by the consumption of contaminated poultry products. Due to the risk of resistance development and its transfer from animals to humans, the Belgian Royal Decree concerning the eradication of Salmonella (C-2007/22784) prohibits treatment of poultry with antimicrobials against zoonotic Salmonella spp. To uncover illicit use, an analytical method using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) for the determination of antimicrobial residues in poultry excreta was developed and validated for classes having an active spectrum against Salmonella spp. in poultry: β-lactams (amoxicillin and penicillin V), fluoroquinolones (enrofloxacin, difloxacin, and flumequine), polymyxins (colistin), sulfonamides in combination with trimethoprim (sulfachloropyridazine, sulfadiazine, and sulfaclozine), and tetracyclines (chlortetracycline and doxycycline). A generic and high-throughput sample preparation was developed. Extraction of samples was performed by ultrasonication using a combination of acetonitrile and McIlvaine buffer, followed by centrifugation and filtration prior to analysis. The method was validated according to Commission Decision 2002/657/EC for linearity, apparent recovery/trueness, repeatability, reproducibility, limit of quantification, limit of detection, specificity, matrix effect, and storage stability in matrix. To demonstrate the applicability of the method, an in vivo experiment was conducted. For each antimicrobial class, one registered drug was selected and administered in the drinking water to two laying hens. Excreta samples were collected every 12h during and until 2days after treatment and analyzed using the developed method.

A generic sample preparation approach for LC–MS/MS bioanalysis of therapeutic monoclonal antibodies in serum applied to Infliximab

In this study, we developed a generic bioanalytical workflow providing sensitive, specific, and accurate absolute quantification of therapeutic monoclonal antibodies in serum. The workflow involves magnetic beads coated with protein A to pull-down therapeutic monoclonal antibodies with affinity for protein A from the biological matrix, followed by tryptic digestion and LC-MS/ MS quantification of a unique signature peptide, considering of course the matrix of interest and other present mAbs, if applicable. The feasibility of this approach was demonstrated for Inflix imab (trade name Remicade) in rat serum. The assigned signature peptide was monitored in the selected reaction monitoring (SRM) mode. Assay variability was determined to be below 20%, except at the QC low level, which was provided through optimization of the sample preparation and monitoring of the LC-MS/MS using a stable isotope labeled signature peptide as internal standard. The 100 ng/ml lower limit of quantification using only 25 µl sample volume, is generally considered as sufficient for pharmaceutical development purposes for monoclonal antibodies.

First steps towards a generic sample preparation scheme for inorganic engineered nanoparticles in a complex matrix for detection, characterization, and quantification by asymmetric flow-field flow fractionation coupled to multi-angle light scattering and ICP-MS

Engineering nanoparticles in complex matrices.

EFFICACY AND TOLERABILITY OF GENERIC ZOLEDRONIC ACID 5 MG (REZOCLASTIN PS) IN THE TREATMENT OF OSTEOPOROSIS: A RETROSPECTIVE ANALYSIS OF CLINICAL EXPERIENCE WITH THE DRUG IN RUSSIA

Objectives. To analyze clinical data of the first domestic zoledronic acid generic preparation for the treatment of osteoporosis (Rezoclastin PS., 5 mg). Materials and Methods. The study included data from 123 patients (118 women and 5 men) treated with Rezoclastin PS 5 mg in medical centers of Moscow, St.-Petersburg and Krasnodar for primary (91.8%) or secondary(8.2%) osteoporosis, with mean age 27-78 years (61,4 ± 9,1 years). 56.6% of patients had severe osteoporosis with compressive deformations of vertebrae. Duration of medical therapy ranged from 6 to 24 months. Results. Study of changers in bone resorption marker CTx (n = 10) showed decline by 78% after 3 months of treatment compared to baseline (p = 0.027). BMD at the lumbar segment of the spine L 1-L 4 increased after 12 months by 3.4% (p <0.001, n = 87) and 24 months by 5.7% (p <0.05, n = 11) at the femoral neck - by 1.6% (p <0.0001, n = 64) and by 2.5% (p <0.05, n = 11), respectively, and in the total proximal femur - by 2.6% (p <0.01, n = 64) and by 3.8% (p <0.05, n = 11), respectively. The level of back pain in the study group significantly decreased at 6 months (p <0.000001), and after 18 and 24 months the pain in most patients subsided. After the first administration of the drug in 40% of patients had adverse events, mainly due to flu-like syndrome. After the second infusion at 12 months adverse reactions rate decreased to only 22.9%, after the third infusion at 24 months to 1.8 %. Conclusions. The parameters of efficacy and adverse reactions of the generic zoledronic acid as our data show is comparable to the brand version of the drug.

Disentangling the attention network test: behavioral, event related potentials, and neural source analyses.

Background: The study of the attentional system remains a challenge for current neuroscience. The “Attention Network Test” (ANT) was designed to study simultaneously three different attentional networks (alerting, orienting, and executive) based in subtraction of different experimental conditions. However, some studies recommend caution with these calculations due to the interactions between the attentional networks. In particular, it is highly relevant that several interpretations about attentional impairment have arisen from these calculations in diverse pathologies. Event related potentials (ERPs) and neural source analysis can be applied to disentangle the relationships between these attentional networks not specifically shown by behavioral measures.Results: This study shows that there is a basic level of alerting (tonic alerting) in the no cue (NC) condition, represented by a slow negative trend in the ERP trace prior to the onset of the target stimuli. A progressive increase in the CNV amplitude related to the amount of information provided by the cue conditions is also shown. Neural source analysis reveals specific modulations of the CNV related to a task-related expectancy presented in the NC condition; a late modulation triggered by the central cue (CC) condition and probably representing a generic motor preparation; and an early and late modulation for spatial cue (SC) condition suggesting specific motor and sensory preactivation. Finally, the first component in the information processing of the target stimuli modulated by the interaction between orienting network and the executive system can be represented by N1.Conclusions: The ANT is useful as a paradigm to study specific attentional mechanisms and their interactions. However, calculation of network effects is based in subtractions with non-comparable experimental conditions, as evidenced by the present data, which can induce misinterpretations in the study of the attentional capacity in human subjects.

Generic on-line solid phase extraction sample preparation strategies for the analysis of drugs in biological matrices by LC–MS/MS

In the present work we investigate the integration of a single hardware platform (Prospekt-2) allowing on-line SPE with pre-/post-trapping dilution and direct injection of plasma extracts, and also compare the benefits and challenges of the different approaches for pharmaceutical drugs with heterogeneous physicochemical properties. In the first part, the generic use of on-line SPE with direct plasma injection or after protein precipitation was investigated for the quantitative analysis of talinolol. In the second part, pre-trapping and post-trapping dilution for on-line SPE is discussed for generic method development on an oxadiazole and its major metabolite. Finally, the difference of performance between direct plasma injection vs. off-line liquid–liquid extraction is also described for the quantification of buprenorphine and naltrexone down to 50 and 100pg/ml using a 0.25ml plasma aliquot. All assays were in human plasma and detection was performed by mass spectrometry detection either on simple or triple stage quadrupoles. Regardless of the tested strategy, assays were found linear, with precision and accuracy with <15% for all quality controls samples and <20% for lower limit of quantitation.

Comment on Tadrous et al.: Comparative gastrointestinal safety of bisphosphonates in primary osteoporosis: a network meta-analysis

Dear Editor, The study by Tadrous et al. [1] identified zoledronic acid as the bisphosphonate with the “highest probability gastrointestinal (GI) adverse events (91 %) and nausea (70 %).” Many clinicians will have been surprised at this finding. First, in contrast to the established mechanisms of upper GI AE following oral preparation of bisphosphonates, there are no known mechanisms explaining GI AEs including nausea when bisphosphonates are administered in IV regimens. Of course, an acute face reaction is not uncommon after zoledronic acid infusion, especially after the first administration and more rarely after the next infusion and this could be accompanied in some cases by stomach upset and nausea. This could have been explored, had the authors included the acute face reaction in their analysis. Second, the frequency of events reported in Table 2 does not seem internally coherent. For alendronate, 54 % reportedly experienced esophageal AEs and 29 % nausea, yet there was no discontinuation of alendronate due to GI adverse events and the total probability of any GI events was stated as 1 %. For zoledronic acid, the authors state that there was no reporting of specific outcomes such as upper GI events or esophageal events, yet cite a probability of any GI event of more than 90 % with discontinuation in 14 %. At any rate, we are left with the impression that the included studies had extreme heterogeneity in their reporting of adverse events and that this may have led to a biased estimate favouring older studies. As a test of this, the authors could have compared the total AE event rate between the placebo groups in the trials. An unforeseen consequence of the conclusions of the study could be a shift away from zoledronic acid, which is now available as a cheaper generic preparation in many countries, to denosumab which remains on patent. Pending a more transparent and robust analysis, we are not persuaded that GI adverse events are more likely with zoledronic acid than with oral bisphosphonates. In reference to adherence, it is surprising the way the authors interpreted their findings when they concluded that annual administration of zoledronic acid may not improve adherence.

Generic Characterization of Apolar Metabolites in Red Chili Peppers (Capsicum frutescens L.) by Orbitrap Mass Spectrometry.

The aim of the present study was to develop a generic analytical method for the identification and quantitation of apolar plant metabolites in biomass using liquid chromatography-photodiode array-accurate mass mass spectrometry (LC-PDA-amMS). During this study, a single generic sample preparation protocol was applied to extract apolar plant metabolites. Compound identification was performed using a single generic screening method for apolar compounds without the need for dedicated fractionation. Such a generic approach renders vast amounts of information and is virtually limited by only the solubility and detector response of the metabolites of interest. Method validation confirmed that this approach is applicable for quantitative purposes. Furthermore, an identification-quantitation strategy based on amMS and molar extinction coefficients was used for carotenoids, eliminating the need for reference standards for each carotenoid. To challenge the validated method, chili peppers (Capsicum frutescens L.) were analyzed to unravel their complex phytochemical composition (carotenoids, glycolipids, glycerolipids, capsaicinoids, lipid-soluble vitamins).

Combining the quick, easy, cheap, effective, rugged and safe approach and clean-up by immunoaffinity column for the analysis of 15 mycotoxins by isotope dilution liquid chromatography tandem mass spectrometry

Optimization and validation of a multi-mycotoxin method by LC–MS/MS is presented. The method covers the EU-regulated mycotoxins (aflatoxins, fumonisins, ochratoxin A, deoxynivalenol, zearalenone, T-2 and HT-2), as well as nivalenol and 3- and 15-acetyldeoxynivalenol for analysis of cereals, cocoa, oil, spices, infant formula, coffee and nuts. The proposed procedure combines two clean-up strategies: First, a generic preparation suitable for all mycotoxins based on the QuEChERS (for quick, easy, cheap, effective, rugged and safe) protocol. Second, a specific clean-up devoted to aflatoxins and ochratoxin A using immunoaffinity column (IAC) clean-up. Positive identification of mycotoxins in matrix was conducted according to the confirmation criteria defined in EU Commission Decision 2002/657/EC while quantification was performed by isotopic dilution using 13C-labeled mycotoxins as internal standards. Limits of quantification were at or below the maximum levels set in the EC/1886/2006 document for all mycotoxin/matrix combinations under regulation. In particular, the inclusion of an IAC step allowed achieving LOQs as low as 0.05 and 0.25μg/kg in cereals for aflatoxins and ochratoxin A, respectively. Other performance parameters like linearity [(r)2>0.99], recovery [71–118%], precision [(RSDr and RSDiR)<33%], and trueness [78–117%] were all compliant with the analytical requirements stipulated in the CEN/TR/16059 document. Method ruggedness was proved by a verification process conducted by another laboratory.

Bioequivalence assessment of two transdermal delivery systems of fentanyl in healthy Chinese volunteers

The objective of this study was to investigate the bioequivalence of two formulations (generic preparation and Durogesic patch) of 4.2 mg fentanyl. They were assessed in relative bioavailability in 20 healthy Chinese male volunteers according to a single dose, 2-sequence, crossover randomized design. The two formulations were administered at two treatment days, separated by a washout period of 14 days. Blood samples were collected at specified time intervals over 144 hours post-dosing. Plasma samples were separated and assayed for fentanyl using a sensitive LC-MS/MS method. Pharmacokinetic parameters were analyzed based on noncompartmental analysis. The value of two formulations was as follows: Cmax, 0.789 (0.256) and 0.821 (0.278) ng/mL; tmax, 45.3 and 41.2 h; t1/2, 21.5 (8.8) and 22.6 (7.2) h; AUC0-T, 52.5 (18.6) and 55.7 (19.7) ng/mL×h; and AUC0-∞, 54.6 (19.3) and 57.5 (21.1) ng/mL×h, respectively. ANOVA and two one-sided t-test procedures showed no significant difference in log-transformed Cmax, AUC0-T and AUC0-∞ while the 90% confidence interval (CI) of the ratio of the geometric means of their values were also used to assess bioequivalence between the two formulations. Based on these statistical inferences it was concluded that the two formulations exhibited comparable pharmacokinetic profiles and that test formulation is bioequivalent to reference formulation. The point estimate (90% CI) of two formulations was: AUC0-T, 96.7% (85 - 105%); AUC0-∞, 97.5% (89 - 110%); Cmax, 96.2% (91 - 104%); tmax, 97.1% (93 - 101%), respectively.