Investigation Of Bioequivalence Research Articles

Concurrent Analysis of Amlodipine, Rosuvastatin, and Hydrochlorothiazide in Solution and Biological Fluid Using LC-MS/MS.

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was created and verified in this investigation. This methodology offers a fast, easy, affordable, economical, and reliable approach to simultaneously determining amlodipine, rosuvastatin, and hydrochlorothiazide in solution and human plasma. Through the extraction process, acetonitrile was utilized as a precipitating agent for the proteins in plasma. The C18 column was injected with a volume of 10 µL, including ondansetron as an internal standard. The analytes were eluted using an isocratic mobile phase (0.1% acetic acid and 1:4 (v/v) methanol). The method was sensitive and selective for the analytes over a dynamic concentration range of 5 to 600 μg/mL in solution and 0.5 to 60.0 μg/mL in plasma. At a minimum of 0.9988 coefficient of determination, linearity was attained. Within and between runs, the precision and accuracy were 2.87 to 11.41% and 86.2 to 113%, respectively. A comparatively quick run time of less than two minutes (high throughput) was achieved. The current method can be used in many applications, such as bioequivalence investigations and therapeutic medication monitoring, to quantify the relevant analytes.

Stability Indicating LC–ESI-MS/MS Method Development and Validation for the Quantitation of Lurbinectedin in Biological Matrices.

The anticancer drug lurbinectedin was measured in plasma samples using a newly designed and validated LC-ESI-MS/MS method. The drug’s examination was conducted using ledipasvir as the internal standard. Following the liquid liquid extraction of 200 μL of plasma, the samples were separated using a ZorbaxSB (25 0mm x4.6 mm, 5 µm)C18 column. The mobile phase comprised of 0.1 %V/V formic acid and acetonitrile in the fraction of 10:90, and an infusion flow rate was 0.80mL/min. The analytes were eluted in 3.5 minutes total. Using a concentration range of 1.50 to 5000ng/mL of lurbinectedin and a correlation coefficient value of 0.9994, the method was validated in compliance with FDA standard standards. Assay accuracy ranged from 95.31% to 104.06% of the nominal values, and both intra- and inter-day precision results were within 4.32%. For the analyte at the LQC level, the matrix factor varies from 94.25% to 104.85% with a %CV of 4.61, whereas at the HQC level, it ranges from 94.62% to 103.88% with a %CV of 4.02. The results of the stability tests show that the approach is quite stable. Regular analysis in bioavailability, quality control, and bioequivalence investigations of biological matrices may be effectively performed using the established approach.

Effects of Postprandial Factors and Second Meal Intake Time on Bioequivalence Investigation of Tadalafil-Loaded Orodispersible Films in Human Volunteers.

Tadalafil (TD) has poor water solubility but is well absorbed without affecting food intake when administered orally. Owing to patient adherence and therapeutic characteristics, a TD-loaded orodispersible film (TDF) is preferable. However, the mechanistic role of dietary status on the clinical pharmacokinetic analysis of TDF in human volunteers should be investigated because the gastrointestinal environment varies periodically according to meal intervals, although commercial 20 mg TD-loaded tablets (TD-TAB, Cialis® tablet) may be taken with or without food. TDF was prepared by dispersing TD in an aqueous solution and polyethylene glycol 400 to ensure good dispersibility of the TD particles. In the fasting state, each T/R of Cmax and AUC between TD-TAB and TDF showed bioequivalence with 0.936-1.105 and 1.012-1.153, respectively, and dissolution rates in 1000 mL water containing 0.5% SLS were equivalent. In contrast, TDF was not bioequivalent to TD-TAB under the fed conditions by the Cmax T/R of 0.610-0.798. The increased dissolution rate of TDF via the micronization of drug particles and the reduced viscosity of the second meal content did not significantly affect the bioequivalence. Interestingly, an increase in second meal intake time from 4 h to 6 h resulted in the bioequivalence by the Cmax T/R of 0.851-0.998 of TD-TAB and TDF. The predictive diffusion direction model for physical digestion of TD-TAB and TDF in the stomach after the first and second meal intake was successfully simulated using computational fluid dynamics modeling, accounting for the delayed drug diffusion of TDF caused by prolonged digestion of stomach contents under postprandial conditions.

Overcoming the challenge of potent endogenous interferences in limaprost quantification: An innovative methodology combining differential mobility spectrometry with LC-MS/MS for ultra-high sensitivity, selectivity and significantly enhanced throughput

Limaprost, an orally administered analogue of prostaglandin E1, possesses potent vasodilatory, antiplatelet, and cytoprotective properties. Due to its extremely low therapeutic doses and exceedingly low plasma concentrations, the pharmacokinetic and bioequivalence studies of limaprost necessitate a highly sensitive quantitative method with a sub-pg/mL level of lower limit of quantification. Moreover, the intensity of endogenous interferences can even exceed the maximum concentration level of limaprost in human plasma, presenting further challenge to the quantification of limaprost. As a result, existing methods have not yet met the necessary level of sensitivity, selectivity, and throughput needed for the quantitative analysis of limaprost in pharmacokinetic and bioequivalence investigations. This study presents a new methodology that combines differential mobility spectrometry (DMS) with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and utilizes a distinctive strategy to achieve more accurate DMS conditions. This integration yields a method that is currently the most sensitive and features the shortest analytical time, making it the sole technique capable of meeting the requirements for limaprost pharmacokinetic and bioequivalence investigations. This method demonstrates robustness and is successfully employed in a pharmacokinetic investigation of limaprost in human subjects, underscoring that the combination of DMS with LC-MS/MS serves as an efficacious strategy for overcoming the challenges inherent in analyzing biological samples afflicted by multiple interferences.

Liquid chromatography-tandem mass spectrometry determination of bumetanide in human plasma and application to a clinical pharmacokinetic study.

Determining a drug's bioavailability and bioequivalence is important for developing and approving a drug product. The procedure supports applications for generic drug products and novel therapeutic substances, makes important decisions regarding safety and efficacy, and measures a drug's concentration in biological matrices. This study aimed to develop and validate a specific, simple, sensitive, and accurate method using liquid chromatography-tandem mass spectrometry (LC-MS) for measuring bumetanide (BUM) in human plasma. Chromatographic separation was achieved using a Hypurity C18 column (4.6× 50 mm, 5μm) under isocratic conditions, and LC-MS detected positive ionization acquisition modes. Protonated precursor to product ion transitions were observed at m/z 365.08 → 240.10 and 370.04 → 244.52 for BUM and internal standard, respectively. The linear range of BUM in plasma samples was 3.490-401.192 ng/mL. The inter-precision value ranged from 1.76% to 4.75%. The inter-accuracy value ranged from 96.46% to 99.95%. The method was adequately validated per the U.S. Food and Drug Administration guidelines, and the results were within permissible bounds. The Cmax and Tmax values were ~53.097 ± 13.537 ng/mL and 1.25 (0.67-5.00)h, respectively. The new approach showed satisfactory results for studying BUM in human plasma with potential use in pharmacokinetic and bioequivalence investigations.

A Multicenter Randomized Bioequivalence Study of a Novel Ready-to-Use Temozolomide Oral Suspension vs. Temozolomide Capsules.

Temozolomide (TMZ) oral suspension (Ped-TMZ, KIZFIZO®) is being developed for the treatment of relapsed or refractory neuroblastoma, a rare cancer affecting infants and young children. The study assessed the safety and the bioequivalence of this novel pediatric formulation with existing TMZ oral capsules. In vitro dissolution profiles and the bioequivalence were evaluated following the European Medicines Agency "Guidelines on the investigation of Bioequivalence". The phase I, multicenter, randomized, open-label, crossover, single-dose bioequivalence study enrolled 36 adult patients with glioblastoma multiforme or lower-grade glioma. Each patient received 200 mg/m2 Ped-TMZ suspension and TMZ capsules (Temodal®) on 2 consecutive days, with the order being randomly assigned. Fourteen blood samples were collected up to 10 h post-dosing. Bioequivalence was assessed by comparing the 90% confidence interval for the ratio of the geometric means of maximum TMZ plasma concentration (Cmax) and the area under the curve (AUCt). Other endpoints included further pharmacokinetic parameters and safety. Both formulations exhibited a fast in vitro dissolution profile with more than 85% of TMZ dissolved within 15 min. For the bioequivalence study, thirty patients completed the trial as per the protocol. The ratio of Ped-TMZ/TMZ capsule geometric means (90% CI) for AUCt and Cmax were 97.18% (95.05-99.35%) and 107.62% (98.07-118.09%), respectively, i.e., within the 80-125% bioequivalence limits. No buccal toxicity was associated with Ped-TMZ liquid formulation. This study showed that Ped-TMZ oral suspension and TMZ oral capsule treatment are immediate release and bioequivalent medicines. There were also no unexpected safety signals or local toxicity (funded by ORPHELIA Pharma; ClinicalTrials.gov number, NCT04467346).

Comprehensive review on method development of galantamine

Galantamine is generally common in the treatment of Alzheimer’s in old people. Galantamine is also used in combination treatments for Alzheimer. Different analytical techniques such as Liquid Chromatography-Mass Spectrometry, Reverse Phase-High Performance Liquid Chromatography,High Performance Liquid Chromatography, Ultra Performance Liquid Chromatography, and Ultraviolet Visible spectrometric method areused in the determination and validation of galantamine and its interactions. Different articles were reviewed and the results were found to be accurate and prudent in determining galantamine in human plasma and also other body fluids. Pharmacokinetic and bioequivalence investigations performed in different articles were summarized. All the methods stated in this article proves precise values and were found to be successful in determining and validating the drug galantamine and its interactions.Every method reviewed in this article are different from each other. This article summarizes few of the developed and validated analytical techniques available for the determination/ estimation/quantification and validation of Galantamine

Mitigation of the convergence issues associated with semi-replicated bioequivalence data.

Semi-replicated designs for investigation of bioequivalence constitute a challenge when mixed models are applied. With the commonly available packages and regardless of choice of covariance structure the software may force variance components into the covariance matrix that render it over-specified. This may give rise to arbitrary estimates of certain variance components, lack of convergence or warnings. Classically the covariance matrix is decomposed as V=ZGZt +R, with G containing the between-subject variance components, Z being the design matrix for the random effects and R containing the within-subject variance components. By abandoning the definitions of G and R, and instead working directly in V, it is possible to specify a correct model with only the variance components of interest. Proof-of-concept for this idea is delivered with a script in the statistical language R. The script is available as supplementary material(Data S1).

Evaluation of drug permeability methods recommended by health authorities

The oral route is the most preferred route for drug administration because of patient compliance. Following oral administration, a drug has to cross several biological barriers before reaching the systemic circulation by transcellular or paracellular transports. Oral drug absorption and bioavailability are influenced by the physicochemical, formulation and physiological variables. Oral absorption of drugs is controlled by dissolution from the dosage form, and permeability across the gastrointestinal membrane. Rate limiting step in absorption is the permeability for compounds with low permeability, and dissolution for compounds with low solubility. According to Food and Drug Administration (FDA) Biopharmaceutics Classification System (BCS)-based biowaiver guidance and European Medicines Agency (EMA) Guideline on the Investigation of Bioequivalence, permeability class of a drug substance can be determined using different methods. The aim of this study was to evaluate the methods in detail recommended by FDA and EMA for determination of permeability of drugs. We surveyed the literature as to the pros and cons of the methods recommended by the health authorities for assessment of permeability. In general, a single method is sufficient for determination of permeability. When a single method fails to demonstrate a permeability classification, two different methods may be used.

Bioequivalence regulation in emerging countries: Example of Moroccan regulations on immediate release formulations and comparison with international guidelines

The purpose of this study was to analyze Moroccan regulations on bioequivalence studies and compare them with some international guidelines. It emerged that, as most common guidelines, Moroccan regulations treated essential questions relating to the conduct of bioequivalence studies while remaining general. An effort to harmonize the Moroccan regulations as closely as possible with international guidelines such as European Medicines Agency and World Health Organization was made. The decree 2-12-198 on bioequivalence studies includes worldwide gold standards such as inclusion and exclusion criteria, study design, choice and number of subjects, conduct of the study, pharmacokinetic parameters, BE acceptance criteria, and biowaiver requirements. It specifically addresses issues such as pro-drug, metabolites, urinary samples, and endogenous substances. Specific precisions such as the case of the modified release forms, the replacement of subjects on the withdrawal, or drop-out of a volunteer are not covered by this general decree and should be part of new directives, in the future. For an emerging country, the integration of Biopharmaceutics Classification System biowaivers within the decree confirms the efforts being made by the Moroccan regulations to join the most advanced guidelines on the investigation of bioequivalence and to prepare the International Council on Harmonisation M9 adoption.

Analysis of the modern approaches for the prevention of antimicrobial resistance: role and place of physical and chemical research methods in vitro and the investigation of bioequivalence

The problem of antimicrobial resistance is one of the key challenges in the modern world. A global analysis of the resistance development to antibacterial drugs has shown that solving this problem requires designing of complex interdisciplinary approaches. Searching for tools that would prevent and suppress the development of antimicrobial resistance is an actual scientific task that has a clear practical orientation. Aim. To analyze modern approaches, to avoid the development of antibacterial drugs resistance and to determine the role of physicochemical research IN VITRO and IN VIVO (bioequivalence studies) in solving this problem. Results. While carrying out the research, we made a systematic analysis of modern international concepts, regulatory guidelines, recommendations and programs for a comprehensive solution to the global problem of antibiotic resistance. During this work, we identified the key areas directly related to the issues of proper pharmaceutical development and research of antibacterial drugs, as well as the introduction of new scientific approaches and procedures for preventing the resistance of these drugs. It has been found that physicochemical methods of analysis can be used for scientifically substantiated creation of regimens of sustainable antibiotic therapy, as well as biopharmaceutical modeling of interaction with other objects (drugs, mineral waters, drinks, etc.). Such tests are an additional tool for excluding the risk of mismatch evaluation when conducting an assessment of generic drugs both in the biowaiver procedure and in the study of bioequivalence. Conclusions. The analysis of modern approaches to prevent the development of antibacterial drugs resistance has shown that it is necessary to use comprehensive application of scientific methods when making a research of this problem. The developed classification of approaches to eliminate antimicrobial resistance highlights the methods of physicochemical and bioanalytical research as a promising tool to reduce the risk of antibiotic resistance.

Investigation of bioequivalence, safety, and tolerability of a fixed-dose combination of nifedipine GITS and candesartan compared with the corresponding loose-dose combination under fed conditions .

To investigate the bioequivalence, safety, and tolerability of single-dose nifedipine gastrointestinal therapeutic system (GITS) and candesartan as a fixed-dose combination (FDC) relative to the loose combination in healthy males under fed conditions. A total of 48 subjects received nifedipine GITS 60 mg and candesartan 32 mg as an FDC or loose combination in an open-label, 2-way crossover, 2-treatment sequence design, with a washout of at least 5 days between treatments. Study medications were administered following an overnight fast of at least 10 hours, and 30 minutes after ingestion of a high-fat test meal. Plasma samples were collected at intervals over a 48-hour period post-dosing. Safety and tolerability parameters were documented throughout the study. For nifedipine, 90% confidence intervals (CIs) for the ratios of FDC/loose combination were within acceptance limits of bioequivalence (i.e., 80 - 125%) for both AUC0-tlast (91.36%; 111.5%) and Cmax (87.93%; 100.5%). For candesartan, 90% CIs for the ratios of FDC/loose combination were within acceptance limits for AUC0-tlast (112.8%; 124.4%), but not for Cmax (120.5%; 137.8%). There were no serious adverse events (AEs) or AEs leading to treatment discontinuation and no clinically relevant changes in vital signs or laboratory parameters. A single dose of the FDC-containing nifedipine GITS 60 mg and candesartan 32 mg, when compared to the corresponding loose combination under fed conditions, met the criterion for bioequivalence based on AUC0-tlast, while the slightly higher Cmax for candesartan is not considered clinically relevant. The FDC displayed safety and tolerability profiles similar to the loose combination.

STUDY OF COMPARATIVE PHARMACOKINETICS AND BIOEQUIVALENCE OF DRUGS AMLODIPINE + VALSARTAN AND EXFORGE®

Objective: Drug Amlodipine+Valsartan is safe and effective for comprehensive treatment of arterial hypertension patients taken combined therapy by prescription. The development of new fix drug combination amlodipine and valsartan will provide in the near future a significant reduction in the cost of treatment. The aim of this work was investigation of bioequivalence for a generic drug Amlodipine+Valsartan, film-coated tablets, 10 mg+160 mg (Polpharma SA, Poland) and Exforge®, film-coated tablets, 10 mg+160 mg (Novartis Pharma AG, Switzerland). Materials and methods: 58 healthy volunteers were enrolled in open label, randomized, two sequence, two treatment cross-over study. Drugs were administered in two periods with a 21-day washout period in-between. Blood samples were collected over a 72-hour period. Amlodipine and Valsartan were measured in plasma using an automated LC-MS/MS assay. Pharmacokinetic parameters were calculated by non-compartmental analyses approach to evaluate AUC0-t, AUC0-∞ and Cmax. ANOVA was performed on the ln-transformed data and the 90% Confidence Interval (CI) was determined. Bioequivalence will be concluded if the 90% CI falls within 80-125% for AUC0-t and Cmax. Results: 53 volunteers completed the study and were considered for the pharmacokinetic and statistical analyses. Descriptive safety data analyses were performed on all 58 subjects. 90%-CI for corrected GMEAN of test and reference ratio was 94.76-105.24% for AUC0-t and 92.78-108.79% for Cmax in the case of amlodipine; 94.93-119.61% for AUC0-t and 90.41-116.03% for Cmax in the case of valsartan. So all pharmacokinetic parameters met the acceptance criteria as the 90% CI were within 80.00-125.00%. Conclusion: This study showed that Amlodipine+Valsartan, film-coated tablets, 10 mg+160 mg (Polpharma SA, Poland) is bioequivalent to reference product Exforge®, film-coated tablets, 10 mg+160 mg (Novartis Pharma AG, Switzerland).

Regulatory assessment of drug dissolution profiles comparability via maximum deviation.

In drug development, comparability of dissolution profiles of 2 different formulations is usually assessed using the similarity factor f2 . In practice, the drug dissolution profiles are deemed similar if the f2 exceeds 50, which occurs when a 10% maximum difference in the mean percentage of the dissolved drug at each time point between test and reference formulation is obtained. According to the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **) use of the f2 is however restricted by a set of validity conditions. If some of these conditions are not satisfied, the f2 is not considered suitable, and alternative statistical methods are needed. In this article, we propose an inferential framework based on the maximum deviation between curves to test the comparability of drug dissolution profiles. The new methodology is applicable regardless whether the validity criteria of the f2 are met or not. Contrary to the f2 , this approach also integrates the variability of the measurements over time and not only their average. To benchmark our method, we performed simulations informed by 3 real case studies provided by the European Medicines Agency and extracted from dossiers submitted to the Centralised Procedure for Marketing Authorisation Application. In the scenarios of the simulation study, the new method controlled its type I error rate when the maximum deviation was greater than the similarity acceptance limit of 10%. The power exceeded 80% for small values of the maximum deviation, while the test was more conservative for intermediate ones. Our results were also very robust to sampling variations. Based on these positive findings, we encourage applicants to consider the new maximum deviation-based method as a valid alternative to the f2 , especially when the validity criteria of the latter are not met.

Planning Bioequivalence Studies of Drugs with Narrow Therapeutic Indices

The principles for assessing therapeutic equivalence based on bioequivalence studies as accepted in Russia are significantly different from those adopted abroad, in particular with respect to drugs with narrow therapeutic indices (NTI). Certification of these drugs based on bioequivalence studies with commonly recognized limits is unacceptable in practice because drugs in this concentration range can cause serious adverse side effects and be more dangerous than the reference drug. The situation becomes especially critical when the reference drug is replaced by a generic. This circumstance creates the need to develop stricter regulations for NTI drugs. This article analyzes possible approaches to planning bioequivalence investigations for NTI drugs as adopted by leading world regulatory institutions in order to harmonize them with bioequivalence studies of NTI drugs in the Russian Federation. General recommendations for planning bioequivalence studies of NTI drugs were formulated based on the analysis.

Measurement of in vivo Gastrointestinal Release and Dissolution of Three Locally Acting Mesalamine Formulations in Regions of the Human Gastrointestinal Tract.

As an orally administered, locally acting gastrointestinal drug, mesalamine products are designed to achieve high local drug concentration in the gastrointestinal (GI) tract for the treatment of ulcerative colitis. The aim of this study was to directly measure and compare drug dissolution of three mesalamine formulations in human GI tract and to correlate their GI concentration with drug concentration in plasma. Healthy human subjects were orally administered Pentasa, Apriso, or Lialda. GI fluids were aspirated from stomach, duodenum, proximal jejunum, mid jejunum, and distal jejunum regions. Mesalamine (5-ASA) and its primary metabolite acetyl-5-mesalamine (Ac-5-ASA) were measured using LC-MS/MS. GI tract pH was measured from each GI fluid sample, which averaged 1.82, 4.97, 5.67, 6.17, and 6.62 in the stomach, duodenum, proximal jejunum, middle jejunum, and distal jejunum, respectively. For Pentasa, high levels of 5-ASA in solution were observed in the stomach, duodenum, proximal jejunum, mid jejunum, and distal jejunum from 1 to 7 h. Apriso had minimal 5-ASA levels in stomach, low to medium levels of 5-ASA in duodenum and proximal jejunum from 4 to 7 h, and high levels of 5-ASA in distal jejunum from 3 to 7 h. In contrast, Lialda had minimal 5-ASA levels from stomach and early small intestine. A composite appearance rate (CAR) was calculated from the deconvolution of individual plasma concentration to reflect drug release, dissolution, transit, and absorption in the GI tract. Individuals dosed with Pentasa had high levels of CAR from 1 to 10 h; individuals dosed with Apriso had low levels of CAR from 1 to 4 h and high levels of CAR from 5 to 10 h; Lialda showed minimal levels of CAR from 0 to 5 h, then increased to medium levels from 5 to 12 h, and then decreased to further lower levels after 12 h. In the colon region, Pentasa and Apriso showed similar levels of accumulated 5-ASA excreted in the feces, while Lialda showed slightly higher 5-ASA accumulation in feces. However, all three formulations showed similar levels of metabolite Ac-5-ASA in the feces. These results provide direct measurement of drug dissolution in the GI tract, which can serve as a basis for investigation of bioequivalence for locally acting drug products.

The free fractions of circulating docosahexaenoic acid and eicosapentenoic acid as optimal end-point of measure in bioavailability studies on n-3 fatty acids

The high complexity of n-3 fatty acids absorption process, along with the huge amount of endogenous fraction, makes bioavailability studies with these agents very challenging and deserving special consideration. In this paper we report the results of a bioequivalence study between a new formulation of EPA+DHA ethyl esters developed by IBSA Institut Biochimique and reference medicinal product present on the Italian market. Bioequivalence was demonstrated according to the criteria established by the EMA Guideline on the Investigation of Bioequivalence. We found that the free fractions represent a better and more sensitive end-point for bioequivalence investigations on n-3 fatty acids, since: (i) the overall and intra-subject variability of PK parameters was markedly lower compared to the same variability calculated on the total DHA and EPA fractions; (ii) the absorption process was completed within 4h, and the whole PK profile could be drawn within 12–15h from drug administration.

Establishing postprandial bio-equivalency and IVIVC for generic metformin sustained release small sized tablets

The objective of current study was to develop metformin hydrochloride modified release small sized tablets, and to evaluate its bioequivalence when compared with the reference product (Glucophage® SR). The physicochemical properties of the formulated and reference tablets were determined and compared. The in vitro dissolution profiles of formulated tablets were obtained using bio-relevant media and IVIVC was established. Bioequivalence investigation was carried out in 32 healthy male volunteers who received a single dose 1,000 mg of both test and reference products in a randomized two-way crossover design in postprandial conditions. After dosing, serial blood samples were collected for a period of 48 h. Metformin concentration was assayed by using a validated LC–MS/MS method. The log-transformed Cmax and AUC were statistically compared by analysis of variance, and the 90 % confidence intervals (CI) of the ratio of the log-transformed Cmax and AUC between the most promising developed formulation and the reference product were determined. It was deduced that the dissolution rate profile of the formulated modified release small sized tablets was similar to the reference product employed in the study. Their similarity and difference factors were found to be well within the established limits. In the bioequivalence study, the difference in Cmax, AUClast and AUCinf between the test and reference product was not statistically significant, with the 90 % CI of 100.73–116.20, 86.16–97.37 and 87.12–96.99 %, respectively. The results suggested that the metformin small tablets formulated with reduced quantity of controlled release polymer were found to be bioequivalent in the postprandial state. For these small tablets, pH 5.5 acetate buffer as a bio-relevant dissolution media for the development of IVIVC.

Bioequivalence Study of Two 50 mg Desvenlafaxine Extended Release Formulations: A Randomized, Single-Dose, Open-Label, Two Periods, Crossover Study

This is a pharmacokinetic study of two formulations containing Desvenlafaxine succinate 50 mg extended release. Its objective was to compare the bioavailability between the Test product (Desvenlafaxine ER produced by Tecnoquimicas S.A., Colombia laboratory) and the Reference product (Pristiq XR® produced by Wyeth laboratory) and to be able to determine the Bioequivalence between the both of them. For this, an open label, two periods, two previously randomized sequences, crossover, single postprandial 100 mg dose study with an 8 days washout period between each period in 24 healthy volunteers was performed, including the collection of 13 plasma samples within 0 and 48 hours from all volunteers who participated in the clinical phase. The analytical method used was High Performance Liquid Chromatography (HPLC) with UV detector. The obtained mean peak concentration (Cmax) for the Test and Reference products were 215.8 ng/mL and 196.9 ng/mL and for the area under the curve up to 48 hours (AUC0-t) 3849,6 ng.h/mL and 3605,4 ng.h/mL respectively. The 90% confidence interval for the Cmax parameter is within the range of 103,58-113,63 and for the AUC0-t parameter, the 90% confidence interval is within 97,96-111,39. Based on the FDA, EMA and WHO bioequivalence investigation guidelines, the CI is within the allowed ranges for bioequivalence and interchangeability declaration of the Tecnoquimicas S.A. product with the Reference product.

Bioequivalence Studies for 2 Different Strengths of Irbesartan/hydrochlorothiazide Combination in Healthy Volunteers: 300/25 mg and 300/12.5 mg Film-coated Tablets

Two bioequivalence studies of irbesartan (CAS 138402-11-6) and hydrochlorothiazide (CAS 58-93-5) combination at 300/12.5 mg and 300/25 mg strengths were carried out in order to assess the bioequivalence of these film-coated tablet formulations in comparison with the marketed reference formulations.Both studies were performed with 30 healthy volunteers according to an open label, randomized, 2-period, 2-sequence, crossover, single dose and fasting conditions design. In each study, test and reference formulations were administered in 2 treatment days, separated by a washout period of 7 days. Blood samples were drawn up to 72 h following drug administration in case of irbesartan and up to 24 h in case of hydrochlorothiazide. Plasma concentrations of both analytes were obtained by a validated HPLC method using MS/MS detection. Log-transformed AUC0-t and Cmax values were tested for bioequivalence based on the ratios of the geometric LSmeans (test/reference).For both studies, the 90% confidence intervals of the geometric LSmean values for the test/reference ratios for AUC0-t [(irbesartan: 300/12.5 mgstrength: 95.33-111.74%. 300/25 mg strength: 91.27-103.93%) (hydrochlorothiazide: 300/12.5 mg strength: 99.63-107.50%. 300/25 mg strength: 95.72-102.24%)] and Cmax [(irbesartan: 300/12.5 mg strength: 98.73-115.03%. 300/25 mg strength: 97.27-112.12%) (hydrochlorothiazide: 300/12.5 mg strength: 97.34-112.06%. 300/25 mg strength: 93.29-106.38%)] were within the bio-equivalence acceptance range of 80-125%.According to the European Guideline on the Investigation of Bioequivalence it may be therefore concluded that both test formulations are bioequivalent to the corresponding reference formulations. Overall, it was judged that both studies were conducted with a good tolerance of the subjects to study drugs.