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Parallel artificial membrane permeability analysis (PAMPA) is used to determine the permeability of compounds through concentrated negatively charged phospholipid bilayer barriers. We employed MacroFlux (a scaled-up version of PAMPA) to test the permeation rate of terazosin hydrochloride (TH) tablets and predict in vivo bioequivalence. The dissolution profiles and permeability of one reference formulation, and seven generic TH tablets, were compared. The dissolution profiles of these generic tablets were equivalent to that of the reference drug in four different media. However, the flux and the total permeated amount of some generic TH tablets were below the lower limit of the confidence interval of the original acceptance range in MacroFlux, which implied risk in the bioequivalence test in vivo. We further evaluated potential factors responsible for this discrepancy by µFlux, including active pharmaceutical ingredient (API) permeability and excipient prescriptions. The analysis showed that different properties of API were a main factor leading to biological inequivalence in the MacroFlux assay, while excipient prescriptions did not have an impact on bioequivalence risk. These data indicated that the flux assay may be a helpful as an auxiliary method for predicting bioequivalence of generic drugs and analyze the factors responsible for bioequivalence risk. [ABSTRACT FROM AUTHOR]

Purpose: Το formulate a methodology for the assessment of bioequivalence using metrics, which are based on the physiologically sound F.A.T. concept. Methods: The equations of the physiologically based finite time pharmacokinetic models for the one-and two-compartment model with one and two input stages of absorption were solved to derive metrics for the extent and rate of absorption. Simulated data were used to study the proper way for the estimation of metrics. A bioequivalence study was analyzed using these metrics. Results: The rate of drug absorption was found to be equal to the slope of the amount absorbed versus time curve. The amount of drug absorbed at the end of the absorption process, corresponding to the blood concentration at F.A.T. is an indicator of the extent of absorption. The plot of the ratio test/reference of the simulated data for the amount absorbed as a function of time becomes constant beyond the end of drug absorption from the formulation exhibiting the longer absorption. The assessment of the bioequivalence study was based on the slope of the amount absorbed versus time curve for the rate of absorption, while the estimate for the constant ratio test/reference for the amount absorbed was used for the assessment of extent of absorption. Conclusions: The assessment of rate in bioequivalence studies can be based on the estimation of slope of the percent absorbed versus time curve while the constant ratio test/reference for the amount of drug absorbed is an indicator of the extent of absorption. [ABSTRACT FROM AUTHOR]

Patients are often switched between generic formulations of the same drug, but in some cases generic interchangeability is questioned. For generic drugs to be approved, bioequivalence with the innovator drug should be demonstrated, but evidence of bioequivalence is not required in the intended patient population or relative to other approved generics. Aim: We aim to identify pathophysiological pharmacokinetic subpopulations for whom there is a difference in comparative bioavailability compared to a healthy population. Methods: We used simulated exposures from a nonparametric model of multiple generics and the originator gabapentin. Exposure was simulated for virtual populations with pharmacokinetic characteristics beyond those of healthy subjects with regard to rate of absorption, volume of distribution and reduced renal function. Virtual parallel design bioequivalence studies were performed using a random sample of 24 simulated subjects, with standard acceptance criteria. Results: Results indicated increased pharmacokinetic variability for patient populations with a lower rate of absorption or a reduced renal function, but no change in the average comparable bioavailability ratio. This increased variability results in a reduced likelihood of demonstrating bioequivalence. Observations were similar for comparisons between all different formulations, as well as between subjects who received the identical formulation in a repeated fashion. No relevant effect was observed for simulations with increased volume of distribution. Conclusion: Our simulations indicate that the reduced likelihood of demonstrating bioequivalence for subjects with altered pharmacokinetics is not influenced by a formulation switch, nor does the average comparable bioavailability ratio change, therefore these results support generic interchangeability and current approval requirements for generics. [ABSTRACT FROM AUTHOR]

Background and Objective: Venlafaxine hydrochloride extended-release (ER) capsules are commonly used to treat depression and anxiety disorders. Evaluation of the bioequivalence of generic formulations with reference products is essential to ensure therapeutic equivalence. The objective of this study was to evaluate the bioequivalence, safety, and tolerability of Chinese-manufactured venlafaxine hydrochloride extended-release capsules compared with USA-manufactured EFFEXOR® XR in healthy Chinese volunteers under fed conditions. Methods: A randomized, open-label, single-dose, crossover study was conducted. Subjects were randomly assigned to receive the test formulation (one 150-mg ER capsule manufactured in China) or the reference formulation (one 150-mg ER capsule manufactured in the USA). The bioequivalence of the two drugs was assessed using the area under the plasma concentration–time curve from time zero to the last sampling time (AUC0–t) and the maximum observed concentration (Cmax). Results: A total of 28 subjects were enrolled and randomly assigned to receive a single dose of either the test or reference capsule. All the subjects completed the study and were included in the pharmacokinetic (PK) and safety analyses. The mean AUC0–t and Cmax of venlafaxine and its active metabolite O-desmethylvenlafaxine were comparable between the test and reference products with both parameters close to 100% and the corresponding 90% confidence intervals within the specified 80–125% bioequivalence boundary. Safety was also assessed between the two products and all adverse events (AEs) in this study were mild in severity. Conclusions: Both the test and reference venlafaxine hydrochloride ER capsules were bioequivalent and showed a similar safety and tolerability profile in the population studied. Clinical Trials Registration: This study was registered at the Drug Clinical Trial Registration and Information Publicity Platform (http://www.chinadrugtrials.org.cn/index.html) with registration number CTR20211243, date: June 1, 2021. [ABSTRACT FROM AUTHOR]

A simple, sensitive, selective, accurate and precise method was developed and fully validated for determination of oxcarbazepine (OXC) in presence of their preservatives and determination of oxcarbazepine (OXC) in human plasma. A reversed phase liquid chromatography (RP-HPLC) with UV detection techniques were applied for separation and quantification of studied drug OXC. Successful separation of the drug from methyl paraben (M.P.), propyl paraben (P.P.) and potassium sorbate (P.ST.) was achieved on a Kromasil C18 column (5 μm particle size, pore size 300 Å, l × I.D. 250 × 4.6 mm). The mobile phase that contain aqueous 0.05M potassium dihydrogen phosphate buffer (pH 7): acetonitrile, (50: 50, %v/v). The method was linear over concentration ranges 5.0–50 μg mL−1 for OXC. Bioanalytical validation of the developed method was carried out according to US-FDA guidelines and revealed a good linear relations over a range of (5.0–50), (0.5–10), (0.05–0.15), and (1.0–10) μg mL−1 for OXC, M.P, P.P, and P.ST, respectively, with a correlation coefficient (R2) of more than 0.999. Limit of detection (LOD) were 1.15, 0.03, 0.01 and 0.04 μg mL−1 for OXC, M.P, P.P, and P.ST, respectively, Intra and inter-day precisions, calculated as percentage relative standard deviation (% RSD), were lower than 2.0%. The developed method can be applied for routine drug analysis, therapeutic drug monitoring and bioequivalence studies through the analysis of plasma samples taken from blood bank. [ABSTRACT FROM AUTHOR]

Despite clinical advances with protein kinase inhibitors (PKIs), oral administration of many PKIs is associated with highly variable plasma exposure and a narrow therapeutic window. We developed a novel hybrid nanoparticle‐amorphous solid dispersion (ASD) technology platform consisting of an amorphous PKI embedded in a polymer matrix. The technology was used to manufacture immediate‐release formulations of 2 tyrosine kinase inhibitors (TKIs), dasatinib and sorafenib. Our primary objective was to improve the absorption properties and reduce the pharmacokinetic (PK) variability of each TKI. The PKs of XS004 (dasatinib‐ASD, 100 mg tablet) and XS005 (sorafenib‐ASD, 2 × 50 mg capsules) were compared with their crystalline formulated reference drugs (140 mg of dasatinib‐reference and 200 mg of sorafenib‐reference). The in vitro biopharmaceutics of dasatinib‐ASD and XS005‐granulate showed sustained increased solubility in the pH range 1.2‐8.0 compared to their crystalline references. In vivo, XS004 was bioequivalent at a 30% lower dose and showed increased absorption and bioavailability, with 2.1‐4.8 times lower intra‐ and intersubject variability compared to the reference. XS005 had an increased absorption and bioavailability of 45% and 2.2‐2.8 times lower variability, respectively, but it was not bioequivalent at the investigated dose level. Taken together, the formulation platform is suited to generate improved PKI formulations with consistent bioavailability and a reduced pH‐dependent absorption process. [ABSTRACT FROM AUTHOR]

Adaptive designs can be selected for bioequivalence studies of drugs for which there are no data on the variability of pharmacokinetic parameters (the within-individual variability coefficient, CVintra). These are designs with prospective plans for modification of volunteer sample size based on analysis of the results obtained within the study. The aim of the present work was to analyze the guidelines and protocols for bioequivalence studies with adaptive designs for the validity of selecting such a design for a number of parameters. The results of this retrospective study identified key points and generated a list of shortcomings. The need for a comprehensive literature search for CVintra values is noted - selection of an adaptive design is justified if no such a search is run and/or when there are conflicting data. Decision criteria for the selection of adaptive designs in bioequivalence studies are presented. Examples given will unify the approach and avoid mistakes in planning further bioequivalence studies. [ABSTRACT FROM AUTHOR]

Model‐informed drug development is an important area recognized by regulatory authorities and is gaining increasing interest from the generic drug industry. Physiologically based biopharmaceutics modeling (PBBM) is a valuable tool to support drug development and bioequivalence assessments. This study aimed to utilize an artificial neural network (ANN) with a multilayer perceptron (MLP) model to develop a sustained‐release matrix tablet of metformin HCl 500 mg, and to test the likelihood of the prototype formulation being bioequivalent to Glucophage® XR, using PBBM modeling and virtual bioequivalence (vBE). The ANN with MLP model was used to simultaneously optimize 735 formulations to determine the optimal formulation for Glucophage® XR release. The optimized formulation was evaluated and compared to Glucophage® XR using PBBM modeling and vBE. The optimized formulation consisted of 228 mg of hydroxypropyl methylcellulose (HPMC) and 151 mg of PVP, and exhibited an observed release rate of 42% at 1 h, 47% at 2 h, 55% at 4 h, and 58% at 8 h. The PBBM modeling was effective in assessing the bioequivalence of two formulations of metformin, and the vBE evaluation demonstrated the utility and relevance of translational modeling for bioequivalence assessments. The study demonstrated the effectiveness of using PBBM modeling and model‐informed drug development methodologies, such as ANN and MLP, to optimize drug formulations and evaluate bioequivalence. These tools can be utilized by the generic drug industry to support drug development and biopharmaceutics assessments. [ABSTRACT FROM AUTHOR]

The comparative bioavailability and bioequivalence of drugs containing magnesium citrate were studied. Logistic regression models were constructed to assess the effect of the background magnesium content on the magnesium concentration after use of the drugs. The following pharmacokinetic parameters were evaluated: the maximum concentration of magnesium in whole blood of volunteers (Cmax), the time to reach the maximum concentration of magnesium in whole blood of volunteers (tmax), and the area under the plasma-concentration(time pharmacokinetic curve (AUC(0-t)). Arecalculation taking into account the endogenous magnesium level was used for a correct calculation of the pharmacokinetic parameters. The studied drugs were found to be bioequivalent with calculated 90% confidence intervals falling within the acceptable range of 80 – 125%. Logistic regression models were constructed where the concentrations after taking the studied drugs were chosen as the dependent variables; the background magnesium contents, the influential factor. The correlation between the background value and Cmax in volunteers that took the studied and reference drugs was noticeable and positive (on the Chaddock scale) at 0.650 and 0.667, respectively, and statistically significant (p < 0.006 and p < 0.005). The resulting model took into account 42.3% and 44.4%, respectively, of the factors determining changes in the Cmax level. It was concluded that construction of a logistic regression model of the relationship between the background magnesium concentration and the concentration after taking the studied drugs could be considered one possible predictor that can be used to assess the bioavailability of drugs containing magnesium salts. [ABSTRACT FROM AUTHOR]

The objective of the conducted research was to design 2 mm orodispersible minitablets of pediatric doses of hydrocortisone (0.5 mg; 1.0 mg) with desirable pharmaceutical properties and eliminate the sensation of a bitter taste using preparation of solid dispersion by ball mill. Hydrocortisone was selected as the model substance, as it is widely utilized in the pediatric population. ODMTs were prepared by compression (preceded by granulation) in a traditional single-punch tablet machine and evaluated using pharmacopoeial tests, DSC, and FTIR analysis. The methods used to evaluate the effectiveness of the taste-masking effect included in vivo participation of healthy volunteers, in vitro drug dissolution and utilization of an analytical device—"electronic tongue". The research employed a preclinical animal model to preliminary investigate the bioequivalence of the designed drug dosage form in comparison to reference products. The study confirmed the possibility of manufacturing good-quality hydrocortisone ODMTs with a taste-masking effect owing to the incorporation of a solid dispersion in the tablet mass. [ABSTRACT FROM AUTHOR]

Objective • Levocetirizine hydrochloride is the R-enantiomer of cetirizine, which is a new-generation histamine H1 receptor antagonist with high safety, selectivity, and affinity. As a high-efficiency non-sedating antihistamine, levocetirizine hydrochloride has been widely used in the clinical treatment of skin, respiratory, and eye allergies. However, the bioavailability of levocetirizine hydrochloride granules remains to be determined. The study examined the relative bioavailability of the test drug (levocetirizine hydrochloride granules (Kangzhitai® )) and determined whether Kangzhitai® was bioequivalent to the reference drug (levocetirizine (Xyzal® )) in healthy individuals. Methods • Twenty eligible healthy male subjects were randomly divided into two groups. Group one received 5 mg of Kangzhitai®, followed by a 10-day wash-out period and 5 mg of Xyzal® on day 11. Group two received the same doses but in a reverse sequence. The subjects fasted for 12 h, and blood samples were collected before (blank) and after administration. The plasma concentration of Kangzhitai® was determined by HPLC-MS-MS. Pharmacokinetic parameters were analyzed using DAS 2.0 software. Results • The main pharmacokinetic parameters Cmax, Tmax, T1/2, AUC0-48, and AUC0-∞ of the Xyzal® and Kangzhitai® groups were as follows: (218.4 ± 46.4) μg/L vs. (213.6 ± 39.3) μg/L, (0.73 ± 0.32)/h vs. (0.75±0.3)/h, (9.2 ± 2.0) h vs. (8.9 ± 2.7) h, (1594.0 ± 337.2) μg·h/L vs. (1652.6 ± 383.5) μg·h/L, and (1683.2 ± 338.5) μg·h/L vs. (1753.7 ± 445.4) μg·h/L. The two-one-sided t tests of Cmax, AUC0-48, and AUC0-∞ showed that th and t1 were both higher than one-sided t0.05. The 90% confidence intervals (CI) for AUC0-48 and AUC0-∞ of Kangzhitai® did not exceed 80%- 125% of AUC0-48 and AUC0-∞ of Xyzal® . The 90% CI for the Cmax of Kangzhitai® did not exceed 70%-143% of the Cmax of Xyzal® . There was no significant difference in Tmax between the two drugs. The relative bioavailability (F, assessed by AUC0-48) of Kangzhitai® vs. Xyzal® was 104.4±18.5%. No adverse events occurred during the drug administration. Conclusion • The results indicated that there was no significant difference in absorption between Kangzhitai® and Xyzal®, which confirmed the bioequivalence of the two drugs. [ABSTRACT FROM AUTHOR]

Quantitative methods and modeling (QMM) are rapidly demonstrating their potential to support generic drug development and assessment. The session explored generic industry perspectives about the challenges impacting generic product development that are the most critical to address by GDUFA research initiatives during the next 5 years. MAIN TEXT On May 9 and 10, 2022, the US Food and Drug Administration (FDA) hosted the Fiscal Year (FY) 2022 Generic Drug Science and Research Initiative Public Workshop as a commitment under the Generic Drug User Fee Amendments of 2017 (GDUFA II). [Extracted from the article]

Background and Objectives: Acoziborole is a novel boron-containing candidate developed as an oral drug for the treatment of human African trypanosomiasis (HAT). Results from preclinical studies allowed progression to Phase 1 trials. We aimed to determine the best dose regimen for all stages of HAT. Methods: Acoziborole was assessed in 128 healthy adult males of sub-Saharan African origin living in France. The study included a single oral administration of a 20- to 1200-mg dose in a randomised double-blind study in cohorts of 8 (6 active, 2 placebo) to assess safety, tolerability, and pharmacokinetics. In three additional open cohorts of 6 participants, the effect of activated charcoal was evaluated, bioequivalence of capsules versus tablets was assessed, and safety in the 960-mg tablet cohorts was monitored. Results: Acoziborole was well tolerated at all doses tested; no dose-related adverse events were observed. The drug appeared rapidly in plasma (at 1 h), reached tmax between 24 and 72 h, and remained stable for up to 96 h, after which a slow decrease was quantifiable until 14 weeks after dosing. Charcoal had little impact on the enterohepatic recirculation effect, except for the 20-mg dose. Bioequivalence between capsule and tablet formulations was demonstrated. The therapeutic single dose for administration under fasted conditions was fixed to 960 mg. The maximum administered dose was 1200 mg. Conclusions: This study showed that acoziborole could be safely assessed in patients as a potential single-dose oral cure for both stages of gambiense HAT. Trial Registration: The study was registered with ClinicalTrials.gov: NCT01533961. [ABSTRACT FROM AUTHOR]

The test drug, a recombinant humanized monoclonal antibody, is a biosimilar candidate for the reference drug. The purpose of this study was to evaluate the bioequivalence of these two drugs. The study was divided into two parts, a pre‐study and a formal trial. The pre‐study included two subjects who were each given a single intravenous infusion of 6 mg/kg test drug. The formal trial was designed to be a randomized, double‐blind, parallel controlled trial in which 70 subjects were randomly assigned 1:1 to receive either test or reference drug as a single 6 mg/kg intravenous infusion. In the pre‐study, the immunogenicity was negative in both subjects and the safety of the test drug was considered to be good. The two groups in the formal trial had similar demographic characteristics. The 90% confidence interval of geometric mean ratios of area under the serum concentration‐time curve from the time 0 to the time of last quantifiable concentration, area under the serum concentration‐curve from time 0 to infinity, and maximum observed serum concentration between the test group and the reference group fell between 80% and 125% and the bioequivalence was recognized. There was no significant difference in the positive rate of antidrug antibodies. The treatment‐emergent adverse events in the test group were similar to those in the reference group. This study showed that the test drug has similar pharmacokinetics, immunogenicity, and safety to the reference drug in healthy male subjects. [ABSTRACT FROM AUTHOR]

Objectives: Certain patient populations (e.g., children and the elderly) may not be able to swallow solid oral dosage forms. In the absence of availability of a dosage form that is appropriate for these patient groups, liquids and/ or soft foods as described in the Food and Drug Administration (FDA)-approved product labeling can be used as a suitable vehicle(s) for oral administration of the specific drug product. The approved labeling of some new drug application (NDA) products contains information for sprinkle administration on liquids or soft foods. Since abbreviated new drug application (ANDA) products must demonstrate bioequivalence (BE) to the reference listed drug (RLD) products, and since the generic drug labeling is the same as RLD, generic applicants are recommended to conduct in vivo BE sprinkle study using one of the soft foods mentioned in RLD labeling. The current FDA guidance specifically recommends that generic applicants conduct a sprinkle BE study if the labeling of a modified-release (MR) RLD product states that the product can be administered sprinkled on soft foods. For ANDAs, such recommendations for in vivo BE sprinkle studies for MR products are routinely communicated in the respective product-specific guidance (PSG) published by FDA and readily available for prospective ANDA applicants. FDA guidance does not recommend sprinkle BE study for an immediate-release (IR) product since the formulation differences between IR generic and RLD products are not expected to impact administration with food vehicle. Materials and Methods: FDALabel and PSG databases were searched for current NDAs with sprinkle labeling and individual PSGs with recommendations for an in vivo sprinkle BE study, respectively. Results from FDALabel were narrowed to NDAs for oral solid dosage forms with approved labeling for sprinkle administration on food vehicles. Only MR NDAs with sprinkle labeling were included in the final analysis as recommended by FDA for inclusion of in vivo sprinkle BE study recommendations in PSGs for generic products. We searched the FDA external PSG database for availability of respective PSGs containing in vivo sprinkle study recommendations for those MR products with approved NDA labeling for sprinkle administration. Results: Of the 57 NDAs with FDA-approved drug products that are labeled to include sprinkle administration, 45 NDAs were MR (tablet, capsule, and granule) products. Forty-two (93%) of the 45 MR products have PSGs with in vivo sprinkle BE study recommendations. Standardized data extraction sheets created by Microsoft Excel 2019 for data extraction were utilized. Conclusion: FDA has a sprinkle-study PSG for almost all currently approved MR NDAs. The results of our study show that in vivo BE study recommendations in PSGs closely match information in the approved drug labeling. Applicants who plan to develop MR generic products should visit the FDA public web page for the availability of the product-specific BE recommendations for the proposed products. [ABSTRACT FROM AUTHOR]

This study is intended to analyze the design implemented in the bioequivalence testing of a generic product based on praziquantel and milbemycin oxime. The main objective of the study is to develop a protocol suitable for testing the bioequivalence and bioavailability of a new generic anthelmintic product intended for the therapeutic interchange of the innovative product Milbemax, whose patent has expired. The achievement of the proposed objective was ensured by the implementation of a single-center, cross-over, randomized, two-phase design separated by a break of 30 days between them. The current study was conducted on 22 clinically healthy Siberian Husky dogs. The analysis of the values obtained during the monitoring of the clinical and hematologic parameters, revealed evolutions within the allowed ranges, with the deviations being rare and devoid of clinical or statistical significance. Providing information regarding the field of bioequivalence of two similar antiparasitic products, being aware of the regulations in force as well as their recommendation by the treating veterinarian, in prophylaxis and anthelmintic therapy, is a good strategy to promote the use and acceptance of the new generic drugs. [ABSTRACT FROM AUTHOR]

The aim. To investigate the polymorphic structure of the API-dapagliflozin propanediol monohydrate and to reveal the absence of an effect of the tabletting process on the polymorphic structure of the API in model compositions of tablets. Materials and methods. Model mixtures of API-dapagliflozin propanediol monohydrate and excipients were studied. The research used the method of designing pharmaco-technological parameters of solid dosage forms, the method of quantum-chemical modelling of the mechanical properties of polymorphic modifications of APIs, the modelling of shear deformation, the nanoindentation method, the Rietveld method for calculating X-ray patterns, X-ray structural analysis of API and selected model compositions of tablets. Results. The polymorphic structure of API-dapagliflozin propanediol monohydrate and its polymorphic structure in selected model compositions of tablets produced by the pressing method were studied and analyzed. An X-ray structural study was carried out, and the qualitative and phase composition of samples and polymorphic modifications of API and model series of tablets were determined. According to the results of the X-ray structural analysis, it was established that there is no polymorphic transition and that the polymorphic structure of API is invariant under the influence of pressing pressure, which ensures the quality of the tablet form. Conclusions. The design of an experimental study was determined based on the application of the QbD concept, design of experiments -- DoE, for designing and ensuring a high-quality technological process -- tabletting of API-dapagliflozin propanediol monohydrate and excipients. To manage a critical technological parameter -- the stability of the polymorphic structure of the API, which guarantees the quality of the tablet form, its bioavailability and bioequivalence, it is necessary to use a set of methods for studying structural changes and polymorphic modifications of the API during the tableting process. According to the results of the X-ray structural study of API and selected model compositions of tablets, it was established that during the process of tabletting under pressure, the structure of the polymorphic modification of dapagliflozin propanediol monohydrate does not change, and no polymorphic transition is observed [ABSTRACT FROM AUTHOR]

Eplerenone (EPL) and spironolactone (SPR) belong to the class of potassium-sparing diuretics. Both drugs are prescribed for the treatment of hypertension and heart failure. Spironolactone is structurally like progesterone and binds to progesterone, androgen and mineralocorticoid receptors. Eplerenone is a selective mineralocorticoid receptor antagonist, so it lacks the anti-androgenic side effects of spironolactone. Using a thorough computer assisted literature survey; this review article touches upon the reported analytical methods for the quantification of both drugs in raw materials, pharmaceutical dosage forms and biological fluids. Bioanalytical methods are widely used for quantitative estimation of drugs and their metabolites in biological matrices. Various analytical methods such as spectrophotometry, spectrofluorimetry, HPLC, TLC, and UPLC have been used in laboratories for the quantitative analysis of these drugs in biological samples and pharmaceutical preparations. Therefore, the aim of this review is to give a summary of the current analytical methods used for the assay of both drugs. The review represents a guide for the QC labs and the bioequivalence centers to analyze the studied drugs. [ABSTRACT FROM AUTHOR]

The aim of this study is to investigate pharmacokinetic parameters of test and reference film tablet formulations of a highly variable drug, pinaverium bromide, under fasting conditions and to assess their bioequivalence in accordance with the FDA and EMA criteria. A randomised open-label, single oral dose, three-sequence, three-period, semi-replicated, cross-over trial was conducted with 36 healthy subjects. The intrasubject variability of reference products for C max and AUC 0-tlast was found to be more than 50%. While bioequivalence was proven according to the FDA reference scaled average bioequivalence approach with only 36 subjects, more than 200 subjects are required to demonstrate bioequivalence in accordance with the EMA bioequivalence guideline. It is believed that the EMA bioequivalence criteria are too stringent for highly variable drugs whose intrasubject variability are more than 30% for both C max and AUC 0-tlast and that in consequence the EMA ought to revise their bioequivalence guidelines for such drugs in the future. [ABSTRACT FROM AUTHOR]

The dissolution test has become the most important quality index in the research and development of solid formulation, especially the evaluation of drug bioequivalence. However, it had low operability, was tedious, and was always overlooked. The previously related studies required a fixed tablet and analysed the recorded video by disso GUARO PRO and Microsoft Paint™. Therefore, we have developed a novel image recognition system to automatically track the moving tablet and analyse the volume change at the same time. Image recognition technology is often used to monitor the dissolution process. The camera system with visible light and infrared camera functions was placed on the dissolution tester. The system collects the plate image for binary processing and then records and calculates its pixel area, which can automatically record the volume change of the tablet in the dissolution test, no matter disintegration or corrosion. [ABSTRACT FROM AUTHOR]

Approval of drug products for market registration warrants, among other data, evidence to support their safety and effectiveness in the target populations. The extent of investigations to provide the supporting evidence varies between the new innovator products and their follow-on versions generally referred to as Generic Drugs Products in the United States and Hybrids in the Europe. The new drug applications entail large data sets encompassing both nonclinical and clinical product developments. Safety and effectiveness in man is studied in sequentially phased clinical trials, including post marketing evaluations (Where applicable). However, for the generic/hybrid products the safety and effectiveness are established through determination of bioequivalence in head-to-head comparison between the originator and the follow-ons. Methods for documentation of bioequivalence for drug products that reach target site(s) through systemic circulation are aligned worldwide. However, establishing bioequivalence of orally inhaled drug products is complex as drug delivery to the local site(s) of action is independent of the systemic circulation. Documentation of bioequivalence gets further complicated due to the Drug-Device combination nature of these products. The guidelines for establishment of BE of locally acting orally inhaled drugs products vary among certain geographies. This article examines the scientific underpinning of distinctions and similarities between the US and EU guidelines. Approval of drug products for market registration warrants, among other data, evidence to support their safety and effectiveness in the target populations. The extent of investigations to provide the supporting evidence varies between the new innovator products and their follow-on versions generally referred to as Generic Drugs Products in the United States and Hybrids in the Europe. The guidelines for establishment of BE of locally acting orally inhaled drugs products vary among certain geographies. This article examines the scientific underpinning of distinctions and similarities between the US and EU guidelines Schematic representation of the Cascade Impactor data evaluation in the US and EU [Display omitted] [ABSTRACT FROM AUTHOR]

The objective of this study was to demonstrate the bioequivalence of 2 oral tablet formulations of rivaroxaban 20 mg in healthy Mexican volunteers under fed conditions. This phase I, single‐blind, single‐dose, randomized, two‐sequence, two‐period crossover study included 32 volunteers. Subjects were randomly assigned to one of two sequences: test formulation (single 20 mg dose) in the first period followed by the reference formulation (single 20 mg dose) in the second, or vice versa. Blood samples were collected predose and at predefined timepoints across a 48‐hour period after drug intake. Rivaroxaban plasma concentrations were measured using a validated high‐performance liquid chromatography‐tandem mass spectrometry method. Pharmacokinetic parameters included maximum plasma concentration (Cmax), area under the plasma concentration‐time curve from time zero to last measurable concentration and to infinity (AUC0‐t, AUC0‐∞), time to reach Cmax, and half‐life. Safety was evaluated through adverse‐event monitoring using subject interviews and recording of vital signs. The 90% confidence intervals for the test/reference geometric mean ratios of Cmax (100.4%–112.7%), AUC0‐t (96.5%–111.6%), and AUC0‐∞ (95.5%–109.5%) were within the bioequivalence acceptance range (80‐125%). Two adverse events (headaches) were recorded. Both formulations of rivaroxaban 20 mg tablets were bioequivalent and well tolerated in a healthy population of Mexican volunteers under fed conditions. [ABSTRACT FROM AUTHOR]

Tebipenem pivoxil hydrobromide (TBP‐PI‐HBr) is a novel oral carbapenem prodrug of tebipenem (TBP), the active moiety, currently in development for treating serious bacterial infections. This study assessed the bioequivalence (BE) of the clinical trial and registration tablet formulations of TBP‐PI‐HBr and evaluated the effect of food on the pharmacokinetics (PKs) of tebipenem. This was a single center, open‐label, randomized, single‐dose, three‐sequence, four‐period crossover, BE, and food‐effect study. Subjects received single 600 mg oral doses of TBP‐PI‐HBr as the reference clinical trial tablet (treatment A) and test registration tablet (treatment B) formulations in alternating sequence while fasting, and then the test formulation under fed conditions. Whole blood samples were collected predose and at specified intervals up to 24 h postdose to evaluate TBP PK parameters. Safety and tolerability were monitored. Thirty‐six healthy, adult subjects were enrolled and completed the study. The criteria for BE were met for the TBP‐PI‐HBr test (registration tablet) and reference (clinical trial tablet) formulations as the 90% confidence intervals for the geometric mean ratios for TBP area under the curve (AUC)0‐t, AUC0‐inf, and maximum plasma concentration (Cmax) fell within the established 80% to 125% BE limits. Dosing with food had no meaningful effect on TBP PK parameters. Five (14%) subjects reported adverse events (AEs) of mild severity. No deaths, serious AEs, or discontinuations due to AEs were reported, and no clinically relevant electrocardiograms, vital signs, or safety laboratory findings were observed. The study results demonstrate the BE of oral TBP‐PI‐HBr registration and clinical trial tablet formulations and indicate that TBP‐PI‐HBr can be administered without regard to meals. [ABSTRACT FROM AUTHOR]

Osteoporosis is a common skeletal disorder, often leading to fragility fracture. Combination therapy with raloxifene, a selective estrogen receptor modulator, and cholecalciferol (vitamin D3) has been proposed to improve the overall efficacy and increase compliance of raloxifene therapy for postmenopausal osteoporosis. To our knowledge, there has been no report of any study on the pharmacokinetic interaction between raloxifene and cholecalciferol. This study aimed to evaluate the possible pharmacokinetic interactions between raloxifene and cholecalciferol in healthy adult male Korean volunteers. Twenty subjects completed this open‐label, randomized, single‐dose, 3‐period, 6‐sequence, crossover phase 1 study with a 14‐day washout period. Serial blood samples were collected from 20 hours before dosing to 96 hours after dosing. The plasma concentrations of raloxifene and cholecalciferol were determined using a validated method for high‐performance liquid chromatography with tandem mass spectrometry. The geometric mean ratios (90%CIs) for area under the plasma concentration–time curve from time 0 to the last quantifiable time point and maximum plasma concentration of raloxifene with or without cholecalciferol were 1.02 (0.87‐1.20) and 0.87 (0.70‐1.08), respectively. For baseline‐corrected cholecalciferol, geometric mean ratios (90%CIs) of area under the plasma concentration–time curve from time 0 to the last quantifiable time point and maximum plasma concentration with or without raloxifene were 1.01 (0.93‐1.09) and 0.99 (0.92‐1.06), respectively. Concurrent treatment with raloxifene and cholecalciferol was generally well tolerated. These results suggest that raloxifene and cholecalciferol have no clinically relevant pharmacokinetic drug‐drug interactions when administered concurrently. All treatments were well tolerated, with no serious adverse events. [ABSTRACT FROM AUTHOR]

Background and Objectives: Selatogrel is a potent, reversible, and selective antagonist of the platelet P2Y12 receptor currently developed for the treatment of acute myocardial infarction (AMI). In the completed Phase I/II studies, selatogrel was subcutaneously (s.c.) administered as a lyophilizate-based formulation by syringe by a healthcare professional. In the Phase III study, selatogrel will be self-administered s.c. as a liquid formulation with an autoinjector at the onset of AMI symptoms to shorten treatment delay. This clinical bridging study compared the pharmacokinetics (PK) of selatogrel between the different formulations. Methods: This was a single-center, randomized, open-label, three-period, cross-over Phase I study in 24 healthy subjects. In each period, a single subcutaneous dose of 16 mg selatogrel was administered as (1) a Phase III liquid formulation by autoinjector (Treatment A), (2) a Phase III liquid formulation by prefilled syringe (Treatment B), or (3) a Phase I/II reconstituted lyophilizate-based formulation by syringe (Treatment C). PK parameters including area under the plasma concentration–time curve from zero to infinity (AUC0–∞), maximum plasma concentration (Cmax), time to reach Cmax(tmax), and terminal half-life (t1/2) were determined using noncompartmental analysis. Pharmacodynamic (PD) parameters were estimated using PK/PD modeling, including the time of first occurrence of inhibition of platelet aggregation (IPA) ≥ 80% (tonset), duration of IPA above 80% (tduration), and responder rate defined as the percentage of subjects with tonset ≤ 30 min and tduration ≥ 3 h. Safety and tolerability were also assessed. Results: Comparing Treatment A to Treatment C, the exposure (AUC0–∞) was bioequivalent with a geometric mean ratio (GMR) (90% confidence interval) of 0.95 (0.92–0.97) within the bioequivalence range (0.80–1.25). Absorption following Treatment A was slightly slower with a tmax occurring approximately 30 min later and a 20% lower Cmax. The autoinjector itself had no impact on the PK of selatogrel, as similar values of Cmax and AUC0–∞ were determined after administration as a Phase III liquid formulation by autoinjector or by prefilled syringe (i.e., GMR [90% confidence interval] of 1.06 [0.97–1.15] and 0.99 [0.96–1.03] for Cmax and AUC0–∞, respectively). PK/PD modeling predicted that the median tonset will occur slightly later for Treatment A (7.2 min) compared to Treatment C (4.2 min), while no relevant differences in tduration and responder rate were estimated between the two treatments. Selatogrel was safe and well tolerated following all three treatments. Conclusions: PK and simulated PD effects of selatogrel were similar across treatments. Clinical Trial Registration: NCT04557280. [ABSTRACT FROM AUTHOR]

B #74 b B Detection of adverse drug reactions in hospitalized patients through laboratory alerts: Hyponatremia and rhabdomyolysis b Gina Mejía Abril, Mónica Valdés Garicano, Diana Campodónico, Raúl Parra Garcés and Francisco Abad Santos I Hospital Universitario de La Princesa, Madrid, Spain i B Objective: b The present work pretends to evaluate the performance of laboratory signals as a method of detecting adverse drug reactions (ADRs), using the examples of hyponatremia and rhabdomyolysis, and to describe the main drugs involved and patient characteristics. B SECTION: A. EVALUATION AND SELECTION OF MEDICINES b B #11 b B Off-label use of rituximab in patients with different types of nephropathies in a tertiary hospital: A retrospective study b Carla Sans Pola, Antònia Agustí Escasany SP 1,2,3 sp , Josep Àngel Bosch Gil SP 1,2 sp , Irene Agraz Pamplona SP 1 sp , Carmen Alerany Pardo SP 1 sp and Immaculada Danés Carreras SP 1,2,3 sp SP 1 sp I Vall d'Hebron Hospital Universitari, Barcelona, Spain; i SP 2 sp I Universitat Autònoma de Barcelona, Barcelona, Spain; i SP 3 sp I Vall d'Hebron Institut de Recerca, Barcelona, Spain i B Objective: b Off-label use of rituximab is commonly requested for patients with resistant nephropathies. This corresponds to a 2.2-fold increase in patients on OAT [from 329 297 patients in 2012 (308.548 patients on VKA and 20.749 patients on DOAC) to 738 340 patients in 2021 (267.639 patients on VKA and 470 701 patients on DOAC)]. Nocebo response was defined as proportion of patients receiving placebo that experienced Adverse Events (AEs), drug response as the proportion of patients receiving pharmacological treatment that suffered AEs, and drug safety as the ratio between drug response and nocebo response. [Extracted from the article]

Objective: The purpose of this single-center, randomized, open, two-period, two-sequence crossover, single-dose administration, bioequivalence research was to evaluate the bioequivalence and safety of the generic formulations of metformin hydrochloride sustained-release (MH-SR) 500 mg tablets (test preparation [T]: Yuantang® SR) and the original formulation (reference preparation [R]: Glucophage® XR) in 36 healthy Chinese volunteers under postprandial conditions. Methods: Subjects received 500 mg T/R in each period, with a 7-day washout period. Venous blood samples of 4 mL each were collected from each subject 19 times spanning predose (0 h) to 36 h postdose. The metformin concentration in deproteinized plasma was determined by high-performance liquid chromatography–tandem mass spectrometry. Bioequivalence (80.00–125.00%) was assessed by adjusted geometric mean ratios (GMRs) and two-sided 90% confidence intervals (CIs) of the area under the curve (AUC) and maximum concentration (Cmax) for each component. SAS 9.4 software was used for statistical analysis and Phoenix WinNonlin software v7 was used to analyze the pharmacokinetic parameters. Results: Thirty-four volunteers completed the clinical study. The 90% CIs (96.12–105.44% for AUC from time zero to the time of the last measurable concentration [AUCt], 96.22–105.54% for AUC extrapolated from time zero to infinity [AUC∞], and 98.42–105.00% for Cmax) of T/R adjusted GMRs were within the bioequivalence acceptance range of 80.00–125.00%, indicating that they are bioequivalent. No serious adverse events occurred in this study, indicating that the two formulations were effective and well tolerated. Conclusions: Yuantang® SR was confirmed to be a well tolerated and bioequivalent alternative to Glucophage® XR when taken under postprandial conditions in healthy Chinese volunteers. The Clinical Trials Registry Platform used for this study was http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml. The trial registration numbers (TRNs) and dates of registrations were CTR20180476 (19 April 2018) for this clinical trial and CTR20171595 (11 January 2018) for the pilot trial. [ABSTRACT FROM AUTHOR]

Background and Objectives: Exogenous human chorionic gonadotropin (hCG) acts on the final phase of the follicle maturation. Choriomon®, a highly purified hCG formulation, is approved in many European and extra-European countries for the induction of ovulation after stimulation of follicular development. The present study compares hCG bioavailability of Choriomon® (Test product) versus a recombinant hCG preparation (Ovitrelle®; Reference product). Methods: In this randomized, two-way cross-over study, 26 healthy women received a single dose of Choriomon® (10,000 IU) and Ovitrelle® (250 µg; 6500 IU) by subcutaneous injection. hCG was determined in serum up to 192 h post-dose. Dose-normalized peak concentration (Cmax) and area under the concentration-time curve up to the time of the last quantifiable concentration (AUC0–t) and extrapolated to infinity (AUC0–∞) were calculated and compared between the two treatments. Results: Serum hCG concentrations increased rapidly with a very similar pharmacokinetic curve for the two products. The test/reference geometric means ratio (GMR) for AUC0–t and AUC0–∞ corresponded to 121.31 and 119.81%, and the upper limits of the 90% confidence intervals (CIs) (130.21% and 128.51%, for AUC0–t and AUC0–∞, respectively) exceeded the 125% bioequivalence threshold. Cmax GMR was 146.89%, indicating a rate of hCG absorption approximately 50% greater for the test product (90% CI 132.30–163.10). Half-life (t1/2) was very similar (36.77 ± 5.11 h and 38.63 ± 6.08 h), whereas time to achieve Cmax (tmax) significantly differed, with median values of 16 h and 24 h for Choriomon® and Ovitrelle®, respectively, (p = 0.0023). Conclusions: The differences between Choriomon® and Ovitrelle® pharmacokinetic parameters can be ascribed to the different raw source of the products and are reflected in the approved dose regimens of the two hCG formulations. The observed lack of bioequivalence between the two compounds at the given doses is not clinically relevant, as results from Phase III studies indicated similar clinical efficacy and safety. The safety data are in line with the known safety profile of the two products. Clinicaltrials.gov registration no: NCT03735030. [ABSTRACT FROM AUTHOR]

A fully liquid hexavalent containing Diphtheria (D), Tetanus (T) toxoids, whole cell Pertussis (wP), Hepatitis B (Hep B), type 1, 2, 3 of inactivated poliovirus (IPV) and Haemophilus influenzae type b (Hib) conjugate vaccine (DTwP-HepB-IPV-Hib vaccine, HEXASIIL®) was tested for lot-to-lot consistency and non-inferiority against licensed DTwP-HepB-Hib + IPV in an open label, randomized Phase II/III study. In Phase III part, healthy infants received DTwP-HepB-IPV-Hib or DTwP-HepB-Hib + IPV vaccines at 6, 10 and 14 weeks of age. Blood samples were collected prior to the first dose and 28 days, post dose 3. Non inferiority versus DTwP-HepB-Hib + IPV was demonstrated with 95% CIs for the treatment difference for seroprotection/seroconversion rates. For DTwP-HepB-IPV-Hib lots, limits of 95% CI for post-vaccination geometric mean concentration ratios were within equivalence limits (0.5 and 2). Vaccine was well-tolerated and no safety concerns observed. Clinical Trial Registration – CTRI/2019/11/022052 [ABSTRACT FROM AUTHOR]

Background: Liraglutide is an acylated glucagon-like peptide-1 (GLP-1) analog, and its pharmacokinetic and pharmacodynamic properties as a GLP-1 receptor (GLP-1R) agonist make it an important therapeutic option for many patients with type 2 diabetes mellitus. This study compared the bioequivalence and safety of liraglutide with the originator product in healthy Chinese adult subjects. Methods: Subjects (N = 36, both sexes) were randomized in a 1:1 ratio into two groups (18 cases each) for a two-cycle, self-crossover trial. Each cycle involved a single subcutaneous injection of the test and reference drugs, with a washout period of 14 days. The plasma drug concentration was quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The main pharmacokinetic parameters were statistically analyzed to assess drug bioequivalence. Furthermore, the safety of the drugs was assessed throughout the trial. Results: The geometric mean ratios of Cmax, AUC0-t, and AUC0-∞ were 103.73%, 103.01%, and 103.03%, respectively, and their 90% confidence intervals (CIs) were consistent with the range of 80.00%-125.00%, indicating that the two formulations had similar pharmacokinetics. Meanwhile, safety results showed that both drugs were well tolerated. Conclusion: Studies have shown that the test drug has similar bioequivalence and safety to the reference drug. Clinical trial registration: (http://www.chinadrugtrials.org.cn/index.html), identifier (CTR20171303). [ABSTRACT FROM AUTHOR]

Rivaroxaban is an oral anticoagulant that is a selective, direct factor Xa inhibitor. It is used to prevent thrombotic events of atherosclerotic etiology and to prevent stroke and peripheral embolism in adult patients with nonvalvular atrial fibrillation. The aim of the studies was to assess the bioequivalence of two orally administered products: test (Zarixa hard capsules) vs. reference (Xarelto® film-coated tablets). Two crossover, two-period, randomized, open-label, laboratory-blinded studies were conducted in healthy Caucasian male and female volunteers. A single oral dose (Study 1: 10 mg fasting, Study 2: 20 mg fed) of the test or reference product was followed by a minimum seven-day washout. Blood was collected up to 48 h after administration. Plasma concentrations of rivaroxaban were measured using a validated LC-MS/MS method. The bioequivalence criteria for 90% confidence intervals (CI) of the log-transformed geometric mean ratios (test/reference) for the two primary pharmacokinetic parameters (AUC(0-t) and Cmax) were set at 80.00-125.00%. Vital signs, laboratory parameters, and adverse events were monitored. A total of 34 out of 36 volunteers completed Study 1, and the geometric mean ratios were 97.96% (90% CI 93.69-102.42%) for AUC(0-t), and 89.35% (90% CI 84.28-94.72%) for Cmax. All 36 volunteers completed Study 2, and the geometric mean ratios were 103.57% (90% CI 98.75-108.63%) for AUC(0-t), and 95.17% (90% CI 87.35-103.70%) for Cmax. All 90% CIs for the primary pharmacokinetic parameter ratios met the acceptance criteria. There were no serious adverse events. Results of both studies indicate that the test product (Zarixa) is bioequivalent to the reference product (Xarelto®). Both products were well tolerated. [ABSTRACT FROM AUTHOR]

Immediate‐release (IR) solid oral drug products constitute a significant portion of approved drug products and products under development. Bioequivalence (BE) assessment for these oral products is important for establishing therapeutic equivalence for generic products to their respective comparator products. In December 2022, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) published the first new draft guideline on BE for IR solid oral dosage forms (M13A). To support the development of ICH M13A, we comprehensively reviewed the landscape of oral IR products approved by the U.S. Food and Drug Administration (FDA) and compared BE recommendations for these products in the current U.S. FDA and European Medicines Agency (EMA) BE guidances. We utilized databases including Drugs@FDA, Orange Book, and product‐specific guidances (PSGs) published on the U.S. FDA and EMA websites to collect information. Oral IR products account for 46% of all FDA‐approved new drug applications currently listed in Orange Book with 82.5% solids, 0.9% semi‐solids, and 16.6% liquids. For all published U.S. FDA PSGs for solid oral IR products, in vivo BE studies with pharmacokinetic (PK) endpoints account for 88% of BE approaches recommended. Of these PK BE studies, 86.5% recommended fasting and fed BE studies, while only 15.9% EMA PSGs recommended both fasting and fed BE studies. This review helps clarify the scope of U.S. solid oral IR products impacted by the new ICH M13A draft guideline and demonstrates how recommendations in draft ICH M13A could significantly harmonize BE recommendations for IR oral products to facilitate global drug development. [ABSTRACT FROM AUTHOR]

Background: Captisol®-enabled-fosphenytoin sodium (CE-fosphenytoin sodium) injection is a modified formulation of fosphenytoin sodium. Objective: We aim to compare the intravenous and intramuscular bioavailability and safety between CE-fosphenytoin sodium, fosphenytoin sodium (Cerebyx®), and phenytoin sodium (intravenous injection only). Methods: In pivotal study 1, 54 subjects were divided into three sequence groups that receive intravenous injection of 250 mg of phenytoin sodium equivalent (PE), CE-fosphenytoin sodium (T), or fosphenytoin sodium (R1) and 250 mg of phenytoin sodium (R2) in period 1. After a 14-day washout period, 36 subjects were randomized to two treatment sequence groups (T-R1 or R1-T, n = 18 per group) in period 2, in which the subjects who received R2 in period 1 were removed, those who received T in period 1 used R1 (T-R1), while those who previously received R1 used T (R1-T). In pivotal study 2, a single intramuscular dose of T (400 mg PE) or R1 (400 mg PE) was administered according to the individual sequential treatment assignment in each period. There was a washout (14 days) period before receiving the next period study drug. Results: T and R1 have similar pharmacokinetic characteristics regarding total and free phenytoin, showing bioequivalence of both drugs in the intravenous and intramuscular administration. The geometric mean ratio was close to 1 (0.98-1.06). The AUC of total and free phenytoin in subjects who intravenously received T and R1 was very similar to those who received R2, although their Cmax was lower than that of the subjects who received R2. Overall, treatment with T and R1 was safe and well-tolerated, without serious adverse events (SAEs) or grade III adverse events (AEs). With intravenous (i.v.) or intramuscular (i.m.) treatment, the incidence of drug-related AEs using T was similar to that using R1. Treatment with T and R1 had clearly superior tolerability than that with R2. Conclusion: CE-fosphenytoin sodium is a promising substitute for fosphenytoin sodium. [ABSTRACT FROM AUTHOR]

Rivoceranib is a selective inhibitor of VEGFR‐2 being developed for the treatment of solid tumor. The objective of the study was to evaluate the effect of food on bioavailability as well as single‐ and multiple‐dose pharmacokinetics (PKs) of 81 and 201 mg doses of rivoceranib. The study was conducted as a two‐part study. In Part 1 (single ascending dose (SAD), open‐label, crossover study design), 2 oral doses of rivoceranib (81 mg or 201 mg) were given to all healthy subjects with a minimum 3‐day washout period between dosing. Part 2 was a multiple ascending dose (MAD), open‐label, crossover design where subjects were divided based on 81 and 201 mg doses. Both doses were administered with and without food in a crossover manner for the SAD and MAD parts. 24 healthy subjects completed Part 1 and 20 subjects completed Part 2. For the 81 mg dose in the SAD and MAD parts of the study, their food effect was not observed. For the 201 mg dose in both parts, food appeared to increase bioavailability by 20%–30% in Part 1, and 30%–40% in Part 2. Median tmax value was delayed when rivoceranib was administered with food at each dose level in both parts of the study. Dose proportionality was confirmed only for the AUC0‐∞ value from Part 1‐fasted cohort but inconclusive for Cmax and AUC parameters under other dosing regimens. In conclusion, rivoceranib when taken with food delays tmax appears to increase bioavailability at 201 mg dose. [ABSTRACT FROM AUTHOR]

Biosimilar regulatory evaluation considers the totality of evidence gathered through analytical, non-clinical and clinical studies. CT-P17 is the first high-concentration (100 mg/mL), citrate-free adalimumab biosimilar to receive regulatory approval in Europe for all indications held by reference adalimumab, following comprehensive non-clinical and clinical development programmes. State-of-the art physicochemical and biological methods demonstrated quality, analytical and functional comparability between CT-P17 and reference adalimumab; non-clinical in vivo studies supported biosimilarity. Three phase I and two phase III studies were conducted, with pharmacokinetic equivalence of CT-P17 and reference adalimumab shown in healthy volunteers, and equivalent efficacy demonstrated in patients with rheumatoid arthritis. Safety and immunogenicity profiles were comparable between CT-P17 and reference adalimumab across studies. CT-P17 is available for administration by autoinjector/prefilled pen (AI/PFP), prefilled syringe (PFS) and PFS with needle guard, providing diverse self-injection options for patients. Equivalent pharmacokinetics and comparable overall safety and usability were demonstrated between AI/PFP and PFS devices during the clinical development programme. All CT-P17 devices include fine, 29-gauge needles; combined with the citrate-free, high-concentration formulation, these characteristics reflect the newer reference adalimumab formulation (100 mg/mL) and are associated with reduced injection-site pain. The high-concentration formulation also facilitates treatment delivery via fewer injections. Compared with reference adalimumab, CT-P17 remains stable for longer at room temperature, enhancing ease of storage for patients and healthcare providers. In summary, the totality of evidence supports the biosimilarity of CT-P17 to high-concentration reference adalimumab, and several distinctive features differentiate it from existing adalimumab biosimilars. [ABSTRACT FROM AUTHOR]

Background: Both the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) and Consolidated Standards of Reporting Trials (CONSORT) guidelines recommend that clinical trials follow a study framework that aligns with their objective to test the relative efficacy or safety (equality) or effectiveness (superiority, noninferiority, or equivalence) between interventions. We conducted a systematic review to assess the proportion of studies that demonstrated inconsistency between the framing of their research question, sample size calculation, and conclusion and those that should have framed their research question differently based on the compared interventions.Methods: We included studies from 5 high-impact-factor orthopaedic journals published in 2017 and 2019 that compared at least 2 interventions using patient-reported outcome measures.Results: We included 228 studies. The sample size calculation was reported in 60.5% (n = 138) of studies. Of these, 52.2% (n = 72) were inconsistent between the framing of their research question, sample size calculation, and conclusion. The majority (n = 137) of sample size calculations were for equality, but 43.8% of these studies concluded superiority, noninferiority, or equivalence. Studies that framed their research question as equality (n = 186) should have been framed as superiority (n = 129), equivalence (n = 52), or noninferiority (n = 3). Only 2 studies correctly framed their research question as equality.Conclusions: Studies published in high-impact journals were inconsistent between the framing of their research question, sample size calculation, and conclusion. Authors may be misinterpreting research findings and making clinical recommendations solely based on p values. Researchers are encouraged to state and justify their methodological framework and choice of margin(s) in a publicly published protocol as they have implications for sample size and the applicability of conclusions.Clinical Relevance: The results of clinical research must be interpreted using confidence intervals, with careful consideration as to how the confidence intervals relate to clinically meaningful differences in outcomes between treatments. The more typical practice of relying on p values leaves the clinician at high risk of erroneous interpretation, recommendation, and/or action. [ABSTRACT FROM AUTHOR]

Highly variable disposition after oral ingestion of acyclovir has been reported, although little is known regarding the underlying mechanisms. Different studies using the same reference product (Zovirax ®) showed that C max and AUC were respectively 44 and 35% lower in Saudi Arabians than Europeans, consistent with higher frequencies of reduced-activity polymorphs of the organic cation transporter (OCT1) in Europeans. In this study, the contribution of physiology (i.e. , OCT1 activity) to the oral disposition of acyclovir immediate release (IR) tablets was hypothesized to be greater than dissolution. The potential role of OCT1 was studied in a validated physiologically-based biopharmaceutics model (PBBM), while dissolution of two Chilean generics (with demonstrated bioequivalence) and the reference product was assessed in vitro. The PBBM suggested that OCT1 activity could partially explain population-related pharmacokinetic differences. Further, dissolution of generics was slower than the regulatory criterion for BCS III IR products. Remarkably, virtual bioequivalence (incorporating in vitro dissolution into the PBBM) correctly and robustly predicted the bioequivalence of these products, showcasing its value in support of failed BCS biowaivers. These findings suggest that very-rapid dissolution for acyclovir IR products may not be critical for BCS biowaiver. They also endorse the relevance of cross-over designs in bioequivalence trials. [ABSTRACT FROM AUTHOR]

According to the authors "... when measured by peak serum digoxin concentration as well as by area under the serum digoxin concentration-time curve, the bioavailability of digoxin appeared to be higher in the fasting state than in the fed state. Thus, the area HT ht can be used as an indicator of the extent of drug's absorption. Drug absorption time is finite because absorption takes place mainly in the upper part of the gastrointestinal tract [[6], [14]]; in some cases, drug can be also absorbed in the colon in finite time [[6], [14]]; Fig. [Extracted from the article]

Introduction: The immediate-release solid oral products containing very soluble and permeable drugs are candidates for the biowaiver process. This work aims to compare in vitro, in silico, and in vivo data to establish if previously published prednisone oral tablet formulations are biowaiver candidates. Method: To achieve this goal, permeation studies were conducted on Caco-2 cells. A previous bioequivalence study between the test and the reference drug product was applied on an in silico evaluation using Gastroplus® to assess the bioequivalence of two other previously proposed formulations. Results: The apparent permeability coefficient for prednisone presented a value of 3.69 x 10-5 cm/s in 180 minutes. The bioequivalence study shows that the tested and reference product was equivalent. The in silico simulations successfully predicted the pharmacokinetics of the tested and the other two formulations since they were validated with the in vivo study. Both exhibit the same plasma concentration vs. time profiles. Conclusions: Through the in silico results, it is possible to infer that the other two formulations tested may be bioequivalent concerning the reference product. This result may be helpful in biowaiver requesting. Toward to reduce costs and the use of human beings in bioequivalence studies, this approach could be an essential way to work in the pharmaceutical industry. [ABSTRACT FROM AUTHOR]

Purpose: To compare the pharmacokinetic profiles, safety and immunogenicity of proposed bevacizumab biosimilar HLX04 with reference bevacizumab in healthy Chinese males. Methods: In this double-blind Phase 1 study, healthy volunteers (N = 208) were randomized 1:1:1:1 to a single 3 mg/kg intravenous infusion of HLX04 or reference bevacizumab sourced from the United States (bevacizumab-US), the European Union (bevacizumab-EU) or China (bevacizumab-CN). Co-primary endpoints were area under the serum concentration–time profile (AUC) from time zero extrapolated to infinity (AUC0–inf) and from zero to last quantifiable concentration (AUClast). Secondary endpoint was the maximum serum drug concentration (Cmax). Study participants were monitored for treatment-emergent adverse events (TEAEs) and samples were collected for anti-drug antibody (ADA) testing throughout the study. Results: Pharmacokinetic parameters were similar across groups. The respective geometric least-squares mean ratios (GLSMR) of AUC0–inf, AUClast and Cmax were: 95.7%, 96.0% and 101.8% for HLX04 versus bevacizumab-US; 94.3%, 94.6% and 100.5% for HLX04 versus bevacizumab-EU; and 90.0%, 90.4% and 98.2% for HLX04 versus bevacizumab-CN. For all test-to-reference comparisons, two-sided 90% confidence intervals of GLSMR for AUC0–inf, AUClast and Cmax fell in the pre-specified bioequivalence range (80–125%). There were no notable differences in the frequency, nature and/or grade of TEAEs. No deaths were reported and no ADAs were detected during the study. Conclusion: HLX04 had similar safety and pharmacokinetic profiles to reference bevacizumab in healthy Chinese males, supporting the confirmatory Phase 3 study investigating the efficacy and safety equivalence between HLX04 and bevacizumab in patients with metastatic colorectal cancer (NCT03511963). Clinical trial registration: The study was registered with Clinicaltrials.gov, NCT03483649. [ABSTRACT FROM AUTHOR]

This study assessed the impact of product particle sizes (fine: 106–500 µm; coarse: 500–1000 µm) on oxycodone pharmacokinetics (PK) following nasal insufflation of milled oxycodone extended‐release (ER) abuse‐deterrent (AD) tablets using immediate‐release (IR) non‐AD product as reference. Additionally, this study assessed the effects of different excipient to drug ratio (EDR) by comparing two products with fine particle size but different EDRs, again using IR non‐AD as the control. Thirty milligrams of oxycodone were administered in each treatment. Coarsely milled 30 mg ER tablets demonstrated significantly lower maximum plasma concentration (Cmax) and partial areas under the concentration‐time curve (AUCs) than those of the finely milled IR tablets. Finely milled ER tablets demonstrated similar Cmax and partial AUCs but higher total systemic exposures than those of finely milled IR tablets. Finely milled 80 mg ER tablets were bioequivalent to IR tablet on all parameters. The finely milled 30 mg ER tablet was not bioequivalent to the coarsely milled 30 mg ER tablet and had higher values for all parameters. The finely milled 30 mg ER tablets (EDR 6.9) showed no PK differences with finely milled 80 mg ER tablets (EDR 4.9). No serious adverse events were reported. The study demonstrated a significant effect of particle sizes (106–1000 µm) on PK of milled and insufflated oxycodone ER AD tablets. EDR difference did not have any significant effects on the PK of finely milled oxycodone ER AD tablets. Particle size distribution should be considered when nasal AD properties of opioid drug products are investigated during drug development. [ABSTRACT FROM AUTHOR]

The present work was aimed at the development of an analytical method with high sensitivity, selectivity, and rapidity for pharmacokinetic studies. The new method for quantitative determination of fludrocortisone in human blood plasma employs HPLC and mass spectrometric detection with electrospray ionization (ESI). The deuterium-labeled analog of fludrocortisone (fludrocortisone-D5) was used as the internal standard. The lower limit of quantitation (LLOQ) was 10 pg/mL. The calibration curve was linear in the range 10 – 1000 pg/mL. The coefficient of reliability was at least 0.99. Liquid extraction was used for sample preparation. The proposed technique was tested by studying the bioequivalence of a generic drug in a single administration to healthy volunteers at a dose of 0.1 mg. [ABSTRACT FROM AUTHOR]

The rate and extent of absorption of a drug from its dosage form is referred to as bioavailability. While bioequivalence between two drug products is attained if their extent and rate of absorption do not relatively differ when administered at the same dose. A bioequivalence study comprises of two or more bioavailability studies which are performed by i) Measurement of active drug substance or its metabolites in the biological fluid; ii) Comparative pharmacodynamic studies in humans; iii) Comparative clinical trials; iv) Comparative in-vitro dissolution studies. The rationale of the study is the monitoring of the pharmacokinetic-pharmacodynamic parameters (AUC, Cmax) after administration of the tested drug. This study is not an experimental study but a form of data analysis and reporting of comparative bioavailability studies. The study data obtained is required to be equipped with applications of new drug products as notified in Schedule Y. Cumulatively, it aids in the development of pharmaceutical preparations in the pharmaceutical industry. This review article aims to illustrate the systematic overview of BA/BE study with an emphasis on its experimental aspects like study design, volunteer selection, dosing regimen, sample collection procedures along with a detailed insight on Informed Consent Document, Case Report Form, Trial Master file and the Protocol which collectively form the backbone of the clinical study. [ABSTRACT FROM AUTHOR]

A procedure for the determination of dexketoprofen trometamol in human plasma by liquid chromatography–mass spectrometry (HPLC–MS/MS) using ibuprofen as an internal standard was proposed and validated. The matrix effect on the analyte response value was estimated; its short-term and long-term stability in a biological matrix and an aqueous acetonitrile solution was investigated. In addition, the stability of the analyte after freezing and thawing of samples was studied. It was shown that the dilution of samples by one half does not affect the accuracy and precision of the analysis. The limit of detection and the lower limit of quantification were 0.01 µg/mL; the linearity range was 0.01–8.50 µg/mL (R2 = 0.9974); the total analysis time was 3.5 min. Intra- and interday accuracy values were in the ranges 96.66–100.00% and 94.97–97.92%, respectively. Sample preparation, including liquid–liquid extraction with ethyl acetate in an acidic medium, is simple and fast. The developed procedure was successfully tested on real plasma samples from healthy volunteers in the framework of a comparative study of the pharmacokinetics and bioequivalence of a generic drug. [ABSTRACT FROM AUTHOR]

Establishing bioequivalence (BE) for dermatological drug products by conducting comparative clinical end point studies can be costly and the studies may not be sufficiently sensitive to detect certain formulation differences. Quantitative methods and modeling, such as physiologically‐based pharmacokinetic (PBPK) modeling, can support alternative BE approaches with reduced or no human testing. To enable PBPK modeling for regulatory decision making, models should be sufficiently verified and validated (V&V) for the intended purpose. This report illustrates the US Food and Drug Administration (FDA) approval of a generic diclofenac sodium topical gel that was based on a totality of evidence, including qualitative and quantitative sameness and physical and structural similarity to the reference product, an in vivo BE study with PK end points, and, more importantly, for the purposes of this report, a virtual BE assessment leveraging dermal PBPK modeling and simulation instead of a comparative clinical end point study in patients. The modeling approach characterized the relationship between systemic (plasma) and local (skin and synovial fluid) diclofenac exposure and demonstrated BE between the generic and reference products at the presumed site of action. Based on the fit‐for‐purpose modeling principle, the V&V process involved assessing observed data of diclofenac concentrations in skin tissues and plasma, and the overall performance of the modeling platform for relevant products. Using this case as an example, this report provides current scientific considerations on good practices for model V&V and the establishment of BE for dermatological drug products when leveraging PBPK modeling and simulation for regulatory decision making. [ABSTRACT FROM AUTHOR]

Tegoprazan, a novel potassium‐competitive acid blocker, is used to treat acid‐related diseases. However, there is no information on the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of the marketed dosage of tegoprazan under various meal timings in a fed and fasted state. The study aimed to assess the effect of meal timing on PKs and PDs of tegoprazan 50 mg after a single administration in healthy male subjects. An open‐label, single‐dose, three‐treatment, three‐period crossover study was conducted. A total of 12 subjects were orally administered a single dose of tegoprazan 50 mg among various conditions: in a fasted state, at 30 min before or 30 min after a high‐fat meal. PK parameters were estimated by the noncompartmental method. Continuous 24‐h intragastric pH monitoring was done for PD analysis. The PKs and PDs of tegoprazan were compared among the various meal timings. Compared with the fasting condition, the PK profile of tegoprazan was similar when administered 30 min before a high‐fat meal; however, delayed absorption with similar systemic exposure was observed when administered 30 min after a high‐fat meal. The magnitude of acid suppression evaluated through the PD parameters increased when administered 30 min after a high‐fat meal compared with fasting the condition and when administered 30 min before a high‐fat meal. However, the increased difference in acid suppression was not clinically significant. Meal timing had no clinically significant effect on the PKs and PDs of tegoprazan 50 mg. Therefore, the marketed dosage of tegoprazan could be administered regardless of the meal timing. Study HighlightsWHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Tegoprazan, a novel potassium‐competitive acid blocker, is used to treat acid‐related diseases. WHAT QUESTION DID THIS STUDY ADDRESS?This study evaluated the effect of food on pharmacokinetics (PKs) and pharmacodynamics (PDs) of tegoprazan under various mealtime conditions. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?This study showed that delayed absorption of tegoprazan was observed at "after meal condition," however, the amount of systemic exposure of "after meal condition" was similar to "fasting condition" and "before meal condition." In addition, gastric acid suppression of tegoprazan was similar between fasting condition and before meal condition, whereas increased gastric acid suppression was observed at after meal condition. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?In the actual clinical environment, patients take medicine under various fed conditions. This study evaluated the effect of food on PKs and PDs of tegoprazan in various clinical conditions, and provided the important information about meal timing when administering tegoprazan. [ABSTRACT FROM AUTHOR]

A bioequivalence (BE) study is one of the key stages of investigations required for the registration of oral generic drugs. The planning of this type of study is determined by many factors, including the linearity of the pharmacokinetics of the active substance. The choice of the drug dose for a BE study will depend on this property in registering several drug strengths. Regulatory requirements for planning BE studies of drugs with non-linear pharmacokinetics are considered using atazanavir and valaciclovir as examples. An analysis of protocols and reports of BE studies received by the SCEEMP according to the State Drug Registry and open published data on BE revealed differences in both the tested drug dosages and the number of tests performed. All characteristics of the given active substance, available literature data, international experience, and current regulatory requirements should be taken into account in planning and evaluating BE studies of drugs with non-linear pharmacokinetics. [ABSTRACT FROM AUTHOR]

Histamine acts by binding to four histamine receptors (H1 to H4), of which the H1 is known to participate in dilate blood vessels, bronchoconstriction, and pruritus. Olopatadine hydrochloride blocks the release of histamine from mast cells and it inhibits H1 receptor activation. Olopatadine hydrochloride is anti-allergic agent that is effectively used. The object of this study had conducted to compare the pharmacokinetics (PKs) and safety characteristics between olopatadine hydrochloride 5 mg (test formulation) and olopatadine hydrochloride 5 mg (reference formulation; Alerac ®) in Korean subjects. This study had conducted an open-label, randomized, fasting condition, single-dose, 2-treatment, 2-period, 2-way crossover. Subjects received single-dosing of reference formulation or test formulation in each period and blood samples were collected over 24 hours after administration for PK analysis. A wash-out period of 7 days was placed between the doses. Plasma concentration of olopatadine were determined using liquid chromatography-tandem spectrometry mass (LC-MS/MS). A total of 32 subjects were enrolled and 28 subjects completed. There were not clinical significantly different in the safety between two treatment groups for 32 subjects who administered the study drug more than once. The geometric mean ratio of test formulation to reference formulation and its 90% confidence intervals for The peak plasma concentration (Cmax) and the areas under the plasma concentration-time curve from 0 to the last concentration (AUClast) were 1.0845 (1.0107-1.1637) and 1.0220 (1.0005-1.0439), respectively. Therefore, the test formulation was bioequivalent in PK characteristics and was equally safe as the reference formulation. [ABSTRACT FROM AUTHOR]

Objectives: High prevalence of vitamin D deficiency mandates prescribing an appropriate form of vitamin D that allows attainment of sufficiency in a cost-effective manner. We aimed to compare vitamin D products in Indian market in terms of composition and cost in 2020 with 2013 to understand price dispersion over 7 years. Methods: Constituents, formulations, and prices of 'branded' and generic vitamin D products were sourced from various drug information compendia and online sources. Price per defined daily dose (DDD), percentage cost variation, and change in prices over 7 years (2020 vs. 2013) was determined. Results: There has been a disproportionate increase in the number of brands and cost variation of cholecalciferol and calcitriol in the last 7 years. The percentage cost variation increased almost 10 times for calcitriol and 4.4 times for alfacalcidiol tablets and cholecalciferol granules. An analysis of >1,100 products in 2020 showed that the predominant form was calcitriol which was combined with calcium in >90% of the products with huge cost variation (>3000%). Ergocalciferol and cholecalciferol were available in 22 and 15 different strengths respectively. Median price/unit of cholecalciferol (60,000IU) was lower for tablets/capsules compared to other formulations; but with >1000% cost variation. Conclusion: A wide cost variation exists with the use of different vitamin D brands and preparations with conventional cholecalciferol tablets and capsules being a low-priced alternative. Quality control measures and strict enforcements of existing regulations are essential to ensure that competitive prices of branded generics are translated into availability and affordability for the population. [ABSTRACT FROM AUTHOR]

This workshop report summarizes the proceedings of Day 2 of a three-day workshop on " Current State and Future Expectations of Translational Modeling Strategies to Support Drug Product Development, Manufacturing Changes and Controls ". From a drug product quality perspective, physiologically based biopharmaceutics modeling (PBBM) is a tool to link variations in the drug product quality attributes to in vivo outcomes enabling the establishment of clinically relevant drug product specifications (CRDPS). Day 2 of the workshop focused on best practices in developing, verifying and validating PBBM. This manuscript gives an overview of podium presentations and summarizes breakout (BO) session discussions related to (1) challenges and opportunities for using PBBM to assess the clinical impact of formulation and manufacturing changes on the in vivo performance of a drug product, (2) best practices to account for parameter uncertainty and variability during model development, (3) best practices in the development, verification and validation of PBBM and (4) opportunities and knowledge gaps related to leveraging PBBM for virtual bioequivalence simulations. [ABSTRACT FROM AUTHOR]