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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]

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]

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]

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]

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]

Liposomal doxorubicin hydrochloride is an antineoplastic agent widely used against human cancers. The data from in vitro drug release test (IVRT) is essential for quality and/or bioequivalence evaluation in drug approval and post-approval regulation of liposomal drug products. However, most of the currently available IVRT methods for liposomal doxorubicin hydrochloride have experimental deficiencies associated with liposomal rupture during the separation process which is needed for selective quantification of released drug from liposomal-bound drug. In addition, many of the methods are time consuming, requiring bulk quantities of liposomal drug product, and lack of automation. We have developed a selective, sensitive, and automated capillary electrophoresis (CE)-based IVRT method, measuring released doxorubicin without additional sampling and separation steps. This method requires a small volume of sample compared to currently available methods. The IVRT release study with liposomal doxorubicin was conducted at different temperatures and pH conditions. It was observed that the release profiles obtained for five formulations including the reference listed drug were similar at pH 6.50 and 47.0 °C. The drug release increased with the increase of media pH and temperature. Complete doxorubicin release (100 %) was obtained in 7 h at pH 6.50 and 47.0 °C, and in less than 3 h at pH 6.50 and 52.0 °C. This CE-based method can be extended for determination of the IVRT profiling of other liposomal drug products. [Display omitted] • Automated capillary electrophoresis-based method was developed for in vitro drug release profiling of liposomal doxorubicin. • Capillary electrophoresis separated and quantitate released doxorubicin from liposomal bound doxorubicin. • Effect of pH, temperature, and ammonium ion concentration was evaluated. • Drug release profiling of five formulations were compared. [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]

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]

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]

Levothyroxine (LT4) is the standard of care for treating hypothyroidism. Despite the established efficacy of LT4, 50% of treated patients fail to achieve normal thyrotropin levels. Oral formulations of LT4 that bypass the gastric phase of dissolution may offset some of the therapeutic shortcomings observed with tablets. An oral solution of LT4 can be administered to patients who are unable to swallow tablets; allows flexibility to individualize dosing; and may mitigate interference with LT4 absorption caused by food, coffee, increased gastric pH from atrophic gastritis, and malabsorption from bariatric surgery. The bioavailability of a novel LT4 oral solution and a reference LT4 tablet were compared in a randomized, laboratory‐blinded, single‐dose, 2‐period, 2‐sequence, crossover study in healthy euthyroid subjects. A single 600‐μg oral dose of LT4 solution (30 mL × 100 μg/5 mL) or tablet (2 × 300‐μg tablet) was administered under fasting conditions in each study period, and total thyroxine concentrations were measured for 72 hours after administration. The ratio of geometric least‐squares means and 90% confidence intervals for area under the concentration‐time curve from time 0 to 72 hours and maximum plasma concentration were calculated. Among 42 subjects in the pharmacokinetic population, the geometric least‐squares mean ratio of area under the concentration‐time curve from time 0 to 72 hours and maximum plasma concentration for baseline‐adjusted thyroxine was 109.1% and 107.9%, respectively, meeting Food and Drug Administration bioequivalence criteria. Adverse events (AEs) were similar between treatment groups with no serious AEs or discontinuations for AEs. Comparable bioavailability was observed between the LT4 oral solution and reference tablet after a single oral 600‐μg dose under fasting conditions. [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]

Glucagon-like peptide-1 (GLP-1) is an endogenous incretin hormone. Liraglutide, a GLP-1 receptor agonist, can lower blood sugar by increasing insulin production and inhibiting the production of glucagon. This study researched the bioequivalence and safety of the test and reference drugs in healthy Chinese subjects. Subjects (N = 28) were randomly divided into group A and group B at a ratio of 1:1 for a two-cycle cross-over study. There was single dose per cycle with subcutaneous injection of the test and reference drugs, respectively. The washout was set at 14 days. Plasma drug concentrations were detected by specific liquid chromatography and tandem mass spectrometry (LC-MS/MS) assays. Statistical analysis of major pharmacokinetic (PK) parameters was conducted to assess drug bioequivalence. In addition, we evaluated the safety of the drugs throughout the trial. The geometric mean ratios (GMRs) of Cmax, AUC0-t, and AUC0-∞ for the test and reference drugs were 107.11%, 106.56%, 106.09%, respectively. The 90% confidence intervals (CIs) were all within 80%-125%, meeting the bioequivalence standards. In addition, both had good safety in this study. The study shows that the two drugs had similar bioequivalence and safety. DCTR: CTR20190914; ClinicalTrials.gov: NCT05029076 [ABSTRACT FROM AUTHOR]

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]

Epirubicin, commonly used as anticancer drug for various types of tumors like breast, liver, lung, stomach, ovaries, and bladder for its improved antitumor efficacy and safety. A rapid, sensitive, and reliable bioanalytical method was developed and validated for epirubicin using conventional reverse phase HPLC with UV detection. The developed method was successfully applied to investigate the pharmacokinetics of epirubicin after intravenous administration of a reference epirubicin and its designed nano-formulations to rats. C18 column was used in an isocratic mode for analyte elution at a flow rate of 1.0 mL/min with UV detection of 234 nm. The mobile phase was composed of acetonitrile 22% (channel A) and 0.025% tri fluoro-acetic acid in water (channel B). Ondansetron was added as an internal standard, and the plasma samples were analyzed after protein precipitation. A concentration range of 0.016–1.024 μg/mL was selected for the construction of calibration curves, with LLOQ of 0.016 μg/mL. Results showed that the value of AUC, half-life, and mean residence time of designed nano-formulation were bounce to 10, 9, and 11 times higher, when compared to the reference epirubicin after intravenous dose of 10 mg/kg of epirubicin to rats, respectively. The designed epirubicin nano-formulations achieved clinically significant pharmacokinetic values in rats. Current method will help epirubicin future research using clinical samples and drug bioequivalence studies on various novel formulations for drug safety purposes. [ABSTRACT FROM AUTHOR]

[Display omitted] In vitro nasal models can potentially facilitate development and approval of nasal drug products. This study aims to evaluate the potential for using regional deposition measurements from in vitro nasal models to evaluate nasal spray performance across several products. To accomplish this, the posterior regions of six anatomically realistic nasal airway models of adult and pediatric subjects, representing Low (L), Mean (M) and High (H) posterior drug deposition (PD) for each of the two age groups, were segmented with high anatomical precision into five regions of interest. These models were previously developed with the goal of quantifying the range of intersubject variability of PD following administration of inhaled corticosteroids. The in vitro regional drug deposition values were measured for the reference listed drug (RLD) product for triamcinolone acetonide and two corresponding generic (test) nasal spray products, as well as an RLD product for fluticasone furoate nasal spray. In general, the pediatric models mostly demonstrated higher PD compared to the adult models. The majority (>85 %) of PD was confined to the front and the inferior meatus regions. Subsequent population bioequivalence (PBE) analyses of the regional nasal deposition suggested that the anatomical differences among subjects may impact the nasal spray performance across different nasal products. [ABSTRACT FROM AUTHOR]

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The article discusses the development of clinical trial registries in China, including the launch of the ChinaDrugTrials.org.cn platform in 2013. It outlines key events in the establishment of the National Clinical Trial Registry and the regulations requiring trial registration. It also mentions concerns about the consistent posting of trial results and suggests the need for data exchange between registries to improve transparency.

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]

Understanding how a disease spreads in a population is a first step to preparing for future epidemics, and machine learning models are a useful tool to analyze the spreading process of infectious diseases. For effective predictions of these spreading processes, node embeddings are used to encode networks based on the similarity between nodes into feature vectors, i.e., higher dimensional representations of human contacts. In this work, we evaluated the impact of homophily and structural equivalence on node2vec embedding for disease spread prediction by testing them on real world temporal human contact networks. Our results show that structural equivalence is a useful indicator for the infection status of a person. Embeddings that are balanced towards the preservation of structural equivalence performed better than those that focus on the preservation of homophily, with an average improvement of 0.1042 in the f1-score (95% CI 0.051 to 0.157). This indicates that structurally equivalent nodes behave similarly during an epidemic (e.g., expected time of a disease onset). This observation could greatly improve predictions of future epidemics where only partial information about contacts is known, thereby helping determine the risk of infection for different groups in the population. [ABSTRACT FROM AUTHOR]

Introduction: Thrombopoietin receptor agonists are commonly second-line drugs in immune thrombocytopenia (ITP) pharmacotherapy in children and prescribed for chronic ITP refractory to first-line therapy. Standard ITP pharmacotherapy in children: includes prescribing glucocorticoids or intravenous immunoglobulins. Thrombopoietin receptor agonists: Currently Romiplostim and Eltrombopag are used in the Russian Federation pediatrics. Their pharmacodynamic features in comparison with other drugs used in ITP are presented in the paper. Increased thrombocytopoiesis is the dominant, but not the only component of Romiplostim and Eltrombopag mechanism of action. It is relevant to study their effect on immune tolerance in ITP, which may be associated with a persistent platelet response in some patients after drug discontinuation. Conclusion: The issue of thrombopoietin receptor agonist efficacy and safety as well as the mode of their use in ITP children treatment continues to be studied. The high cost of drugs continues to be a limiting factor to their earlier prescription. Generic drugs – Romiplostim and Eltrombopag partly solve the problem, promote their earlier prescription in ITP, but require additional study of their bioequivalence and therapeutic equivalence in comparison with the original drugs. [ABSTRACT FROM AUTHOR]

A biosimilar is a biological product that is highly similar to and has no clinically meaningful differences from a US Food and Drug Administration (FDA)‐approved reference product. The development and approval of biosimilars is critical to enhancing the availability of safe, effective, and affordable treatment options for patients. Utilization of pharmacodynamic (PD) biomarkers can help streamline biosimilar development programs as the current process can be costly and time‐consuming. Whereas PD biomarkers have not been prominently used across biosimilar approvals to date, moving forward, there is ample opportunity to increase the use of PD biomarkers in biosimilar development programs in place of comparative clinical studies with efficacy end point(s). This includes utilizing PD biomarkers that were not used as surrogate end points in approval of reference products. This mini‐review summarizes how PD biomarkers have been used in biosimilar development programs to date and then discusses evidentiary considerations for PD biomarkers. In addition, study design considerations for clinical pharmacokinetic and PD assessment of proposed biosimilars are discussed. Finally, the FDA's applied regulatory science activities related to PD biomarkers for biosimilars conducted in support of the FDA's Biosimilars Action Plan are reviewed. This included conducting three clinical studies to address information gaps about PD biomarkers for biosimilars and inform general methodological best practices. In summary, enhancing our understanding of key evidentiary considerations and optimal study designs for incorporating PD biomarkers in the evaluation of proposed biosimilars can help bring more treatment options to patients faster. [ABSTRACT FROM AUTHOR]

The potential for pharmacodynamic (PD) biomarkers to improve the efficiency of biosimilar product development and regulatory approval formed the premise for the virtual workshop Pharmacodynamic Biomarkers for Biosimilar Development and Approval hosted by the US Food and Drug Administration (FDA) and Duke Margolis, September 2021. Although the possibility of PD biomarkers replacing the to‐date routine comparative phase III confirmatory study currently expected by the FDA was discussed, the motivation and feasibility for biosimilar sponsors developing such markers and the regulatory risks entailed largely were not. Even more fundamental is the already established greater comparative value of the pharmacokinetic (PK) study as the most sensitive clinical assay for detecting subtle differences between two products. Consequently, the comparative analytical assessment and the head‐to‐head PKs will have already answered the core questions as to the biosimilarity of the candidate product to its reference. No further actionable information is obtained with either a PD study or a comparative clinical phase III study even as they may provide some reassurance of what is already known. When a suitable PD biomarker is available for the originator reference product they have already been used for biosimilar development. We must carefully consider the core requirements and timelines inherent in biosimilar development and how they occur in parallel rather than in the series we see for originator products. In order to improve the efficiency of biosimilar development, we need to ask the right questions based on a full understanding of how biosimilars have been developed to date and can be in the future. [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]

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]

Ketoprofen belongs to a group of widely used non-steroidal anti-inflammatory drugs (NSAIDs). It is found in several doses and various forms of medications. Therapeutic efficacy is related to the rate of release of the active substances, which depends on the formulation, the quality of the constituent substances, and solubility. In order to determine the efficacy of drug products containing ketoprofen available on the pharmaceutical market in Poland, studies comparing the release profiles of the active substance contained in specific formulations and doses, Ketokaps MAX, 50 mg, soft capsules, Ketonal Active, 50 mg, hard capsules, Ketokaps MED, 100 mg, soft capsules, Refastin, 100 mg, film-coated tablets and Ketonal Forte, 100 mg, film-coated tablets have been conducted. Drug release has been tested using FaSSGF and FaSSIF bioequivalent media in a type IV flow apparatus. The results indicate that the product Ketokaps MAX, 50 mg has a shorter release time of ketoprofen and a faster reached maximum concentration of the released active substance than the market product Ketonal Active, 50 mg. The same outcomes will be achieved by the product Ketokaps MED, 100 mg compared to the market products Refastin, 100 mg, and Ketonal Forte, 100 mg. In vitro studies confirm that the tested products differ noticeably in the kinetics of release of the active substance. Ketokaps MAX, 50 mg and Ketokaps MED, 100 mg achieve c max in a shorter time. [ABSTRACT FROM AUTHOR]

We conducted a phase I bioequivalence trial in healthy Chinese subjects in the fasting and postprandial states. The goal of this trial was to compare the pharmacokinetics and safety of the test preparation Cefaclor granule (Disha Pharmaceutical Group Co., Ltd.) and the reference preparation Cefaclor suspension (Ceclor®, Eli Lilly and Company). In this trial, 24 subjects were selected in the fasting and postprandial states, respectively. Enrolled subjects randomly accepted a single dose of 0.125 g Cefaclor granule or Cefaclor suspension. The washout period was set as 2 days. Blood samples were collected within 8 h after administration in the fasting state and within 10 h after administration in the postprandial state. Plasma concentrations were determined by Liquid chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters (AUC, Cmax) were used to evaluate bioequivalence of the two drugs. In the fasting trial, the geometric mean ratios (90% confidence intervals CIs) for Cmax, AUC0-t, and AUC0-∞ were 93.01% (85.96%-100.63%), 97.92% (96.49%-99.38%) and 97.95% (96.52%-99.41%), respectively. The GMR (90% CIs) for Cmax, AUC0-t, and AUC0-∞ in postprandial state were 89.27% (81.97%-97.22%), 97.31% (95.98%-98.65%) and 97.31% (95.93%-98.71%), respectively. The 90% CIs of AUC and Cmax in the fasting and postprandial states were within the 80-125% bioequivalence range. Therefore, Cefaclor granule and Cefaclor suspension were bioequivalent and displayed similar safety profiles. Furthermore, food intake affected the pharmacokinetic parameters of both drugs. [ABSTRACT FROM AUTHOR]

Aceclofenac controlled-release (CR) is a once-a-day tablet with 200 mg of aceclofenac, and is bioequivalent to conventional aceclofenac. However, its safety in humans has not been well studied in Korea. Therefore, we aimed to evaluate the overall incidence and patterns of adverse events (AEs), the effectiveness of aceclofenac CR, and the differences in incidence rates of the AEs based on each patient's baseline charateristics. This study was conducted on patients receiving aceclofenac CR in clinical practice at each investigational institution to treat musculoskeletal pain and inflammation. The subjects were administered one tablet of aceclofenac CR (200 mg once-a-day) and were observed for 4 weeks post-administration. Factors affecting the occurrence of AEs were evaluated, and the Visual Analogue Scale (VAS) was used to measure the pain intensity. Among 14,543 subjects, the incidence rate of AEs was 0.86%, and that of adverse drug reactions was 0.74%. No serious AEs and unexpected adverse drug reactions were monitored. The incidence rates of AEs were significantly higher in females, inpatient treatment, individuals with concurrent disorders, and those receiving concomitant medications, respectively (all P < 0.05). Four weeks post-using aceclofenac CR, the mean changes in VAS was significantly decreased compared to prior administration. The overall clinical efficacy rate was 91.63%. This study confirmed that no severe adverse reactions were observed for aceclofenac CR exceeding those previously reported for safety results of conventional formulation of this drug in routine clinical practice settings. The use of aceclofenac CR might not violate the previously reported information on the safety and effectiveness of aceclofenac. [ABSTRACT FROM AUTHOR]

The objective of this study was to examine the effects of diet energy density on ranking for dry matter intake (DMI), residual feed intake (RFI), and greenhouse gas emissions. Forty-two mature, gestating Angus cows (600 ± 69 kg body weight [ BW ]; body condition score [ BCS ] 5.3 ± 1.1) with a wide range in DMI expected progeny difference (−1.38 to 2.91) were randomly assigned to two diet sequences; forage then concentrate (FC) or concentrate then forage (CF). The forage diet consisted of long-stem native grass hay plus protein supplement (HAY; 1.96 Mcal ME/kg DM). The concentrate diet consisted of 35% chopped grass hay and 65% concentrate feeds on a dry matter basis (MIX; 2.5 Mcal ME/kg DM). The GreenFeed Emission Monitoring system was used to determine carbon dioxide (CO 2 ), oxygen (O 2 ), and methane (CH 4 ) flux. Cow performance traits, ultrasound back fat and rump fat, feed DMI, and gas flux data were analyzed in a crossover design using a mixed model including diet, period, and sequence as fixed effects and pen and cow within sequence as random effects. For all measured traits excluding DMI, there was a diet × sequence interaction (P < 0.05). The correlation between MIX and HAY DMI was 0.41 (P = 0.067) and 0.47 (P = 0.03) for FC and CF sequences, respectively. There was no relationship (P > 0.66) between HAY and MIX average daily gain (ADG), regardless of sequence. Fifty-seven percent of the variation in DMI was explained by metabolic BW, ADG, and BCS for both diets during the first period. During the second period, the same three explanatory variables accounted for 38% and 37% of the variation in DMI for MIX and HAY diets, respectively. The negative relationship between BCS and DMI was more pronounced when cows consumed the MIX diet. There was no relationship between MIX and HAY RFI, regardless of sequence (P > 0.18). During the first period, correlations for CO2, CH4, and O2 with MIX DMI were 0.69, 0.81, and 0.56 (P ≤ 0.015), respectively, and 0.76, 0.74, and 0.64 (P < 0.01) with HAY DMI. During the second period, correlations for CO2, CH4, and O2 with MIX DMI were 0.62, 0.47, and 0.56 (P ≤ 0.11), respectively. However, HAY DMI during the second period was not related to gas flux (P > 0.47). Results from this experiment indicate that feed intake of two energy-diverse diets is moderately correlated while ADG while consuming the two diets is not related. Further experimentation is necessary to determine if gas flux data can be used to predict feed intake in beef cows. [ABSTRACT FROM AUTHOR]

Aims: Acalabrutinib, a selective Bruton tyrosine kinase inhibitor, is approved for the treatment of mantle cell lymphoma and chronic lymphocytic leukaemia. Many critically ill patients are unable to swallow and need oral medications to be delivered via a nasogastric (NG) tube. Furthermore, critically ill patients are typically administered proton‐pump inhibitors (PPIs) to prevent stress ulcers. Concomitant administration with PPIs reduces acalabrutinib exposure and is not currently recommended. To evaluate acalabrutinib in subjects co‐administered with PPIs who require NG delivery, a phase 1, open‐label, randomized, crossover, single‐dose study was conducted in healthy subjects. Methods: The study assessed the relative bioavailability of an acalabrutinib suspension—in regular, degassed Coca‐Cola—administered via NG tube (Acala‐NG) versus the pharmacokinetics (PK) of an acalabrutinib capsule administered orally with water. In addition, the PPI effect was evaluated by comparing the PK following Acala‐NG in the presence or absence of rabeprazole. Results: Exposure of acalabrutinib and its active metabolite (ACP‐5862) were comparable following administration of Acala‐NG versus the oral capsule (Geo mean ratio, % ref [90% confidence interval, CI]: acalabrutinib AUCinf: 103 [93‐113]; Cmax: 144 [120‐173]). In addition, exposure was similar following administration of Acala‐NG with and without a PPI (Geo mean ratio, % ref [90% CI]: acalabrutinib AUCinf: 105 [79‐138]; Cmax: 95 [66‐137]). No safety or tolerability concerns were observed, and all adverse events were mild and resolved without treatment. Conclusions: Acala‐NG with or without a PPI is safe and well‐tolerated without impeding bioavailability. [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]

In vitro bioequivalence studies are strictly limited to the comparison of dissolution performance to a reference drug. These studies are performed without considering the chemical similarity between the generic and reference drug formulations. This work has focused on developing a groundbreaking method based on the laser-induced breakdown spectroscopy (LIBS) technique for the in vitro bioequivalence determination of immediate-release solid oral dosage form generic drugs and as an alternative method for establishing the biowaiver of in vivo generic drug studies. The novel LIBS-based methodology to determine in vitro bioequivalence is fast, easy to perform, and can be carried out without the requirement of tedious and complicated sample pre-treatment, nor expensive instrumentals and reagents, almost directly on the drug samples. Furthermore, the proposed methodology demonstrated that it is enough to identify the spectrochemical similarity of the formulation between generic drugs to a reference drug through the chemometric study of their LIBS spectra, based on the determination of the differentiation and similarity factors, f 1 and f 2 , respectively, used in the pharmaceutical industry in this purpose. After analysing their LIBS spectra, the generic drugs selected for this work have all been shown to be in vitro bioequivalent, given their f 1 values of less than 15 and f 2 values greater than 50, according to the technical regulations on which the American and European medicines agencies are based for the approval of registration for generic immediate-release solid oral dosage form drugs. This has been evidenced even for drugs from Class III and Class IV of the biopharmaceutical classification system, whose active principle nominal concentration is very low as 0.1 and 0.25 mg/tablet, respectively. for the first time the LIBS technique has been successfully used in an advanced application for the pharmaceutical industry. The proposed method constitutes a reliable and specialized methodology for the establishment of formulation similarity between two drugs, without the requirement of separate identification of each of their components, which is a new and potential tool to determine the in vitro bioequivalence for generic immediate-release solid oral dosage form drugs. [Display omitted] • For the first time, the LIBS technique is used in an advanced pharma application. • Drugs with a nominal content of 1 mg/tablet can be analysed by LIBS. • To statistically compare LIBS spectra, the f1 and f2 factors are introduced. • LIBS is used to accurate predict the generic drugs in vitro bioequivalence. [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]

Introduction: The adalimumab biosimilar (ADAbio) Amgevita® has a similar efficacy and safety profile as the adalimumab reference (ADA) Humira®. We studied the clinical consequences of a non-medical switch from ADA to ADAbio in adult patients with mainly established rheumatoid arthritis (RA), psoriatic arthritis (PsA), and spondyloarthritis (SpA). Methods: Patients that received treatment with ADA for at least three months were switched to ADAbio. Data was collected retrospectively from 1 year before the switch up to 6 months after. Results: A total of 603 patients were switched from ADA to ADAbio (switch group). During a 1-year follow-up, over 93% of all patients underwent a successful transition in terms of disease activity and safety from ADA to biosimilar, supporting the bioequivalence of both drugs in patients with stable inflammatory rheumatic joint diseases. Forty patients (6.6%) switched back to ADA (re-switch group). There were no objective changes in disease activity score in 28 joints using C-reactive protein (DAS28-CRP), or adverse effects before and after the switch between both groups. Conclusions: In line with earlier reports, the transition to ADAbio went successful in the majority of patients with stable inflammatory rheumatic joint diseases. Patient-reported symptoms without objective signs that indicate a flare of disease activity after the switch to ADAbio are probably explained by nocebo effects. A pre-emptive approach to counteract nocebo effects and stimulate placebo response may have a positive impact on health outcomes for patients and preserve the economic benefits of cost savings that can be achieved by prescribing a biosimilar instead of the reference drug. [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]

The coronavirus disease 2019 (COVID‐19) has presented unprecedented challenges to the generic drug development, including interruptions in bioequivalence (BE) studies. Per guidance published by the US Food and Drug Administration (FDA) during the COVID‐19 public health emergency, any protocol changes or alternative statistical analysis plan for COVID‐19‐interrupted BE study should be accompanied with adequate justifications and not lead to biased equivalence determination. In this study, we used a modeling and simulation approach to assess the potential impact of study outcomes when two different batches of a Reference Standard (RS) were to be used in an in vivo pharmacokinetic BE study due to the RS expiration during the COVID‐19 pandemic. Simulations were performed with hypothetical drugs under two scenarios: (1) uninterrupted study using a single batch of an RS, and (2) interrupted study using two batches of an RS. The acceptability of BE outcomes was evaluated by comparing the results obtained from interrupted studies with those from uninterrupted studies. The simulation results demonstrated that using a conventional statistical approach to evaluate BE for COVID‐19‐interrupted studies may be acceptable based on the pooled data from two batches. An alternative statistical method which includes a "batch" effect to the mixed effects model may be used when a significant "batch" effect was found in interrupted four‐way crossover studies. However, such alternative method is not applicable for interrupted two‐way crossover studies. Overall, the simulated scenarios are only for demonstration purpose, the acceptability of BE outcomes for the COVID19‐interrupted studies could be case‐specific. [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]