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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]

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 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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

In this study, a new, fast and sensitive HPLC method with fluorometric detection was developed for the determination of mesalazine in human plasma and applied to a pharmacokinetic study. Mesalazine was precolumn derivatized with NBD-Cl and the fluorescent derivative was separated on a C18 (150 × 4.6 mm × 2.6 μm) analytical column at 30 ºC using a mobile phase composed of acetonitrile—0.1% o-phosphoric acid in water (70:30, v/v) by isocratic elution with flow rate of 1.0 mL min−1. The method was based on the measurement of the derivative using fluorescence detection (λex = 280 nm, λem = 325 nm). The retention time of mesalazine is 3.08 ± 0.06 min. Nortriptiline was used as internal standard. This currently developed method was validated according to ICH criteria by evaluating the specificity, linearity, precision, accuracy and robustness. The method was determined to be linear in a concentration range of 0.25–1.5 μg mL−1 with the correlation coefficient of 0.9997. LOD and LOQ were found to be 0.075 and 0.25 μg mL−1, respectively. Intraday and interday RSD values were less than 5.92%. The plasma concentration–time profile and pharmacokinetic parameters such as AUC0–t, AUC0–∞, Cmax, tmax, t1/2, were calculated according to the assays. The presented method can certainly be used for bioequivalence and bioavailability investigations and routine analysis of the drug in plasma. [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]

Low-temperature biopreservation and 3D tissue engineering present two differing routes towards eventual on-demand access to transplantable biologics, but recent advances in both fields present critical new opportunities for crossover between them. In this work, we demonstrate sub-zero centigrade preservation and revival of autonomously beating three-dimensional human induced pluripotent stem cell (hiPSC)-derived cardiac microtissues via isochoric supercooling, without the use of chemical cryoprotectants. We show that these tissues can cease autonomous beating during preservation and resume it after warming, that the supercooling process does not affect sarcomere structural integrity, and that the tissues maintain responsiveness to drug exposure following revival. Our work suggests both that functional three dimensional (3D) engineered tissues may provide an excellent high-content, low-risk testbed to study complex tissue biopreservation in a genetically human context, and that isochoric supercooling may provide a robust method for preserving and reviving engineered tissues themselves. Powell-Palm et al. demonstrate sub-zero centigrade preservation and revival of autonomously beating, 3D human induced pluripotent stem cell (hiPSC)-derived cardiac microtissues via isochoric supercooling, without the use of chemical cryoprotectants. Their study suggests that functional 3D engineered tissues may provide a high-content, low-risk testbed to study complex tissue biopreservation in a genetically human context, and that isochoric supercooling may provide a robust method for preserving and reviving engineered tissues themselves. [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]

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]

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]

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]

Introduction: Cross-sectional survey of 92 board-certified practicing Midwestern ophthalmologists to determine why prescribing habits favor brand-name drugs over generics and to identify approaches for increasing generic drug utilization. Methods: A survey was sent to members of state ophthalmology societies, private practice groups, and individual ophthalmologists to evaluate basic demographic/practice information, knowledge and opinions on generic drugs, frequency of drug representative visits, understanding of the Food and Drug Administration's process of evaluating generics, knowledge of patients' financial status and preferences, and action items that would increase generic utilization. Results: Three factors increase the likelihood of ophthalmologists switching patients to generic drugs: increased knowledge of (1) generic options, (2) price differences between brand-names and generics, and ((3) patient preference for generics. The following four factors decrease the likelihood of ophthalmologists switching patients to generic drugs: (1) increased disease severity, (2) feeling that patient outcomes may be affected by choice of brand-name versus generic, (3) personal preference for taking a brand-name drug over a generic for their own hypothetical eye disease even if both were free, and (4) increased personal preference for taking a brand-name drug for their hypothetical eye disease. Conclusion: Ophthalmologists should continue to update themselves on generic medication options, become familiar with the price difference of generics versus brand-name drugs for commonly prescribed medications, and seek patients' opinions on generics and correct them when possible to increase generic utilization. In addition, studies evaluating the clinical equivalence of generic drugs relative to brand-name drugs should be performed and may help increase generic utilization. [ABSTRACT FROM AUTHOR]

Background: Temozolomide is an alkylating agent approved by the U.S. Food and Drug Administration in 1999 for the treatment of patients with primary brain tumors. The aim of this study was to confirm the bioequivalence and safety of two strengths (20–100 mg) of generic temozolomide in the form of TOZ039 and Temodal® capsules administered to brain tumor patients. Study design: An open-label, randomized, two-phase, two-period, crossover pharmacokinetic study was performed in a single institution. The reference and test drugs were prescribed at a dose of 150 mg/m2 daily from days 1 to 5 of a 28-day cycle in the first phase; in the second phase, either a 150- or 200-mg/m2 dose was prescribed, depending on patient tolerance. On days 1 and 2 of each phase, a fixed 200-mg dose was administered either as ten 20-mg capsules in the first cycle or two 100-mg capsules in the second cycle. Drug administration in the first two days was randomized, i.e., if TOZ309 was administered on day 1, Temodal® was administered on day 2, and vice versa. The rest of the prescribed dose was administered in the form of Temodal® and spread equally over days 3–5. Blood samples were obtained for pharmacokinetic evaluation on days 1 and 2. Bioequivalence was demonstrated if the geometric means ratio of the three main pharmacokinetic parameters (mean maximum plasma concentration (Cmax), area under the concentration–time curve (AUC) 0-t, AUC 0-∞) fell within the equivalence boundary of 80–125%. Results: Twenty-nine glioblastoma multiforme or anaplastic astrocytoma patients were enrolled and dosed with the test and reference formulations under fasting conditions. The 90% confidence interval of the geometric means ratio for Cmax (91.08%, 106.18%), AUC0-t (98.62%,102.18%), and AUC0-∞ (98.65%, 102.21%) was well within the 80%–125% range for the 20-mg capsule, as was the Cmax (90.49%, 113.32%), AUC0-t (99.89%, 104.63%) and AUC0-∞ (99.99%, 104.67%) for the 100-mg capsule drug product. Additionally, all the secondary pharmacokinetic parameters were not significantly different. After two cycles of treatment, there was no mortality among the 29 patients, treatment-related severe adverse events, or events that would require study discontinuation; however, one significant adverse effect (life-threatening seizures) occurred and was related to disease progression. Adverse events were reported in 82.8% (24/29) patients, and treatment emergent adverse events were reported in 72.4% (21/29) patients. Conclusion: It can be concluded that 20-mg and 100-mg capsules of TOZ309 are bioequivalent to Temodal® capsules of the same strength under fasting conditions. Trial registration: https://www.chinadrugtrials.org.cn/index.html, CTR2017 0122. [ABSTRACT FROM AUTHOR]

There appears to be a mismatch between the assumed therapeutic equivalence of generic drugs, their interchangeability, and reported clinical discomfort following generic drug use and drug switches. In this article, we describe why we are of the opinion that the current regulatory approach to the evaluation of generic drugs based on average bioequivalence is sufficient to expect therapeutic equivalence in the clinical setting. This has often been debated, specifically as adverse drug reactions related to generic drug switches are regularly reported. We agree that clinical discomfort during a bioequivalent drug switch may indeed be caused by different exposures to the active substance. However, this difference in exposure is not a result of the characteristics or quality of generic drugs; it is caused by the pharmacokinetic within-subject variability of the active substance, i.e., the variability on the bioavailability of the active substance, when comparing two occasions of administration of the same drug product, to the same patient. Therefore, reported clinical discomfort following generic drug use and drug switches does not warrant a change in the regulatory approach to the evaluation of the bioequivalence of generic drugs. Switching from a brand-name drug to currently approved generic drugs, or between different generic drugs, will in principle result in comparable exposure, within boundaries determined by the within-subject variability of the pharmacokinetics of the active substance involved. [ABSTRACT FROM AUTHOR]

Desmopressin is a synthetic analogue of the natural antidiuretic hormone arginine vasopressin. Over the years, it has been clinically used to manage nocturnal polyuria in children with enuresis. Various pharmaceutical formulations of desmopressin have been commercialized for this indication—nasal spray, nasal drops, oral tablet and oral lyophilizate. Despite the fact that desmopressin is a frequently prescribed drug in children, its use and posology is based on limited pediatric data. This review provides an overview of the current pediatric pharmacological data related to the different desmopressin formulations, including their pharmacokinetics, pharmacodynamics and adverse events. Regarding the pharmacokinetics, a profound food effect on the oral bioavailability was demonstrated as well as different plasma concentration–time profiles (double absorption peak) of the desmopressin lyophilizate between adults and children. Literature about maturational differences in distribution, metabolism and excretion of desmopressin is rather limited. Regarding the pharmacodynamics, formulation/dose/food effect and predictors of response were evaluated. The lyophilizate is the preferred formulation, but the claimed bioequivalence in adults (200 µg tablet and 120 µg lyophilizate), could not be readily extrapolated to children. Prescribing the standard flat-dose regimen to the entire pediatric population might be insufficient to attain response to desmopressin treatment, whereby dosing schemes based on age and weight were proposed. Moreover, response to desmopressin is variable, whereby complete-, partial- and non-responders are reported. Different reasons were enumerated that might explain the difference in response rate to desmopressin observed: different pathophysiological mechanisms, bladder capacity and other predictive factors (i.e. breast feeding, familial history, compliance, sex, etc.). Also, the relapse rate of desmopressin treatment was high, rendering it necessary to use a pragmatic approach for the treatment of enuresis, whereby careful consideration of the position of desmopressin within this treatment is required. Regarding the safety of the different desmopressin formulations, the use of desmopressin was generally considered safe, but additional measures should be taken to prevent severe hyponatremia. To conclude the review, to date, major knowledge gaps in pediatric pharmacological aspects of the different desmopressin formulations still remain. Additional information should be collected about the clinical relevance of the double absorption peak, the food effect, the bioequivalence/therapeutic equivalence, the pediatric adapted dosing regimens, the study endpoints and the difference between performing studies at daytime or at nighttime. To fill in these gaps, additional well designed pharmacokinetic and pharmacodynamic studies in children should be performed. [ABSTRACT FROM AUTHOR]

This multicenter, randomized, double-blind, parallel-controlled trial aimed to compare the pharmacokinetics (PK) of IBI301 with rituximab in patients with CD20-positive (CD20+) B-cell lymphoma, who achieved a complete response/unconfirmed complete response after standard treatments. Patients were randomized (1:1) to receive IBI301 or rituximab (375 mg/m2, IV). Patients who continuously benefitted from the trial after the PK phase underwent the extension phase to receive up to three cycles of 3-month-cycle of rituximab/IBI301 maintenance therapy. PK was described using the area under the serum concentration–time curve from time zero to infinity (AUC0-inf), AUC from time zero to last quantifiable concentration (AUC0-t), and maximum serum concentration (Cmax). Pharmacodynamics (PD), incidence of adverse events and immunogenicity were evaluated. PK was defined equivalent, if 90% confidence intervals (CIs) for geometric mean ratios of PK endpoints fell within the margin of 0.8–1.25. Overall, 181 patients were enrolled in IBI301 (n = 89) and rituximab (n = 92) groups. Geometric mean ratios of AUC0-inf, AUC0-t, and Cmax were 0.91 (90% CI 0.85, 0.97), 0.91 (90% CI 0.86, 0.97), and 0.96 (90% CI 0.92, 1.01) between treatment groups, all within the bioequivalence range. Peripheral CD19+ and CD20+ B-cell counts were similar at each prespecified time point between the groups. No difference in immunogenicity was observed. The incidences of treatment-emergent adverse events (84.3% vs. 83.5%) and treatment-related AEs (56.2% vs. 61.5%) were comparable (IBI301 vs. rituximab). IBI301 was PK bioequivalent to rituximab in patients with CD20+ B-cell lymphoma. The PD, safety, and immunogenicity profiles of IBI301 were similar to those of rituximab. [ABSTRACT FROM AUTHOR]

In this paper, the method of estimating bioequivalence, whose main goal is to break the drug concentration curve in the body into components, is considered, implying that this curve is a signal that demonstrates the behavior of the drug. These components are directly related to the main stages of the drug. Denoting the boundaries of these stages, we can, with a minimum of error, compare drugs by the duration and nature of these stages. To isolate the components, methods such as the method of independent components, the window dispersion method, and the study of the variance gamma process will be used. [ABSTRACT FROM AUTHOR]

Viable cell concentration (VCC) is one of the most important process attributes during mammalian cell cultivations. Current state-of-the-art measurements of VCC comprise offline methods which do not allow for continuous process data. According to the FDA's process analytical technology initiative, process monitoring and control should be applied to gain process understanding and to ensure high product quality. In this work, the use of an inline capacitance probe to monitor online VCCs of a mammalian CHO cell culture process in small-scale bioreactors (250 mL) was investigated. Capacitance sensors using single frequency are increasingly common for biomass monitoring. However, the single-frequency signal corresponds to the cell polarization that represents the viable cell volume. Therefore single-frequency measurements are dependent on cell diameter changes. Measuring the capacitance across various frequencies (frequency scanning) can provide information about the VCC and cope with changing cell diameter. Applying multivariate data analysis on the frequency scanning data successfully enabled direct online monitoring of VCCs in this study. The multivariate model was trained with data from 5 standard cultivations. The model provided a prediction of VCCs with relative errors from 5.5 to 11%, which is a good agreement with the acceptance criterion based on the offline reference method accuracy (approximately 10% relative error) and strongly improved compared with single-frequency results (16 to 23% relative error). Furthermore, robustness trials were conducted to demonstrate the model's predictive ability under challenging conditions. The process deviations in regard to dilution steps and feed variations were detected immediately in the online prediction of the VCC with relative errors between 6.7 and 13.2%. Thus in summary, the presented method on capacitance frequency scanning demonstrates its suitability for process monitoring and control that can save batches, time, and cost. [ABSTRACT FROM AUTHOR]

Dechlorane plus (DP) is a chlorinated flame retardant with high production volume (HPV) and is widely used in our daily necessities. In the present study, a laboratory-scale microcosm was built up to simulate the uptake, depuration, bioaccumulation, and stereoselective enrichment of DP in a lower concentration and equilibration condition. Common carp (Cyprinus carpio) were used for 32 days exposure and 32 days depuration. The concentration ratios of syn-DP to total DP (fsyn values) in fish examined were lower than that in commercial products. Rate constants of uptake (kS) and elimination (ke) for the syn- and anti-DP were calculated using a first-order kinetic model. The uptake rate constants of syn- and anti-DP were 0.63 and 0.89 day−1, respectively. The depuration rate constants of syn-DP (0.11 day−1) were similar to anti-DP (0.096 day−1), suggesting that anti-DP is absorbed faster than syn-DP by common carp. The estimated bioconcentration factors for both syn-DP (5700 L/kg) and anti-DP (9300 L/kg) were higher than the bioconcentration hazard criteria outlined in the Stockholm Convention, suggesting the bioconcentration potential to aquatic organisms for DP. [ABSTRACT FROM AUTHOR]

Introduction: The bioequivalence of two formulations of desmopressin (dDAVP), a vasopressin analogue prescribed for nocturnal enuresis treatment in children, has been previously confirmed in adults but not in children. In this study, we aimed to study the pharmacokinetics (PK) and pharmacodynamics (PD) of these two formulations, in both fasted and fed children, including patients younger than 6 years of age.Methods: Previously published data from one PK study and one PK/PD study in children aged between 6 and 16 years were combined with a new PK/PD study in children aged between 6 months and 8 years, and analysed using population PK/PD modelling. Simulations were performed to further explore the relative bioavailability of both formulations and evaluate current dosing strategies.Results: The complex absorption behaviour of the lyophilizate was modelled using a double input, linked to a one-compartmental model with linear elimination and an indirect response model linking dDAVP concentration to produced urine volume and osmolality. The final model described the observed data well and elucidated the complexity of bioequivalence and therapeutic equivalence of the two formulations. Simulations showed that current dosing regimens using a fixed dose of lyophilizate 120 μg is not adequate for children, assuming children to be in the fed state when taking dDAVP. A new age- and weight-based dosing regimen was suggested and was shown to lead to improved, better tailored effects.Conclusions: Bioequivalence and therapeutic equivalence data of two formulations of the same drug in adults cannot be readily extrapolated to children. This study shows the importance of well-designed paediatric clinical trials and how they can be analysed using mixed-effects modelling to make clinically relevant inferences. A follow-up clinical trial testing the proposed dDAVP dosing regimen should be performed.Clinical Trial Registration: This trial has been registered at www.clinicaltrials.gov (identifier NCT02584231; EudraCT 2014-005200-13). [ABSTRACT FROM AUTHOR]

Purpose: To detect putative differences in the miRNomic profile of follicular fluids collected after follicular-phase-stimulation (FPS-FFs) and paired luteal-phase-stimulation (LPS-FFs) in the same ovarian cycles (DuoStim). Methods: Exploratory study at a private IVF center and University involving FPS-FFs and paired-LPS-FFs collected from 15 reduced ovarian reserve and advanced maternal age women undergoing DuoStim (n = 30 paired samples). The samples were combined in 6 paired pools (5 samples each) and balanced according to maternal age and number of cumulus-oocyte-complexes. Micro-RNAs were isolated and sequenced. Four miRNAs were then selected for further validation on 6 single pairs of FPS-FFs and LPS-FFs by qPCR. Results: Forty-three miRNAs were detected in both FPS-FFs and paired-LPS-FFs after sequencing and no statistically significant differences were reported. Thirty-three KEGG pathways were identified as regulated from the detected miRNAs. Four miRNAs (miR-146b, miR-191, miR-320a, and miR-483) were selected for qPCR validation since consistently expressed in our samples and possibly involved in the regulation/establishment of a healthy follicular environment. Again, no significant differences were reported between FPS-FFs and paired-LPS-FFs, also when the analysis was corrected for maternal age and number of cumulus-oocyte-complexes in generalized linear models. Conclusions: These data complement the embryological, chromosomal, and clinical evidence of equivalence between FPS and LPS published to date. [ABSTRACT FROM AUTHOR]

Introduction: Mesenchymal stem cells (MSCs) represent a very important cell source in the field of regenerative medicine and for bone and cartilage tissue engineering applications. Three-dimensional (3D) bioprinting has the potential to improve the classical tissue engineering concept as this technique allows the printing of cells with high spatial control of cell allocation within a 3D construct. In this study, we systematically compared different hydrogel blends for 3D bioprinting of MSCs by testing their cytocompatibility, ability to support osteogenic differentiation and their mechanical properties. In addition, we compared four different MSC populations isolated from different human tissues for their osteogenic differentiation capacity in combination with different hydrogels. The aim of this study was to identify the best MSC source and the most suitable hydrogel blend for extrusion-based bioprinting of 3D large-scaled osteogenic constructs. Materials and Methods: MSCs were isolated from different tissues (umbilical cord, adipose tissue, bone marrow). MSCs were seed onto or into different hydrogels and analyzed for cell viability, proliferation and osteogenic differentiation. In addition, viscoelastic properties of the hydrogels were determined. MSC-containing cubes with the size of 1 cm3 were printed by means of 3D extrusion-based bioprinting and analyzed by (immuno)histology for cell survival and production of a calcified extracellular matrix. Results: Adipose tissue derived MSCs (ASCs) showed the highest osteogenic differentiation potential. A complex hydrogel blend consisting of fibrin, gelatin, hyaluronic acid, glycerol (F/G/H/Gl), tuned with hydroxyapatite, showed the best viscoelastic properties in combination with an excellent biocompatibility towards ASCs. This cell/hydrogel combination was used to bioprint 3D cubes. The cubes showed good mechanical stability and the printed ASCs were viable and able to calcify the hydrogel after bioprinting. Conclusions: The combination of the HA-tuned F/G/H/Gl hydrogel blend along with ASCs can be considered as a very promising bioink for 3D bioprinting of artificial bone tissue equivalents for prospective applications in tissue engineering and regenerative medicine. [ABSTRACT FROM AUTHOR]

Results of a retrospective analysis of bioequivalence studies of generic angiotensin II receptor antagonists are presented. Losartan, valsartan, and telmisartan medicines can be considered highly variable with respect to the pharmacokinetic parameter for maximum blood-plasma concentration. Candesartan, irbesartan, and olmesartan medicines do not demonstrate high intra-individual variance in bioequivalence studies. Current regulatory recommendations and approaches to bioequivalence studies of highly variable medicines are discussed. Recommendations for the design and evaluation of test results of angiotensin II receptor antagonists are formulated. [ABSTRACT FROM AUTHOR]

In France, more than 2.5 million patients are currently treated with levothyroxine, mainly as the marketed product Levothyrox®. In March 2017, at the request of French authorities, a new formulation of Levothyrox® was licensed, with the objective of avoiding stability deficiencies of the old formulation. Before launching this new formulation, an average bioequivalence trial, based on European Union recommended guidelines, was performed. The implicit rationale was the assumption that the two products, being bioequivalent, would also be switchable, allowing substitution of the new for the old formulation, thus avoiding the need for individual calibration of the dosage regimen of thyroxine, using the thyroid-stimulating hormone level as the endpoint, as required for a new patient on initiating treatment. Despite the fact that both formulations were shown to be bioequivalent, adverse drug reactions were reported in several thousands of patients after taking the new formulation. In this opinion paper, we report that more than 50% of healthy volunteers enrolled in a successful regulatory average bioequivalence trial were actually outside the a priori bioequivalence range. Therefore, we question the ability of an average bioequivalence trial to guarantee the switchability within patients of the new and old levothyroxine formulations. We further propose an analysis of this problem using the conceptual framework of individual bioequivalence. This involves investigating the bioavailability of the two formulations within a subject, by comparing not only the population means (as established by average bioequivalence) but also by assessing two variance terms, namely the within-subject variance and the variance estimating subject-by-formulation interaction. A higher within individual variability for the new formulation would lead to reconsideration of the appropriateness of the new formulation. Alternatively, a possible subject-by-formulation interaction would allow a judgement on the ability, or not, of doctors to manage patients effectively during transition from the old to the new formulation. [ABSTRACT FROM AUTHOR]

Most attempts to answer the question of whether populations of groups can undergo natural selection focus on properties of the groups themselves rather than the dynamics of the population of groups. Those approaches to group selection that do emphasize dynamics lack an account of the relevant notion of equivalent dynamics. I show that the theory of 'dynamical kinds' I proposed in Jantzen (Synthese 192(11):3617–3646, 2014) can be used as a framework for assessing dynamical equivalence. That theory is based upon the notion of a dynamical symmetry, a transformation of a system that commutes with its evolution through time. In the proposed framework, structured sets of dynamical symmetries are used to pick out equivalence classes of systems. These classes are large enough to encompass the range of phenomena we associate with natural selection, yet restrictive enough to guarantee a sort of causal homogeneity. By characterizing dynamical kinds via symmetry structures in this way, the question of levels of selection becomes a precise question about which populations respect the dynamical symmetries of Darwinian evolution. Standard population genetic models suggest that populations undergoing evolution by natural selection are partially characterized by a group of fitness-scaling symmetries. I demonstrate conditions under which these symmetries may be satisfied by populations of individuals, populations of groups of individuals, or both simultaneously. [ABSTRACT FROM AUTHOR]

Purpose: Abiraterone acetate is a highly variable drug and has been approved for the treatment of patients with metastatic castration-resistant prostate cancer in many countries. This study was conducted to compare the pharmacokinetic profile between the test product (abiraterone acetate tablet) and reference product ZYTIGA® (250 mg) mainly.Methods: To overcome the high intra-subject variability of abiraterone, a two-sequence and four-period crossover study was designed to assess bioequivalence between the two products in 32 healthy male Chinese subjects under fasting conditions. The plasma concentration of abiraterone was analyzed by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) assay and the reference-scaled procedure was used to determine bioequivalence for the pharmacokinetics parameters.Results: The point estimate of geometric mean ratios with 90% confidence interval (CI) of maximum observed concentration (Cmax) and the area under the concentration-time curve (AUC0t) for abiraterone in the test and reference products were 100.19% (90% CI 87.05-115.32%) and 105.99% (90% CI 96.34-116.62%), respectively, and were both within the range of 80.00-125.00%. The 95% confidence upper limit bound for [Formula: see text] was - 0.1079 for Cmax and was - 0.0515 for AUC0t.Conclusions: Bioequivalence was demonstrated between the two abiraterone acetate products. The study also confirmed high intra-subject variability, for abiraterone: coefficient of variation (CV, %) of Cmax values for the test and reference products were 40.33% and 46.58%, while for AUC0t were 24.02% and 34.16%, respectively.Trial Registration: http://www.chinadrugtrials.org.cn/ : CTR20170997. [ABSTRACT FROM AUTHOR]

Purpose: To demonstrate the bioequivalence of the planned maleate salt-based commercial glasdegib tablet formulation [International Council for Harmonization (ICH) glasdegib] to the clinical di-hydrochloride (di-HCl) salt-based glasdegib formulation (di-HCl glasdegib). Additionally, to estimate the effects of a high-fat, high-calorie meal and proton-pump inhibitor (PPI) on the pharmacokinetics of ICH glasdegib.Methods: This Phase I open-label study (ClinicalTrials.gov: NCT03130556) enrolled 24 healthy subjects to receive two different tablet formulations of single-dose 100-mg glasdegib under fasted conditions. A subset of healthy volunteers (n = 12) received single-dose 100-mg ICH glasdegib following a high-fat, high-calorie meal or concurrently with a PPI (rabeprazole).Results: The adjusted geometric mean ratio (ICH glasdegib:di-HCl glasdegib) and 90% confidence intervals (CI) of area under the plasma concentration-time curve from time zero to infinity (AUCinf) and maximum plasma concentration (Cmax) were 104.0% (99.7‒108.5%) and 101.6% (96.1‒107.4%), respectively, within the acceptance range for bioequivalence (80‒125%). The adjusted geometric mean ratio (90% CIs) for AUCinf and Cmax under fed conditions were 84.3% (78.6‒90.6%) and 69.0% (61.8‒77.0%), respectively, relative to fasted conditions. When ICH glasdegib was administered concurrently with the PPI, the adjusted geometric mean ratio (90% CI) of AUCinf and Cmax were 100.6% (93.2‒108.6%) and 80.5% (70.7‒91.6%), respectively, relative to fasted conditions. Glasdegib was generally well tolerated under all conditions studied.Conclusions: The ICH glasdegib tablet formulation was bioequivalent to the clinical di-HCl formulation under fasted conditions. A high-fat, high-calorie meal or concurrent PPI treatment had a minimal effect on glasdegib exposure, and was not considered clinically meaningful. [ABSTRACT FROM AUTHOR]

Planning issues for darunavir (DRV) bioequivalence studies are considered. DRV is an antiviral (HIV) agent classified as an HIV protease inhibitor. Bioequivalence test results must be submitted for registration of generic drugs in the RF according to Federal Law 61-FZ. Bioequivalence study protocols and reports for DRV preparations that were submitted for review to the SCEEMP were analyzed. Differences in study designs including administration after fasting or meals, with or without a low dose of ritonavir, numbers of volunteers included in the study, and intra-subject variability were found. The internet was also searched for data on DRV variability. Recommendations for planning bioequivalence studies of DRV preparations were formulated based on the analysis. [ABSTRACT FROM AUTHOR]

Background: The pharmacokinetics of bisoprolol and amlodipine administered as a fixed-dose combination (FDC) tablet have not been sufficiently studied in healthy Chinese subjects to support a medical need for using the FDC in hypertension.Objective: This study was conducted to compare the pharmacokinetic profiles of the bisoprolol-amlodipine FDC tablet with the bisoprolol tablet and amlodipine tablet administered concomitantly under both fasting and fed conditions.Methods: An open-label, randomized, two-period, two-sequence crossover study was designed under both fasting and fed conditions. The plasma concentrations of bisoprolol and amlodipine were analyzed using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay, and the pharmacokinetic parameters of maximum concentration (Cmax) and area under the concentration-time curve (AUC) were used to evaluate bioequivalence.Results: The point estimate of geometric mean ratios of Cmax and AUC from the time of dosing to the last measurable concentration (AUCt) for bisoprolol were 97.85% and 99.46% in the fasting state, and 93.87% and 98.95% in the fed state, respectively. For amlodipine, the geometric mean ratios of Cmax and AUCt were 100.03% and 96.76% in the fasting state, and 106.56% and 103.07% in the fed state. No cases of treatment-emergent adverse events were reported during the entire study period.Conclusions: Bioequivalence was achieved for bisoprolol and amlodipine FDC under both fasting and fed conditions, and all treatments were safe and well tolerated by all study subjects.Trial Registration: ClinicalTrials.gov: NCT03226275. [ABSTRACT FROM AUTHOR]

Purpose: This study compared pharmacokinetics, pharmacodynamics, safety and immunogenicity profiles of INTP5 (a potential pegfilgrastim biosimilar) with that of Neulasta®.Methods: In this randomised, assessor-blind, crossover study, 344 healthy subjects received single subcutaneous dose of both INTP5 and Neulasta at 3 mg/0.3 ml (n = 172) or 6 mg/0.6 ml (n = 172) dose. The primary endpoints were AUC0-t, AUC0-∞ and Cmax of pegfilgrastim; and AUEC0-t and Emax of absolute neutrophil count (ANC).Results: All 344 subjects dosed were included in the safety and immunogenicity analyses, and 292 subjects in the pharmacokinetic and pharmacodynamic analyses. At 6 mg dose, test to reference ratio (90% CI) of AUC0-t was 105.65% (99.60-112.06%), AUC0-∞ was 105.72% (99.55-112.28%) and Cmax was 103.62% (98.19-109.35%); while test to reference ratio (95% CIs) of ANC AUEC0-t was 100.79% (97.75-103.92%) and Emax was 98.70% (95.52-101.98%). Both the primary endpoints met the bioequivalence criteria (CIs within 80-125%). Similarly, at 3 mg dose, these endpoints were within the acceptance range of 80-125%. CD34+ profiles were similar and 95% CIs were within acceptance range at both doses. Adverse events were reported in 54 (15.7%; 8.72% in INTP5 vs. 8.39% in Neulasta) subjects; most events were mild. The incidences of anti-drug antibodies were low and similar between INTP5 and Neulasta and no neutralising antibodies were detected.Conclusions: Pharmacokinetic and pharmacodynamic bioequivalence was established between INTP5 and Neulasta following 3 and 6 mg doses. Safety and immunogenicity profiles were similar between INTP5 and Neulasta. [ABSTRACT FROM AUTHOR]

Objective: Lenalidomide is a 4-amino-glutaryl derivative of thalidomide and belongs to a new generation of immunomodulatory agents for the treatment of patients with myelodysplastic syndrome and multiple myeloma. The aim of this study is to evaluate the bioequivalence and safety of a capsule containing 25 mg of a test formulation of lenalidomide and a 25 mg Revlimid® capsule in healthy, Chinese adult males for good quality anti-cancer medicine with lower costs.Methods: This was a single-center, randomized, open-label, single-dose, two-period, crossover pharmacokinetic study. Forty-eight healthy, adult Chinese males were administered a test lenalidomide or Revlimid® capsule, 24 in a fasted and 24 in a fed state, followed by crossover to the other capsule.Results: Twenty-four subjects in the fasting group and 23 in the postprandial group completed the clinical trial. Subjects administered test lenalidomide and Revlimid® capsules in the fasting state had a Cmax of 564 ± 153 and 609 ± 121 ng/mL, respectively; an AUC0-t of 1660 ± 211 and 1660 ± 235 h ng/mL, respectively; and an AUC0-∞ of 1670 ± 210 and 1670 ± 237 h ng/mL, respectively. In the fed state, the subjects had a Cmax of 389 ± 105 and 383 ± 101 ng/mL, respectively; an AUC0-t of 1770 ± 314 and 1740 ± 360 h ng/mL, respectively; and an AUC0-∞ of 1800 ± 316 and 1760 ± 362 h ng/mL, respectively. Both capsules were well tolerated, with no serious adverse events observed.Conclusion: According to the criteria for bioequivalence, the test formulation of lenalidomide and Revlimid® was determined to be bioequivalent. [ABSTRACT FROM AUTHOR]

Introduction: Sarilumab is a human monoclonal antibody that blocks the interleukin-6 receptor alpha (IL-6Rα). The phase 3 SARIL-RA-EASY study (EASY) assessed the robustness of an autoinjector (pen) for administering sarilumab when used by adults with active moderate-to-severe rheumatoid arthritis (RA) who are candidates for anti-IL-6R therapy in an unsupervised real-world setting.Methods: EASY was a 12-week, multicenter, randomized, open-label, parallel-group usability study of the sarilumab pen and prefilled syringe. Patients were randomized 1:1:1:1 to sarilumab 150 or 200 mg every 2 weeks (q2w) administered via pen or syringe, plus background disease-modifying antirheumatic drugs. Patients reported their ability to remove the pen cap and initiate and complete injections; negative responses were defined as product technical complaints (PTCs). The primary endpoint was the number of validated product technical failures (PTFs; PTC with a validated technical cause). This study was not powered to demonstrate bioequivalence or differences in efficacy among groups.Results: A total of 217 patients were randomized. There were 600 successful injections with the sarilumab pen in 108 patients and no pen-associated PTFs. One PTC was observed (the pen was mistakenly activated before injection). At week 12, 88% of patients indicated the pen was “easy” to use, and 98% reported they were “satisfied” with the pen. Proportions of patients achieving an American College of Rheumatology 20/50/70 response and a 28-joint disease activity score by C-reactive protein < 2.6 were similar at each dose between the pen and syringe groups, as were the pharmacokinetics. There were no clinically meaningful differences in adverse events (AEs), serious AEs, and AEs leading to discontinuation in the pen and syringe groups. The most common treatment-emergent AEs were infections and neutropenia.Conclusion: This study demonstrated the ease of use and robustness of the sarilumab pen when used by patients with RA in an unsupervised setting. Pharmacokinetics, safety, and efficacy were generally similar for the pen and syringe groups (NCT02057250).Funding: Sanofi Genzyme and Regeneron Pharmaceuticals, Inc.Trial Registration: Clinicaltrials.gov identifier, NCT02057250. [ABSTRACT FROM AUTHOR]

Aims: The objective of the study was to compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties of an insulin glargine formulation, Glaritus® (test) with the innovator’s formulation Lantus® (reference) using the euglycemic clamp technique in a single-dose, double-blind, randomized, two sequences, four-period replicate crossover study in healthy volunteers (n = 40).Methods: Subjects received subcutaneous administration of the insulin glargine (0.4 IU/kg) formulation at two occasions for test and reference and a 20% glucose solution was infused at variable rate to maintain euglycemia for 24 h.Results: Both PK [area under the plasma concentration time curve (AUC0-24 h) and maximum insulin concentration (Cmax)] and PD endpoints [area under glucose infusion rate time curve (AUCGIR0-24) and maximum glucose infusion rate (GIRmax)] demonstrated bioequivalence of Glaritus to Lantus with the 90% confidence interval of geometric mean ratio of test to reference entirely contained within 0.80-1.25. Both formulations showed equivalent geometric least-square mean LSM value (0.08 nmol/L) for Cmax. The geometric LSM AUC0-24 h value for Glaritus® (1.09 h nmol/L) was comparable to Lantus (1.05 h nmol/L). Median Tmax values were also identical (12 h for both), and median t1/2 values were also equal (18 h for both). For GIRTmax, the difference between the means for the two was not statistically significant. No AEs related to study formulations were reported, and both products were well tolerated.Conclusions: The test product (Glaritus) was found to be bioequivalent to the reference product (Lantus).Clinical trial registration number: CTRI/2015/06/005890; http://www.ctri.nic.in/. [ABSTRACT FROM AUTHOR]

Background and Objectives: The purpose of this study was to apply the reference-scaled average bioequivalence (RSABE) approach to evaluate the bioequivalence and to investigate the pharmacokinetic properties of two formulations of fixed dose combination (FDC) tablet of sofosbuvir (SOF) and ledipasvir (LED) (400/90 mg) in 36 healthy Egyptian volunteers.Methods: The study was performed in single-dose, randomized-sequence, open-label, reference-replicated, 3-period crossover design (RTR, TRR, RRT), with a washout period of 2 weeks. A rapid and simple LC-MS/MS method was developed and validated for the simultaneous estimation of SOF and LED using eplerenone as an internal standard (IS).Results: The results showed that the 90% confidence intervals (CIs) for natural log-transformed ratios of Cmax, AUClast and AUC∞ of SOF (89.95-115.31, 98.77-109.75 and 98.79-109.75) were within the RSABE acceptance limits. The 90% CIs for natural log-transformed ratios of Cmax and AUClast of LED (87.33-115.15 and 83.82-112.26) were within the FDA bioequivalence limits (80.00-125.00). In addition, the in vitro dissolution study was done and both formulations released > 85% of drug within 15 min in the proposed dissolution medium.Conclusions: In conclusion, bioequivalence between the two fixed-dose combination products was demonstrated for both active ingredients. [ABSTRACT FROM AUTHOR]

The pharmacokinetics, bioequivalence, and safety of Femorix® (Valenta Pharm Co., Russia) and Aubagio® (SanofiWinthrop Industrie, France) film-coated tablets (14 mg) were compared in a double-blind randomized investigation in parallel groups of healthy volunteers. The bioavailabilities of Femorix® film-coated tablets (14 mg, Valenta Pharm Co., Russia) were 96.18% [87.92 - 105.22%] for ln(Cmax) and 96.24% [88.67 - 104.44%] for ln(AUC0-72) of those for Aubagio® film-coated tablets (14 mg, Sanofi Winthrop Industrie, France), which fell in the commonly accepted range (80 - 125%) for proving the bioequivalence of the tested products. [ABSTRACT FROM AUTHOR]

Background: Few publications focus on adverse events (AEs) or suspected adverse drug reactions (SADRs) registered during bioequivalence (BE) studies.Objective: The aim was to characterise AEs reported in BE studies at a Mexican investigation site between the years 2011 and 2016, and to estimate occurrence using maximum plasma concentration (Cmax) and area under the plasma concentration curve from administration to last observed concentration at time t (AUC0–t) values, with the Gini index method.Methods: Reported AEs were recorded from 61 BE studies that were conducted by Laboratorios Clínicos de Puebla de Bioequivalencia, which is a third-party laboratory certified by the Mexican health authorities to conduct BE studies. AEs were then characterised in terms of occurrence, study period, nature, type, severity, causality and outcomes. The Gini index method was then applied, after excluding AEs that were classified as not drug-related, and distributions of SADRs were quantified according to estimated Cmax and AUC0–t cut-off values.Results: We classified the occurrence of SADRs in 61 BE studies after calculating Gini index-based pharmacokinetic cut-off values for 42 drugs evaluated in healthy Mexicans. Although more SADRs occurred above Cmax and/or AUC0–t cut-off values in most studies, some therapeutic classes (cardiovascular and respiratory systems) were associated with larger numbers of SADRs occurring below split points.Conclusions: The present data confirm the safety of BE studies, but indicate the need for further assessments of inter-individual differences according to the incidence of SADRs. The Gini index method represents an easy statistical approach for analysing safety data collected from BE studies and offers a risk management strategy for new generic medicines. [ABSTRACT FROM AUTHOR]

Economic sustainability is of paramount importance in the rapidly evolving therapeutic scenario of multiple sclerosis (MS). Glatiramoids are a class of drugs whose forefather, glatiramer acetate, has been used as a disease modifying drug (DMD) in patients with MS for over 20 years. Its patent expired in 2015; new versions of such drug are nowadays available on the market, potentially contributing to lowering prices and enhancing a better allocation of economic resources. In this review, we analyze the recommendations underlying the approval of both generic drugs and biosimilars by regulatory authorities, and we provide methodological tools to contextualize the design of studies on these new classes of drugs. We examine in more detail the preclinical and clinical data of Copemyl, a new member of the glatiramoid class, focusing on its biological and immunological properties and illustrating randomized controlled trials that led to its authorization. [ABSTRACT FROM AUTHOR]

The randomized crossover (2 × 2) protocol is a standard design for studies of bioequivalence, reducing intraindividual variability. Determination of cohort size for studies of bioequivalence is an important element in planning studies and must be evidence-based. The aim of the present work was to produce and validate an algorithm for determining the required cohort size for studies of bioequivalence using computer simulation. The proposed algorithm is based on a procedure for assessing the power of the statistical test for known numbers of observations, variance, and preset values of acceptable first-order error levels. [ABSTRACT FROM AUTHOR]

In recent years, pathways for the development and approval of bioequivalent inhaled products have been established for regulated markets, including the European Union (EU), and a number of orally inhaled products (OIPs) have been approved in the EU solely on the basis of in vitro and pharmacokinetic data. This review describes how these development pathways are structured and their implications for the treatment of airway diseases such as asthma. The EU guidance follows a stepwise approach that includes in vitro criteria as the first step. If all in vitro criteria are not met, the second step is based on pharmacokinetic evaluations, which include assessments of lung and systemic bioavailability. If all pharmacokinetic criteria are not met, the third step is based on clinical endpoint studies. In this review, the scientific rationale of the European Medicines Agency guidance for the development of bioequivalent OIPs is reviewed with the focus on the development of bioequivalent OIPs in the EU. Indeed, we discuss the advantages and disadvantages of the weight-of-evidence and stepwise approaches. The evidence indicates that the EU guidance is robust and, unlike clinical endpoint studies, the pharmacokinetic studies are far more sensitive to measure the minor differences, i.e. deposition and absorption rates, in drug delivery from the test and reference products and, thus, should be best suited for assessing bioequivalence. The acceptance range of the 90% confidence intervals for pharmacokinetic bioequivalence (i.e. 80-125% for both the area under the plasma concentration-time curve and maximum plasma concentration) represent appropriately conservative margins for ensuring equivalent safety and efficacy of the test and reference products. [ABSTRACT FROM AUTHOR]