Reference Product Research Articles

A Phase I Clinical Trial to Evaluate the Bioequivalence of an Adalimumab Biosimilar Adalimumab-WIBP and Humira®.

The high costs associated with biological agents often limit accessibility for many patients, whereas biosimilars allow the wider application of biological treatment. The objectives of this phase I clinical trial were to compare the pharmacokinetics, immunogenicity, and safety profiles of the biosimilar adalimumab-WIBP and the reference product Humira® and to assess the precision of the bioequivalence evaluation. In this randomized, double-blind, parallel-group bioequivalence study, 164 healthy male Chinese participants were selected and randomly divided into two groups on a 1:1 ratio. The subjects were administered a single 40 mg subcutaneous dose of either adalimumab-WIBP or Humira®. Blood samples extracted at multiple intervals after administration were analyzed to interpret pharmacokinetic parameters, and any adverse events were documented. Alongside ensuring safety measures, the subjects were monitored for immunogenicity. The pharmacokinetic results demonstrated similar serum concentration-time curves in both groups. There were no significant differences in safety and no differences in immunogenicity profiles between the two groups. The bioequivalence was confirmed: the 90% confidence interval for the geometric mean ratio of the main pharmacokinetic parameters was within the range of 80-125%. The trial indicated the bioequivalence between adalimumab-WIBP and the reference product Humira® based on pharmacokinetics, immunogenicity, and safety profile. These findings reinforce the use of the adalimumab-WIBP biosimilar as a possible therapeutic alternative to Humira®.

The impact of financial incentives promoting biosimilar products in oncology: A quasi-experimental study using administrative data.

Biosimilars have the potential to save a significant amount of money in cancer treatment costs. However, barriers exist in the adoption of biosimilar products. Japan introduced a new health policy in 2022 to promote the use of biosimilars in oncology by offering financial incentives to eligible hospitals. This study aims to examine the association between these financial incentives and prescription patterns. The study analyzed Diagnosis Procedure Combination (DPC) data to assess the impact of the new health policy on the use of biosimilar products in oncology. The policy provided an additional fee for hospitals using biosimilar products. The study included patients with specific types of cancer and analyzed the proportion of monthly biosimilar prescriptions using the number of prescriptions of reference and biosimilar products. A generalized synthetic control method was used for analysis. From April 2020 to March 2023, the study involved 27,737 patients in 114 hospitals, with 63 eligible hospitals receiving financial incentives. The average number of prescriptions of the drugs (rituximab, trastuzumab, and bevacizumab) increased gradually in both eligible and ineligible hospitals. The financial incentives were associated with a significant increase in the proportion of biosimilar product prescriptions, with a monthly increase of 0.092 per month (95% CI, 0.040-0.145) [9.2%, 95% CI, 4.0-14.5] compared to ineligible hospitals. Our study indicates that providing financial incentives to hospitals to utilize biosimilar products increased their prescriptions. Japan's recent health policy of moderate financial incentives is an effective approach to increasing prescriptions of biosimilar products.

Development of Novel Frontsheets With Protective Coatings to Increase the Durability and Reliability of Glass‐Free Lightweight PV Modules

ABSTRACTIn this work, novel PET‐based frontsheet materials with UV‐cured coatings were developed and investigated. UV‐curing urethane acrylates were selected as innovative, fluorine‐free coating systems. Polyurethane coatings exhibit excellent UV resistance, chemical and moisture resistance and, thus, high durability in outdoor applications. A homogeneous application without coating defects such as bubbles, voids or detachments was achieved. Material tests with cross‐cut tests showed no separation from the PET substrate. The water vapor transmission rates and the physical (optical and thermal) and chemical properties of the novel polymeric frontsheets were measured and compared with uncoated reference systems and products already on the market. The aging‐related changes after irradiation and humid heat storage were investigated and described in detail. Based on this comprehensive study, the newly developed frontsheets can be considered a suitable alternative to polymeric frontsheets with fluorine‐containing top layers.

Pharmaceutical Equivalence of Film-Coated and Chewable Tablets: A Comparative Dissolution Study Using Pulverized Chewable Tablets

Famotidine is a histamine H2 receptor antagonist used in the treatment of gastrointestinal disorders. It is available in multiple formulations, including film-coated tablets, chewable tablets, oral suspension, and injections. The purpose of this study was to develop and evaluate the film-coated tablet (FT) containing famotidine, magnesium hydroxide, and precipitated calcium carbonate, designed to be pharmaceutically equivalent to the marketed chewable tablet (CT). To achieve the pharmaceutical equivalence of two tablets, the dissolution profiles of FT should be similar to those of CT. However, since CT is intended to be chewed before swallowing, testing it in its intact form would not provide accurate results. Therefore, pulverized chewable tablets (PCT) were used as the reference product. The dissolution, performed by the paddle method at 50 rpm, was analyzed by the validated UV method. Similarity factor (f2) and difference factor (f1) were calculated to assess the equivalence of the dissolution profiles. The results demonstrated that the dissolution profiles of the FT and CT were similar. Additionally, the acid-neutralizing capacity test confirmed the equivalence of the two antacids. This study is one of the first to propose that dissolution tests for pharmaceutical equivalence should be conducted on pulverized CTs when developing generic equivalents to CTs.

Preparation of Ready-to-use Therapeutic Foods Based on Soy, Millet, Rice, Corn, and Sugar for the Management of infant with Moderate Acute Malnutrition

The prevalent number of children in developing countries from suffering MAM is increasing daily and this has significant cost implications for their treatment. Therefore, the management of MAM should be a public health priority. Ready-to-use therapeutic foods (RUTF) play a fundamental role in the management protocol for severe acute malnutrition in children aged 6 to 59 months. In our study, we aim to enhance the value of ready-to-use foods prepared from local products, namely soya, millet, rice, maize and sugar (SOMRIS<sup>10-16</sup>). The objective was to develop a formula meeting the recommended nutritional and microbiological requirements in order to use it as a substitute for reference products for the treatment of moderate acute malnutrition. It has allowed to develop a ready-to-use therapeutic food using the linear programming technique, then produced according to traditional methods. The nutritional and microbiological qualities have been determined and confirm that the formula based on soy, millet, rice, corn, and sugar (SOMRIS<sup>10-16</sup>), meets the nutritional and microbiological needs recommended for children with moderate acute malnutrition. It will be subjected to the clinical trial processes in force in order to use it with complete peace of mind.

Pooled safety analysis from the VOLTAIRE clinical trials of adalimumab-adbm and adalimumab reference product in patients with rheumatoid arthritis, Crohn’s disease, and chronic plaque psoriasis

ABSTRACT Objectives This analysis reported the incidence of safety endpoints across five phase 3 randomized controlled clinical trials in patients with rheumatoid arthritis (RA), Crohn’s disease (CD), and chronic plaque psoriasis (PsO) who received ≥ 1 dose of adalimumab-adbm or adalimumab reference product (RP). Methods Exposure-adjusted incidence rates for safety endpoints were calculated per 100 patient-years and reported by disease indication and treatment arm. Subgroup analyses by patient age and sex were also conducted. Results The mean length of follow-up was 62 weeks, 48 weeks, and 32 weeks for patients with RA, CD, and PsO, respectively. Rates of SAEs and discontinuations due to AEs were similar among patients with RA and PsO, but slightly higher among those with CD. Incidence rates of all safety endpoints were consistent between the adalimumab-adbm and adalimumab RP treatment arms within each indication Subgroup analyses of patients with RA, CD, and PsO showed no between-group differences by age and sex. Conclusions In patients with RA, CD, and PsO, there were no differences between biosimilar adalimumab-adbm or the adalimumab RP regarding the rate of adverse events, serious adverse events, discontinuations due to adverse events, deaths, or any adverse events of special interest.

Nonclinical Similarity of the Biosimilar Candidate ABP 938 with Aflibercept Reference Product.

ABP 938 is being developed as a biosimilar to Eylea® (aflibercept reference product [RP]), an anti-vascular endothelial growth factor (VEGF) drug used in the management of retinal diseases. Previously, a comparative analytical similarity assessment demonstrated that ABP 938 and aflibercept RP have the same amino acid sequence and exhibit similar higher-order structure and biological activity. The nonclinical studies described here were designed to assess the in vitro pharmacology and the in vivo pharmacokinetics (PK), toxicokinetics (TK), and safety profiles of ABP 938 compared to aflibercept RP. In vitro target-binding kinetics and affinity for VEGF-A and placental growth factor (PIGF) isoforms were evaluated using surface plasmon resonance (SPR). Effector functions were assessed by cell-based assays. PK was evaluated in a nonterminal intravitreal (IVT) ocular distribution study in rabbits. Safety was assessed in a 1-month IVT study in cynomolgus monkeys. SPR results demonstrated that ABP 938 is similar to aflibercept RP in binding kinetics and affinity for VEGF-A111, VEGF-A121, VEGF-A165, VEGF-A189, PlGF-1, and PlGF-2 isoforms. No antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, or complement-dependent cytotoxicity was observed with ABP 938 and aflibercept RP. Results from thenonterminal ocular distribution study in rabbits indicated that there were no meaningful differences in the distribution kinetics between intravitreally injected ABP 938 and aflibercept RP. Additionally, there was no evidence of ocular or systemic toxicity associated with IVT administration of ABP 938 in a repeat-dose, 1-month toxicology study in cynomolgus monkeys; toxicokinetic and toxicology profiles were similar to aflibercept RP. This integrated assessment of results from the in vitro pharmacology assessment and in vivo PK and TK/toxicology profiles formed the nonclinical portion of the totality of evidence demonstrating ABP938 is a biosimilar to aflibercept RP.

Bioequivalence of lisdexamfetamine dimesylate hard capsules formulations

Lisdexamfetamine (LDX), an inactive prodrug of dexamphetamine, is used as a second-line treatment for attention deficit hyperactivity disorder (ADHD) and for moderate to severe binge eating disorder (BED). The objective of this study is to evaluate the bioequivalence of two LDX formulations, including the reference product manufactured by Patheon Pharmaceuticals (Venvanse® 70 mg) versus a formulation manufactured by Eurofarma Laboratórios S/A. A randomized, crossover, open-label study was conducted with two treatments, two periods, two sequences, and 48 healthy participants of both sexes who received oral administration of the medications. A total of 24 blood samples were collected from each participant, from T0 (before taking the medication) to 10 hours later. The plasma concentration of LDX was quantified using liquid chromatography coupled with mass spectrometry (LC-MS/MS). Both formulations were well tolerated, and no serious adverse events were reported. Cmax and AUC0-t were compared: the ratio between the test and reference formulations for Cmax was 106.22% with a 95% confidence interval (CI) of 97.72% - 116.66% and a power of 98.75%. The ratio between the test and reference formulations for AUC0-t was 106.28%, CI (100.68% - 112.19%), with a power of 100.00%. The ratio between the test and reference formulations for AUC0-inf was 106.29%, CI (100.71% - 112.17%), with a power of 100.00%. The formulations were shown to be statistically bioequivalent in terms of their rate and extent of absorption, based on criteria established by the Brazilian Health Regulatory Agency (ANVISA).

Rain event detection and magnitude estimation during Indian summer monsoon: Comprehensive assessment of gridded precipitation datasets across hydroclimatically diverse regions

Accurate precipitation estimates are quintessential for hydrologic modeling and climate studies. Different gridded precipitation products are available in any region, and selecting the best one is essential for hydroclimatic modeling and analysis. In the current study, observation- (APHRODITE), reanalysis- (IMDAA, ERA5-Land, PGF), satellite-based (IMERG, CHIRPS, PERSIANN-CDR), and hybrid (MSWEP) gridded precipitation products with different spatial and temporal resolutions are evaluated using several continuous, categorical, graphical, and interval-based performance measures towards detecting Indian Summer Monsoon Rainfall (ISMR) events and estimating their magnitudes for the subcontinent of India, considering IMD gauge-based gridded as reference product. We confine our analysis to the monsoon season (i.e., June to September), the principal rainy season in the Indian sub-continent. The dearth of data and limited rain gauge-based observations from non-uniform sparse monitoring networks across India necessitated grid-to-grid comparative evaluations instead of point-to-grid assessments. We propose a new ranking framework to determine the suitability of precipitation datasets for twenty-seven hydroclimatic regions comprising homogeneous rainfall zones, Köppen-Geiger climate zones, and major river basins. Results from the comprehensive evaluation suggest that (1) APHRODITE, MSWEP, and ERA5-Land best approximate precipitation event occurrences across India, (2) MSWEP and ERA5-Land are most suitable (highest rank) alternatives at the regional level, while APHRODITE is found to be next suitable dataset owing to its persistent dry bias, (3) performances of CHIRPS and IMERG have reasonably lower rank score across India, (4) close agreement of examined datasets is noted over semi-arid and sub-humid regions (e.g., peninsular and central India), whereas ERA5-Land, IMDAA, and APHRODITE fail to detect and reproduce the intensity of the events along the west coast and northeastern India, (5) PGF and PERSIANN-CDR are the least situated datasets. Moreover, the present study provides a unique and innovative perspective to characterise the precipitation over a vast topographic, ecologic, and climatic gradient region like India.

Improved injection site reactions after switching from adalimumab reference to adalimumab biosimilar LBAL for ulcerative colitis: A case report.

Adalimumab (ADA) is an antitumor necrosis factor agent that is used for the treatment of inflammatory bowel disease. However, its cost has resulted in varying degrees of restricted access across global healthcare economies. Biosimilars are agents that contain a similar version of the active substance of an already approved original biologic agent and are intended to be used for the same indication as the reference product. In general, biosimilars follow the originator; therefore, information on its efficacy and safety had been few. Some studies have reported on replacement of the originator with a biosimilar of the same efficacy because of medical reasons. A 15-year-old girl with steroid-dependent ulcerative colitis that relapsed after vedolizumab was treated with ADA reference. Six weeks after starting ADA reference, her gastrointestinal symptoms had completely resolved, however, immediately after the eighth dose of ADA reference, redness, swelling, and pruritus were noted at the injection site on the left thigh. Allergic reaction caused by the ADA reference. ADA reference was changed to ADA biosimilar LBAL. ADA biosimilar LBAL was continued without any symptoms, such as local swelling, redness, or itching. In addition, there was no deterioration of gastrointestinal symptoms. We showed the efficacy and safety of ADA biosimilar LBAL as an alternative to ADA reference, which caused injection site reactions. Changing from ADA reference to ADA biosimilar because of adverse events may be an option that needs careful observation, considering that the originator and the biosimilar are not exactly the same.

Safe and well-tolerated long-term parenteral nutrition regimen: omega-3-fatty-acid-enriched Medium Chained/ Long Chained Triglycerides emulsion.

Background and AimsA limited number of randomized controlled trials (RCTs) have examined the use of lipid emulsions (LEs) of different compositions in home parenteral nutrition (HPN), and there are very few data on the long-term use of omega-3 (n-3) polyunsaturated fatty acids (PUFAs). The study´s objective was to assess safety and tolerability of an n-3 PUFA-enriched LE in adult patients suffering from chronic intestinal failure (CIF) requiring long-term HPN. MethodsIn this prospective, randomized, controlled, double-blind, multicentre, international clinical trial, which was conducted at eleven sites, adult patients in need of HPN including lipids received either the investigational product, an n-3 PUFA-enriched medium/long-chain triglyceride (MCT/LCT) LE, or the reference product, a standard MCT/LCT LE, for an average duration of eight weeks. The primary outcome was the sum of changes of liver function parameters (total bilirubin, aspartate transaminase and alanine transaminase) from baseline to final visit. Secondary objectives included fatty acid pattern in plasma and red blood cells (RBCs) and triene:tetraene ratio in plasma. Results74 patients were enrolled up to premature study termination. Liver function parameters showed no clinically relevant differences between study groups and remained within normal ranges. The n-3 PUFAs EPA and DHA increased in plasma and RBCs in the Lipidem group and were higher in the Lipidem group than the reference group at the end of the study resulting in an increased n-3-index in RBCs with Lipidem. Average n-3-index was >8. The plasma triene:tetraene ratio decreased in both groups. ConclusionThis study is one of the largest comparing two LEs in the complex setting of HPN treatment of adult patients. Although it has been early terminated its results considerably contribute to the evidence on safety and efficacy of longer-term use of LEs in HPN treatment. The n-3 PUFA-enriched LE Lipidem was safe and well-tolerated, particularly in terms of liver function. Lipidem provided an additional supply of n-3 PUFAs and led to positive changes in fatty acid profiles of plasma and RBCs. The n-3-index was in the desirable range at the end of the study in patients receiving Lipidem. There was no evidence of essential fatty acid deficiency with Lipidem. ClinicalTrials.gov IdentifierNCT03282955 Trial RegistrationEudraCT Number: 2015-000849-23

Efficacy and Safety of Biosimilar Cetuximab Versus Innovator Cetuximab in Indian Patients With Head and Neck Cancer: A Multicenter, Randomized, Double-Blind, Phase III Trial.

Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer, with approximately 225,419 new cases with over 125,000 deaths annually in India. This trial compared the efficacy and safety of biosimilar cetuximab versus innovator cetuximab (IC) in combination with platinum-based chemotherapy in patients with recurrent locoregional or metastatic SCCHN. This phase III trial is a multicenter, randomized, double-blind and parallel group study performed in Indian patients with recurrent locoregional or metastatic SCCHN. Patients were randomly assigned in 2:1 ratio to receive biosimilar cetuximab and IC in combination with cisplatin and fluorouracil via intravenous infusions. The primary end points were disease control rate (DCR) and overall response rate (ORR) as per response evaluation criteria in solid tumors version 1.1. The secondary end points included pharmacokinetics (PK), immunogenicity, safety, and tolerability. Of 180 patients enrolled, 120 patients received biosimilar cetuximab and 60 patients received IC treatment. No significant statistical difference was observed in the primary outcomes between two groups. Treatment difference in DCR and ORR response was found to be -5.21 (90% CI, -8.94 to -1.48) and -4.79 (90% CI, -19.42 to 9.84), respectively, indicating noninferiority to reference product. The incidence of treatment-emergent adverse events (AEs; biosimilar cetuximab: 89.2% v IC: 91.7%; P = .8364) and serious AEs (biosimilar cetuximab: 23.3% v IC: 13.3%; P = .0603) and PK parameters were comparable between treatment groups. The immunogenicity findings showed higher incidence of anticetuximab antibodies in the biosimilar cetuximab group compared with the IC group at the end of Study. The findings of this study demonstrated noninferiority along with comparable PK, safety, and immunogenicity of biosimilar cetuximab and IC in patients with recurrent or metastatic SCCHN.

Immunogenicity of adalimumab reference product and adalimumab-adbm in patients with rheumatoid arthritis, Crohn’s disease and chronic plaque psoriasis: a pooled analysis of the VOLTAIRE trials

ObjectiveThis post hoc analysis compared the immunogenicity of the biosimilar adalimumab-adbm (Cyltezo) with the adalimumab reference product (RP; Humira) across indications, including rheumatoid arthritis (RA), Crohn’s disease (CD) and plaque psoriasis (PsO), and by patient sex in the VOLTAIRE trials programme.MethodsIn each active-comparator randomised controlled trial (RCT), immunogenicity was assessed at various time points by the proportion of patients with antidrug antibodies (ADAs) and neutralising antibodies (nAbs), using acid dissociation followed by electrochemiluminescence assay. Assay sensitivity was 50 ng/mL, and drug tolerance was ≥30 µg/mL (free drug) at the low positive control level.ResultsMinor differences in immunogenicity parameters (ADAs, ADA titres and nAbs) were evident between adalimumab-adbm and adalimumab RP across these three immune-mediated inflammatory diseases (IMIDs). The proportion of ADA-positive and nAb-positive patients increased from baseline over time in all three RCTs, as expected, and was similar in the RA and CD RCTs but with higher numbers of ADA-positive and nAb-positive patients reported in the PsO trial. Subgroup analysis by patient sex showed the same trend.ConclusionsDifferences among the RCTs may partially be explained by concomitant background therapy (methotrexate) in the RA trial, stable doses of azathioprine, 6-mercaptopurine or methotrexate in 36% of patients with CD and absence of background therapy in the PsO RCT. The analyses further confirm the biosimilarity of adalimumab-adbm with the adalimumab RP across IMIDs and provide supporting evidence that adalimumab-adbm is an interchangeable biosimilar with consistent clinical results in patients originally treated with the RP.Trial registration numbersVOLTAIRE-RA (NCT02137226; EudraCT 2012-002945-40); VOLTAIRE-CD (NCT02871635; EudraCT 2016-000612-14); VOLTAIRE-PsO (NCT02850965; EudraCT 2016-000613-79).

Pharmacokinetics and bioequivalence of ezetimibe tablet in healthy Chinese subjects under fasting and fed conditions.

The purpose of this study is to evaluate the pharmacokinetics (PK) parameters of an ezetimibe 10 mg (test drug) and assess its bioequivalence to the branded reference product in healthy Chinese subjects under fasting and fed conditions. A single-center, randomized, open-label, four-period, two-sequence, full replicate crossover study was conducted in 88 healthy Chinese subjects under fasting or fed conditions. Subjects received a single oral dose of 10 mg ezetimibe tablet as test or reference formulation. There was a minimum 14-day washout period between each dose. Blood samples were collected at prescribed time intervals, the plasma concentration of free ezetimibe and total ezetimibe (ezetimibe + ezetimibe glucuronide) was determined by a validated ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Pharmacokinetik and bioavailability parameters were estimated via non-compartmental methods. Adverse events were also recorded. 40 and 48 eligible healthy subjects were enrolled in the fasted and fed study. Under fasting state, total ezetimibe with 90% confidence intervals (CIs) of Cmax, AUC0-t, and AUC0-∞ were 87.17% (81.99 - 92.66%), 95.98% (92.38-99.72%), and 96.04% (91.37 - 100.95%), respectively. Under fed state, total ezetimibe with 90% confidence intervals (CIs) of Cmax, AUC0-t, and AUC0-∞ were 98.71% (90.11 - 108.13%), 98.32% (94.71 - 102.06%), and 97.90% (92.68 - 103.42%), respectively. The 90% CIs of the ratio of geometric means (GMRs) of Cmax, AUC0-t, AUC0-∞ of the test and reference formulation in both fasting and fed conditions fell within the conventional bioequivalence criteria of 0.80 - 1.25. No severe adverse events were observed. The test and reference 10-mg ezetimibe tablets were bioequivalent under fasting and fed conditions in Chinese subjects. Both preparations showed good safety and tolerability.

Efficacy and safety of the ustekinumab biosimilar ABP 654 in patients with moderate-to-severe plaque psoriasis: a randomized, double-blinded, active-controlled, comparative clinical study over 52 weeks.

ABP 654 is a biosimilar to ustekinumab reference product (RP). ABP 654 has been shown to have an amino acid sequence identical to ustekinumab RP and they are similar in structure, purity, and potency as well as clinical pharmacokinetics and safety in healthy volunteers. This randomized, double-blinded, active-controlled, single-transition, comparative clinical study (ClinicalTrials.gov ID NCT04607980) was conducted to compare the efficacy, safety, and immunogenicity of ABP 654 and ustekinumab RP in patients with moderate-to-severe plaque psoriasis. Patients were randomized in a 1:1 ratio to receive ABP 654 or ustekinumab RP at a weight-based dose of 45 mg or 90 mg administered subcutaneously on day 1 (week 0), week 4, and week 16. At week 28, patients with a ≥75% improvement in Psoriasis Area and Severity Index (PASI) were re-randomized such that those initially randomized to ABP 654 continued to receive ABP 654 and those initially randomized to ustekinumab RP were re-randomized to either continue on ustekinumab RP or transition to ABP 654. The primary efficacy endpoint was PASI percent improvement from baseline to week 12. Secondary endpoints included additional efficacy measurements as well as an assessment of adverse events and antidrug antibodies. At week 12, the observed mean (SD) PASI percent improvement from baseline was 81.9 (19.9) and 81.9 (19.6) for the ABP 654 and ustekinumab RP treatment groups, respectively. The point estimate of the mean difference in PASI percent improvement from baseline to week 12 between the treatment groups was 0.14 with a 2-sided 90% confidence interval (CI) of (-2.6, 2.9), well within the prespecified similarity margin of (-10, +10). In addition, throughout the study, secondary efficacy analyses and safety and immunogenicity profiles were similar across the treatment groups. These results indicate that ABP 654 and ustekinumab RP are clinically similar in efficacy, safety, and immunogenicity in patients with moderate-to-severe plaque psoriasis. Further, a single transition from ustekinumab RP to ABP 654 at week 28 had no impact on the efficacy, safety, or immunogenicity results for the remainder of the 52-week study, supporting a conclusion of no clinically meaningful differences between ABP 654 and ustekinumab RP.

Pharmacokinetics and Bioequivalence of Two Powders of Azithromycin for Suspension: A Nonblinded, Single-Dose, Randomized, Three-Way Crossover Study in Fed and Fasting States Among Healthy Chinese Volunteers.

Azithromycin, a macrolide antibiotic, is commonly used to treat mild-to-moderate bacterial infections. This research aimed to evaluate the pharmacokinetics (PK) properties and bioequivalence (BE) of two azithromycin (EQ 100 mg base/packet) powders for suspension in Chinese healthy participants in fed and fasting conditions. A total of 90 Chinese healthy participants were enrolled in this nonblinded, single-dose, randomized, semireplicate, three-period, three-sequence, crossover study. Of them, 42 and 40 were categorized to the fed and fasting conditions, respectively. The washout period between doses was 21 days. Blood specimens were harvested prior to administering the drug and 194 h following administration. The plasma levels of azithromycin were analyzed using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach. PK parameters were measured using noncompartmental analysis. This research compared BE between the reference and test products using the average bioequivalence (ABE) or reference-scaled average bioequivalence (RSABE) method, considering the within-subject variability (SWR) of the reference preparation. Adverse events (AEs) were monitored to examine safety and tolerability. The RSABE method (SWR ≥ 0.294) was used to determine the BE of maximal plasma concentration (Cmax) in both fed and fasting conditions. In the ABE approach, (SWR < 0.294) was adopted to assess the BE of the area under the plasma concentration-time curve from time zero to the last measurable time point (AUC0-t) and determine the area under the plasma concentration time curve from time zero to time infinity (AUC0-inf). In the fasting condition, the point estimate of the test/reference ratio for Cmax was 1.08, with a 95% upper confidence bound of - 0.05 < 0.00. The geometric mean ratio (GMRs) for AUC0-t and AUC0-inf was 115.21% [90% confidence interval (CI) 107.25-123.27%] and 113.07% (90% CI 105.14-121.61%), respectively. In the fed condition, the point estimate of the test/reference ratio for Cmax was 0.94, with a 95% upper confidence bound of - 0.10 < 0.00. The GMR for AUC0-t and AUC0-inf was 99.51% (90% CI of 91.03-108.78%) and 99.43% (90% CI 91.73-107.78%), respectively. These data all satisfied the BE criteria for drugs with high variability. All AEs were transient and mild, and no severe AEs were observed. Our study indicated that the test and reference products of azithromycin (EQ 100 mg base/packet) powder for suspension were bioequivalent and safe in healthy Chinese participants, irrespective of the feeding condition. CLINICAL TRIAL REGISTRATION (CHINADRUGTRIALS.ORG.CN): CTR20232646, registered on 25 August 2023.

Self-Nanoemulsifying/ Self-Assembled Cubic Nanoparticles Lyophilized Tablet: A Novel Biphasic Release Approach to Enhance the Bioavailability of a Lipophilic Drug.

This study aimed to prepare a combined self-nanoemulsifying and self-assembled cubic nanoparticles (SNE/SAC) lyophilized tablet eliciting biphasic release pattern escorted with enhanced bioavailability for drugs hampered with slow dissolution and poor absorption. The antimuscarinic Darifenacin hydrobromide (DRF) was selected as a model drug used to treat overactive bladder-associated nocturia. The DRF-SNE/SAC lyophilized tablet was prepared so that upon reconstitution a mixture of DRF-loaded cubic nanoparticles and nanoemulsion dispersion is obtained. The nanoemulsion portion is responsible for the fast release followed by controlled release of the remaining dose loaded in cubic nanoparticles. A comparative pharmacokinetic study adopting randomized crossover design in male albino rabbits versus marketed product Frequefenacine® tablet was performed. Half of the dose (52.05% ± 4.21%) was rapidly released in the first 4h followed by sustained release of the remaining drug where (90.16% ± 8.85%) was released in 24h. The tested system showed 2.45 folds higher % relative bioavailability and 1.57 folds higher Cmax with 1.62 longer residence time relative to reference product. The results endow the ability of the developed DRF-SNE/SAC lyophilized tablet to be considered as a propitious approach for the treatment of overactive bladder-associated nocturia without midnight dose administration.

Evaluation of the Seegene Allplex™ RV master assay for one-step simultaneous detection of eight respiratory viruses in nasopharyngeal specimens

BackgroundThe Seegene Allplex™ RV Master (RVM) assay is a one-step multiplex real-time reverse transcription polymerase chain reaction (RT-PCR) system for detecting eight viral respiratory pathogens from nasopharyngeal swab, aspirate, and bronchoalveolar lavage specimens. The eight RVM targets are: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Influenza A (Flu A), Influenza B (Flu B), Human respiratory syncytial virus (RSV), adenovirus (AdV), rhinovirus (HRV), parainfluenza virus (PIV), and metapneumovirus (MPV). The assay is based on Seegene’s multiple detection temperature (MuDT) technology and provides cycle threshold (Ct) values for each of its viral targets upon PCR completion. ObjectiveWe aimed to evaluate the diagnostic performance of the RVM assay by calculating sensitivity, specificity, accuracy, Positive Predictive Value (PPV), Negative Predictive Value (NPV), Positive Percent Agreement (PPA), Negative Percent Agreement (NPA), and Overall Percent Agreement (OPA) compared to definite diagnosis and analogous reference assays. Study designDiagnostic sensitivity, specificity, accuracy, PPV, and NPV were calculated by comparing the results of the RVM assay to that of definite diagnosis assays; while PPA, NPA, and OPA were calculated by comparing results of the RVM assay to that of analogous reference products. Definite diagnosis and reference methods comprised whole genome sequencing and PCR genotyping, the Allplex™ SARS-CoV-2/FluA/FluB/RSV and Respiratory Panels 1, 2, and 3 assays (Seegene), and the Xpert® Xpress SARS-CoV-2/FluA/FluB/RSV Plus assay (Cepheid). Reproducibility of the RVM assay using fully-automated and semi-automated nucleic acid (NA) extraction workflows and as performed by independent operators was also assessed. In total, 249 positive respiratory specimens and at least 50 negative specimens for each target tested were used for this evaluation study. ResultsSensitivity, specificity, accuracy, PPV, NPV, PPA, NPA, and OPA ranged from 95.7 % to 100 % for detecting all eight targets tested on the RVM assay. Reproducibility PPA, NPA, and OPA between automated and semi-automated NA extraction workflows were all >97.9 %, while the reproducibility PPA, NPA and OPA between independent operators were all 100 %. ConclusionThese results demonstrate a high level of sensitivity, specificity, accuracy and diagnostic predictive value of the RVM assay and high agreement with comparable reference assays in identifying all eight of its targets. Taken together, our study underscores the diagnostic utility of the RVM assay in detecting eight viral respiratory pathogens.

The Importance of Real-World Data in Evaluating the Safety of Biosimilars: A Descriptive Study of Clinical Practice in an Oncohematological Italian Population.

The clinical safety and efficacy of rituximab biosimilars compared to the reference rituximab (Mabthera) have been well established in randomized trials. However, concerns persist regarding the safety of changing from the reference product to biosimilars, and particularly between different biosimilars. This prospective multicenter observational study was conducted in 13 oncohematology units of eight Italian regions. The study included 800 patients with non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) who received rituximab between March 2018 and June 2022. To minimize survivorship bias, only newly diagnosed patients (i.e., those without prior rituximab treatment) were included in the analysis of adverse drug reactions (ADRs). Thus, this study focused on 505 incident cases (79.8% of the initial cohort) from 13 centers. A total of 3681 rituximab infusions were administered, and 16.8% of the patients experienced at least one ADR. These were observed most frequently during the first infusion (44 patients, 52%) and the second infusion (17 patients, 20%). The most frequent reactions were general disorders and administration site conditions (n. 50, 8% serious). These findings support the clinical safety of rituximab biosimilars and suggest that switching between biosimilars does not increase the risk of adverse events. This evidence may alleviate concerns about biosimilar use, potentially leading to broader acceptance and reduced healthcare costs.

Skin adhesion of a newly developed, bioequivalent rotigotine patch formulation in comparison to the originator product: Results of a multi-center, randomized, crossover trial in patients with Parkinson's disease.

To demonstrate adequate skin adhesion of a new once-daily rotigotine transdermal patch (ROT-TDS) compared to the originator product (reference) in patients with Parkinson's disease (PD). Pharmacokinetic bioequivalence (PK BE) was assessed with the 4 mg/24h patches in healthy adults in a single-/multiple-dose, crossover trial. The trial investigating skin adhesion in PD patients (stable dose ≥ 8 mg/day rotigotine) was performed with the 8 mg/24h patches as a multiple-dose, crossover trial (4 alternating once-daily patch applications). Skin status (seborrhea, sweating) was characterized at screening. Adhesion was assessed 5 minutes after application and 5 minutes before removal of each patch. Systemic safety and skin irritation/sensitization were monitored. ROT-TDS was bioequivalent to the reference product in the PK BE trial in 48 randomized healthy subjects. In the skin adhesion trial in 43 randomized PD patients, the cumulative mean percentage of adhesion (90% CI) at the end-of-dosing interval was 92.948% (90.156 - 95.740%) for ROT-TDS and 90.471% (87.574 - 93.367%) for the reference. For ROT-TDS, 80.23% of patches were ≥ 90% adhered at the end-of-dosing interval, while this was the case for 67.44% of the reference patches. Safety and skin tolerability of both products were comparable; the most frequent treatment-related adverse event was application-site pruritus for both treatments at comparable extent. ROT-TDS - with shown BE to the originator reference product - displayed similar safety and local tolerability as the reference product in patients with PD. The results show a trend to improved skin adhesion of the new patch compared to the reference in the target population.