Drugs in Research & Development最新文献

{"title":"In-Use Physicochemical Stability of Sandoz Rituximab Biosimilar in 0.9% Sodium Chloride Solution After Prolonged Storage at Room Temperature Conditions.","authors":"Roman Borišek, André Mischo, Tobias Foierl","doi":"10.1007/s40268-024-00496-0","DOIUrl":"10.1007/s40268-024-00496-0","url":null,"abstract":"<p><strong>Background and objective: </strong>Often, stability studies do not cover all facets of ensuring patient safety for biologics, unless the impact of the in-use and out-of-fridge conditions is also assessed. This study investigated the physicochemical and biological stability of Sandoz rituximab biosimilar (SDZ-RTX).</p><p><strong>Methods: </strong>In a worst-case setting, two SDZ-RTX batches in vials were exposed to long-term conditions (5 ± 3 °C) for at least the shelf-life period (36 months). These batches were exposed to out-of-fridge conditions of up to 25 ± 2 °C/60 ± 5% relative humidity in total for 14 days, and subsequently to 30 ± 2 °C/75 ± 5% relative humidity for 7 days. Thereafter, these batches were diluted to 1 mg/mL in 0.9% NaCl in 250-mL polyethylene infusion bags and stored at either 25 ± 2 °C/60 ± 5% relative humidity for 30 days or 30 ± 2 °C/75 ± 5% relative humidity for 14 days, representing in-use conditions. The stability of SDZ-RTX was assessed using a variety of analytical methods, including size-exclusion chromatography, cation exchange chromatography, non-reducing capillary electrophoresis sodium dodecyl sulfate, complement-dependent cytotoxicity-bioactivity, and subvisible particle count by light obscuration.</p><p><strong>Results: </strong>Results for all assessments were within the stringent shelf-life acceptance criteria for SDZ-RTX for both batches under both in-use conditions.</p><p><strong>Conclusions: </strong>These data show that the physicochemical and biological quality of SDZ-RTX diluted in 0.9% NaCl infusion bags is assured, even after prolonged worst-case (out-of-fridge and in-use) storage at elevated temperatures up to 30 °C, if the medication is prepared under aseptic conditions according to the Summary of Product Characteristics.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142669506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics and Pharmacodynamics of Rusfertide, a Hepcidin Mimetic, Following Subcutaneous Administration of a Lyophilized Powder Formulation in Healthy Volunteers.","authors":"Nishit B Modi, Sarita Khanna, Sneha Rudraraju, Frank Valone","doi":"10.1007/s40268-024-00497-z","DOIUrl":"https://doi.org/10.1007/s40268-024-00497-z","url":null,"abstract":"<p><strong>Background and objective: </strong>Hepcidin, an endogenous peptide hormone, binds to ferroportin and is the master regulator of iron trafficking. Rusfertide, a synthetic peptide, is a potent hepcidin mimetic. Clinical studies suggest rusfertide may be effective in the treatment of polycythemia vera. This study investigated the dose-ranging pharmacokinetics, pharmacodynamics, and safety of a lyophilized formulation of rusfertide.</p><p><strong>Methods: </strong>A randomized open-label crossover study was conducted in two groups of healthy adult subjects to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of subcutaneous rusfertide doses that ranged from 10 to 60 mg of a lyophilized formulation and 20 mg of an aqueous prefilled syringe formulation that were used in clinical trials.</p><p><strong>Results: </strong>Rusfertide showed a rapid initial absorption. Median time to peak plasma concentrations for the lyophilized formulation was 24 h for doses of 10-30 mg and 2-4 h for doses of 45 and 60 mg. Mean terminal half-life ranged from 19.6 to 57.1 h. Rusfertide peak concentration and area under the concentration-time curve increased with an increasing dose, but in a less than dose-proportional manner. Metabolites M4 and M9 were identified as major metabolites. At the rusfertide 20-mg dose, the lyophilized formulation had an area under the concentration-time curve from time zero to infinity approximately 1.5-fold higher than the aqueous formulation. The elimination half-life was comparable for the two formulations. Dose-related decreases in serum iron and transferrin-iron saturation were seen following rusfertide treatment. The majority of treatment-emergent adverse events were mild; treatment-related treatment-emergent adverse events seen in ≥10% of subjects were injection-site erythema and injection-site pruritus.</p><p><strong>Conclusions: </strong>Rusfertide was well tolerated; the pharmacokinetic and pharmacodynamic results indicate that lyophilized rusfertide is suitable for once-weekly or twice-weekly administration.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioequivalence Analysis of Ondansetron Hydrochloride Tablets in Healthy Chinese Subjects: A Randomized, Open-Label, Two-Period Crossover Phase I Study.","authors":"Caiyun Jia, Na Zhao, Haojing Song, Yiting Hu, Yufang Xu, Caihui Guo, Wanjun Bai, Zhanjun Dong","doi":"10.1007/s40268-024-00493-3","DOIUrl":"https://doi.org/10.1007/s40268-024-00493-3","url":null,"abstract":"<p><strong>Background: </strong>Ondansetron is a highly selective 5-HT3 receptor antagonist that alleviates nausea and vomiting. Bioequivalence evaluation ensures that the efficacy of generic drugs is consistent with that of the original drug.</p><p><strong>Objective: </strong>The objective of this study was to evaluate the bioequivalence of ondansetron hydrochloride (HCl) tablets taken in single doses under fasting and postprandial conditions in healthy subjects.</p><p><strong>Methods: </strong>In this randomized, open-label, two-cycle, crossover phase I study, liquid chromatography‒tandem mass spectrometry (LC‒MS/MS) was used to determine the ondansetron concentration in dipotassium-ethylenediaminetetraacetate (K₂-EDTA) plasma after the subjects received a single 8 mg of ondansetron and reference formulation. Twenty-six healthy subjects received one tablet of ondansetron under fasting conditions and 28 subjects received one under postprandial conditions. Bioequivalence was established if the 90% confidence interval (CI) was 80.00-125.00%. The pharmacokinetic parameters were calculated via WinNonLin 8.1 software and the bioequivalence data were evaluated via Phoenix WinNonlin 8.1 statistics software.</p><p><strong>Results: </strong>The geometric mean ratio (GMR) of the maximum observed concentration (C_max), the area under the plasma concentration‒time curve (AUC) from time zero to the last sampling time (AUC_0-t), and the AUC from time zero to infinity (AUC_0-∞) from the test/reference formulation under fasting conditions were 90.50, 90.43, and 90.25, respectively. The 90% CIs were 83.75-97.79, 82.64-98.95, and 82.25-99.03, respectively. The GMRs of C_max, AUC_0-t, and AUC_0-∞ after a high-fat meal were 96.85, 93.57, and 93.77, respectively; the 90% CIs were 88.43-106.07, 87.35-100.24, and 87.35-100.68, respectively.</p><p><strong>Conclusion: </strong>The test and reference formulations of ondansetron HCl have bioequivalence for healthy adult subjects under fasting and postprandial conditions.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"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.","authors":"Junbo Shao, Xingxing Liu, Jing Lin, Jiao Chen, Xiaoyan Xie","doi":"10.1007/s40268-024-00492-4","DOIUrl":"https://doi.org/10.1007/s40268-024-00492-4","url":null,"abstract":"<p><strong>Background and objectives: </strong>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.</p><p><strong>Methods: </strong>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 (S_WR) of the reference preparation. Adverse events (AEs) were monitored to examine safety and tolerability.</p><p><strong>Results: </strong>The RSABE method (S_WR ≥ 0.294) was used to determine the BE of maximal plasma concentration (C_max) in both fed and fasting conditions. In the ABE approach, (S_WR < 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 (AUC_0-t) and determine the area under the plasma concentration time curve from time zero to time infinity (AUC_0-inf). In the fasting condition, the point estimate of the test/reference ratio for C_max was 1.08, with a 95% upper confidence bound of - 0.05 < 0.00. The geometric mean ratio (GMRs) for AUC_0-t and AUC_0-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 C_max was 0.94, with a 95% upper confidence bound of - 0.10 < 0.00. The GMR for AUC_0-t and AUC_0-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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics, Pharmacodynamics, and Safety of Intravenous Efgartigimod and Subcutaneous Efgartigimod PH20 in Healthy Chinese Participants.","authors":"Shan Jing, Yu Zhang, Yang Lin, Xiaowen Gu, Jing Liu, Antonio Guglietta, Jan Noukens, Tonke Van Bragt, Lina Wang, Jiajia Chen, Harald Reinhart, Xia Pu","doi":"10.1007/s40268-024-00490-6","DOIUrl":"https://doi.org/10.1007/s40268-024-00490-6","url":null,"abstract":"<p><strong>Background: </strong>Efgartigimod, a human immunoglobulin G (IgG)1-derived Fc fragment targeting the neonatal Fc receptor, has been developed into intravenous (IV) and subcutaneous (SC) formulations for treating generalized myasthenia gravis (gMG) and other autoimmune diseases. Data in the Chinese population were not available to date, and while both formulations have been approved in the USA, the EU, Japan and China for the treatment of gMG.</p><p><strong>Objective: </strong>We present the pharmacokinetic, pharmacodynamic, and safety of IV and SC PH20 efgartigimod in healthy Chinese participants.</p><p><strong>Methods: </strong>In two independent, double-blinded, placebo-controlled, phase I studies of the IV and SC formulations of efgartigimod, healthy Chinese adults were randomized 3:1 to receive active treatment or matching placebo once every 7 days for four doses. Primary endpoints were pharmacokinetic parameters.</p><p><strong>Results: </strong>After the fourth IV infusion, a mean maximum observed concentration (C_max) of 194 µg/mL was reached at the end of the 1 h infusion; the mean area under concentration-time curve from time zero to 168 h (AUC_0-168h) was 5300 µg × h/mL. After the fourth SC injection, a mean C_max of 42.1 µg/mL was achieved with a median T_max of 47.74 h; the mean AUC_0-168h was 4790 µg × h/mL. Maximal mean reductions from baseline in total IgG levels were reached approximately 24 days after the first dose (60.7%, IV formulation; 66.4%, SC formulation). Treatment-related adverse events (TRAEs) were reported in seven (58.3%) participants receiving SC efgartigimod, mostly injection-site reactions. No TRAEs or AEs of special interest were reported in the IV study.</p><p><strong>Conclusions: </strong>The efgartigimod IV and SC pharmacokinetic, pharmacodynamic, and safety profiles in Chinese participants were similar to the known profiles in non-Chinese participants. Both formulations effectively reduced total IgG levels by a similar percentage.</p><p><strong>Clinical trial registration: </strong>CTR20211952 and CTR20211805.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical and Toxicology Assessment of ALW-II-41-27, an Inhibitor of the Eph Receptor A2 (EphA2).","authors":"Theodore J Kottom, Kimberly E Stelzig, Madeline R Pellegrino, Marc Bindzus, Eunhee S Yi, Andrew H Limper","doi":"10.1007/s40268-024-00483-5","DOIUrl":"10.1007/s40268-024-00483-5","url":null,"abstract":"<p><strong>Background and objective: </strong>The EphA2 receptor inhibitor ALW-II-41-27 has proven to be an effective in vitro antagonist of Pneumocystis β-glucan-induced proinflammatory signaling. This suggests its potential as a candidate for initial anti-inflammatory drug testing in the rodent model of Pneumocystis pneumonia (PCP).</p><p><strong>Methods: </strong>Initially, single-dose intraperitoneal (IP) injections of ALW-II-41-27 were administered at concentrations of 0, 10, 15, 20, and 30 mg/kg over a 24-h treatment period. Pharmacokinetics were assessed in plasma, bronchoalveolar lavage fluid (BALF), and epithelial lining fluid (ELF). Following these assessments, a final single mg/kg dosing was determined. Mice received daily IP injections of either vehicle or 20.0 mg/kg of ALW-II-41-27 for 10 days, with their weights recorded daily. On day 11, mice were weighed and euthanized. Lungs, liver, and kidneys were harvested for H&E staining and pathology scoring. Lung samples were further analyzed for proinflammatory cytokines using enzyme-linked immunosorbent assay (ELISA) and extracellular matrix production using quantitative PCR (qPCR). Postmortem blood collection was conducted for complete blood count (CBC) blood chemistry analysis. Lastly, ALW-II-41-27 was administered to mice prior to fungal β-glucans challenge to determine in vivo effects on lung inflammation.</p><p><strong>Results: </strong>This report describes the PK assessment of ALW-II-41-27 given via IP in C57BL/6 mice. After PK data were generated, we tested ALW-II-41-27 at 20 mg/kg IP in mice and noted no significant changes in daily or final weight gain. ELISA results of proinflammatory cytokines from lung tissues showed no major differences in the respective groups. qPCR analysis of extracellular matrix transcripts were statistically similar. Examination and pathology scoring of H&E slides from lung, liver, and kidney in all groups and subsequent pathology scoring showed no significant toxicity. Blood chemistry and CBC analyses revealed no major abnormalities. Additionally, administering ALW-II-41-27 before intratracheal inoculation of fungal β-glucans, known to induce a strong proinflammatory response in the lungs, significantly reduced lung tissue IL-1β levels.</p><p><strong>Conclusions: </strong>In our initial general safety and toxicology assessments, ALW-II-41-27 displayed no inherent safety concerns in the analyzed parameters. These data support broader in vivo testing of the inhibitor as a timed adjunct therapy to the deleterious proinflammatory host immune response often associated with anti-Pneumocystis therapy.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"425-434"},"PeriodicalIF":2.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11455733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141894723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trametinib Sensitivity is Defined by a Myeloid Differentiation Profile in Acute Myeloid Leukemia.","authors":"Mathieu Quesnel-Vallières, David C Schultz, Alena Orlenko, Yancy Lo, Jason Moore, Marylyn Ritchie, David Roth, Martin Carroll, Yoseph Barash, Kristen W Lynch, Sara Cherry","doi":"10.1007/s40268-024-00491-5","DOIUrl":"10.1007/s40268-024-00491-5","url":null,"abstract":"<p><strong>Background and objective: </strong>Acute myelogenous leukemia (AML) is a common blood cancer marked by heterogeneity in disease and diverse genetic abnormalities. Additional therapies are needed as the 5-year survival remains below 30%. Trametinib is a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor that is widely used in solid tumors and also in tumors with activating RAS mutations. A subset of patients with AML carry activating RAS mutations; however, a small-scale clinical trial with trametinib showed little efficacy. Here, we sought to identify transcriptomic determinants of trametinib sensitivity in AML.</p><p><strong>Methods: </strong>We tested the activity of trametinib against a panel of tumor cells from patients with AML ex vivo and compared this with RNA sequencing (RNA-Seq) data from untreated blasts from the same patient samples. We then used a correlation analysis between gene expression and trametinib sensitivity to identify potential biomarkers predictive of drug response.</p><p><strong>Results: </strong>We found that a subset of AML tumor cells were sensitive to trametinib ex vivo, only a fraction of which (3/10) carried RAS mutations. On the basis of our RNA-Seq analysis we found that markers of trametinib sensitivity are associated with a myeloid differentiation profile that includes high expression of CD14 and CLEC7A (Dectin-1), similar to the gene expression profile of monocytes. Further characterization confirmed that trametinib-sensitive samples display features of monocytic differentiation with high CD14 surface expression and were enriched for the M4 subtypes of the FAB classification.</p><p><strong>Conclusions: </strong>Our study identifies additional molecular markers that can be used with molecular features including RAS status to identify patients with AML that may benefit from trametinib treatment.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"489-499"},"PeriodicalIF":2.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456044/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142308896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin Bioavailability After Oral Administration of a New Delayed-Release Form in Healthy Male Volunteers.","authors":"Samira Ait Abdellah, Caroline Gal, Isabelle Guinobert, Valérie Bardot, Véronique Raverot, Annarita Vitacca, Claude Blondeau, Bruno Claustrat","doi":"10.1007/s40268-024-00482-6","DOIUrl":"10.1007/s40268-024-00482-6","url":null,"abstract":"<p><strong>Background: </strong>Two main types of galenic formulation, immediate release and prolonged release, have been developed to optimize melatonin bioavailability. We recently described the kinetic profile of a prolonged-release form generating a peak of plasma melatonin 1 h (T_max) after intake, followed by a prolonged decay over time. We have developed a new oral form of melatonin with the aim of producing a melatonin peak several hours after intake.</p><p><strong>Objective: </strong>The objective is to investigate melatonin bioavailability after administration of this new delayed-release form (DR form).</p><p><strong>Methods: </strong>In this single-centre open-label study, 12 healthy male volunteers received one tablet of the DR form containing 1.9 mg melatonin, 10 mg zinc and 200 mg lemon balm extract (Melissa officinalis L aerial parts). Blood samples were collected for 12 h, beginning at 8:00 am. Plasma concentrations of melatonin and 6-sulfatoxymelatonin (6-SMT), the main hepatic melatonin metabolite, were determined by radioimmunoassay.</p><p><strong>Results: </strong>A progressive increase in plasma melatonin concentrations was observed from 20 min and a peak about 3 h after intake (C_max 740 ± 824 pg/mL; T_max 179 ± 60 min). Concentrations remained high between 140 and 220 min, the concentration remaining physiologically significant (over 100 pg/mL) up to 7 h after intake. The DR form was well tolerated.</p><p><strong>Conclusions: </strong>The melatonin release profile was consistent with what was anticipated for the DR form. The DR form generated a 2 h delayed T_max compared with a prolonged-release form previously evaluated. This suggests that the DR form is suitable for the treatment of certain sleep disorders such as short sleep duration or early awakening.</p><p><strong>Trial registry: </strong>Registration number: NCT05419466.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"415-423"},"PeriodicalIF":2.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142037513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Analytical Evaluation of the Proposed Biosimilar FYB206 and its Reference Medicinal Product Keytruda^®.","authors":"Jakob C Stüber, Kerstin Uhland, Alwin Reiter, Steffen Jakob, Florian Wolschin","doi":"10.1007/s40268-024-00485-3","DOIUrl":"10.1007/s40268-024-00485-3","url":null,"abstract":"<p><strong>Background and objective: </strong>Biological medicinal products improve patients' lives, but access is limited, mainly due to high costs. Patents for many existing biological products are expiring, and generic versions, which are referred to as biosimilars, are produced to serve as an alternative to the reference medicinal product (RMP) cutting down the costs and expanding access. The present paper assesses the analytical similarity between Formycon's FYB206 pembrolizumab biosimilar candidate and Keytruda^®, an RMP that is approved to treat various types of cancer, with the intention of determining FYB206's suitability to enter clinical biosimilar trials.</p><p><strong>Methods: </strong>Monoclonal antibodies (mAbs) are biological medicinal products that are characterized by a high overall heterogeneity. Due to the complex nature of these molecules, a comprehensive comparative analytical assessment was designed to demonstrate analytical similarity in all clinically relevant quality attributes between RMP and the corresponding biosimilar candidate. This exercise addresses physicochemical, biophysical as well as functional characteristics.</p><p><strong>Results: </strong>The comparative analytical evaluation results demonstrate that the proposed biosimilar is structurally and functionally highly similar to the RMP, showing only minor differences for some quality attributes that are justified to be noncritical for clinical efficacy and safety.</p><p><strong>Conclusion: </strong>Based on physicochemical and biological characteristics, FYB206 is suitable to enter the clinical phase.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"447-464"},"PeriodicalIF":2.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142127135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Chronic Dolutegravir Administration on the Trace Amine Profile in Wistar Rats.","authors":"Natasha Henning, Tracy A Kellermann, Carine Smith","doi":"10.1007/s40268-024-00484-4","DOIUrl":"10.1007/s40268-024-00484-4","url":null,"abstract":"<p><strong>Background: </strong>Dolutegravir (DTG), an integrase strand inhibitor, is currently used as the first-line treatment for HIV. Despite relatively poor tissue penetration, the risk of adverse effects in metabolic and excretory systems should be considered. The trace aminergic system and trace amines are emerging as relevant role players in many chronic diseases that are commonly diagnosed but poorly understood. Trace amines are biogenic amines that are endogenously produced and can also be ingested by the intake of trace amine-rich food. Trace amines are known to differentially regulate inflammatory and neurological outcome.</p><p><strong>Objective: </strong>This study investigated the effects of DTG on the trace amine profile in a wistar rat model.</p><p><strong>Methods: </strong>A total of 24 healthy wistar rats were randomly divided into four experimental groups: male and female controls and male and female DTG-treated. Blood and tissue samples were collected following a 12-week DTG administration study. Liquid chromatography-tandem mass spectroscopy (LC-MS/MS) was used to determine trace amine concentrations in urine, plasma, brain, and gastrointestinal tissue.</p><p><strong>Results: </strong>Current data illustrate that polyamines differ significantly (p < 0.05) between males and females in various matrices. DTG significantly (p < 0.05) reduced jejunal tyramine and urinary synephrine levels.</p><p><strong>Conclusion: </strong>Data do not raise major concerns about DTG in the context of the trace amine profile. However, given the importance of the dysregulated trace amine profile in various diseased states, including HIV, current data warrant clinical investigation to further evaluate the significance of DTG-associated effects on the trace amine profile.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"435-445"},"PeriodicalIF":2.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11455829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142037467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}