Drugs in Research & Development最新文献

{"title":"Demonstration of Physicochemical and Functional Similarity of Biosimilar Pegfilgrastim-cbqv to Pegfilgrastim.","authors":"Henriette Kuehne, Janice M Davis, LeeAnne Merewether, Matthew McQueen, Elizabeth Valentine, Glen Young, Benjamin T Andrews, Dimitri Diaz, Karen J Miller","doi":"10.1007/s40268-024-00471-9","DOIUrl":"10.1007/s40268-024-00471-9","url":null,"abstract":"<p><strong>Background: </strong>Pegfilgrastim-cbqv/CHS-1701 (UDENYCA<sup>®</sup>) (hereafter referred to as pegfilgrastim-cbqv) was approved in 2018 by the US Food and Drug Administration as a biosimilar for pegfilgrastim (Neulasta<sup>®</sup>) (hereafter referred to as pegfilgrastim). Both pegfilgrastim-cbqv and pegfilgrastim are conjugates of recombinant human granulocyte colony stimulating factor (r-metHuG-CSF) with a 20 kDa polyethylene glycol (PEG) indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients receiving myelosuppressive anticancer drugs. The demonstration of analytical similarity for PEG-protein conjugates presents unique challenges since both the protein and PEG attributes must be characterized.</p><p><strong>Objective: </strong>The current study demonstrates the analytical similarity of pegfilgrastim-cbqv and the reference product, pegfilgrastim. In addition to the physicochemical and functional characterization of the protein, the study assessed attributes specific to PEGylation including PEG size and polydispersity, site of attachment, linker composition, and PEGylation process-related variants.</p><p><strong>Methods: </strong>The structural, functional, and stability attributes of pegfilgrastim-cbqv and pegfilgrastim were compared using state-of-the-art analytical methods. For the protein, the primary structure, disulfide structure, and secondary and tertiary structures were assessed using traditional protein characterization techniques such as mass spectrometry (MS), circular dichroism (CD), intrinsic fluorescence, and differential scanning calorimetry (DSC), as well as more advanced techniques such as two-dimensional (2D) nuclear magnetic resonance (NMR) and hydrogen deuterium exchange (HDX). For the PEG moiety, the site of attachment, occupancy, linker composition, size and polydispersity were compared using mass spectrometry (both intact and after endoprotease digestion), multiangle light scattering detection (MALS), and Edman degradation. Purity assessments included the assessment of both protein variants and PEGylation variants using chromatographic and electrophoretic analytical separation techniques. The functional similarity between pegfilgrastim-cbqv and pegfilgrastim was compared using both a cell-based bioassay and surface plasmon resonance (SPR). The degradation rates and stability profiles were compared under accelerated and stressed conditions.</p><p><strong>Results: </strong>Biosimilarity was demonstrated by a thorough assessment of physiochemical and functional attributes, as well as comparative stability, of pegfilgrastim-cbqv relative to pegfilgrastim. These studies demonstrated identical primary structure and disulfide structure, highly similar secondary and tertiary structure, as well as functional similarity. The impurity profile of pegfilgrastim-cbqv was comparable to that of pegfilgrastim with only minor differences in PEGylation variants and a slight offset i","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"285-301"},"PeriodicalIF":2.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11315836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141494031","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":"A Randomized, Open-Label, Phase I, Single-Dose Study of Antisense Oligonucleotide, Vupanorsen, in Chinese Adults with Elevated Triglycerides.","authors":"Xiaojie Wu, Jicheng Yu, Beikang Ge, Jeffrey Wang, Xiaoran Han, Chunye Zhang, Xiaomeng Mao, Hindu Kalluru, Candace Bramson, Steven G Terra, Jing Liu","doi":"10.1007/s40268-024-00467-5","DOIUrl":"10.1007/s40268-024-00467-5","url":null,"abstract":"<p><strong>Background: </strong>Vupanorsen is a GalNAc₃-conjugated antisense oligonucleotide targeting angiopoietin-like 3 (ANGPTL3) mRNA shown to reduce atherogenic lipoproteins in individuals with dyslipidemia.</p><p><strong>Objectives: </strong>The aim of this study was to satisfy Chinese regulatory requirements and support ethnic sensitivity assessment by evaluating pharmacokinetics (PK), pharmacodynamics (PD), and safety of vupanorsen in healthy Chinese adults with elevated triglycerides (TG).</p><p><strong>Methods: </strong>In this phase I, parallel-cohort, open-label study, 18 Chinese adults with elevated fasting TG (≥ 90 mg/dL) were randomized 1:1 to receive a single subcutaneous dose of vupanorsen 80 mg or 160 mg. PK parameters, PD markers (including ANGPTL3, TG, non-high-density lipoprotein cholesterol [non-HDL-C]), and safety were assessed.</p><p><strong>Results: </strong>Absorption of vupanorsen was rapid (median time to maximum concentration [T_max]: 2.0 h for both doses), followed by a multiphasic decline (mean terminal half-life 475.9 [80 mg] and 465.2 h [160 mg]). Exposure (area under curve [AUC] and maximum plasma concentration [C_max]) generally increased in a greater than dose-proportional manner from 80 mg to 160 mg. Time-dependent reductions in ANGPTL3 and lipid parameters were observed. Mean percentage change from baseline for the 80-mg and 160-mg doses, respectively, were - 59.7% and - 69.5% for ANGPTL3, - 41.9% and - 52.5% for TG, and - 23.2% and - 25.4% for non-HDL-C. No serious or severe adverse events (AEs), deaths, or discontinuations due to AEs were reported. Three participants experienced treatment-related AEs; all were mild and resolved by end of study.</p><p><strong>Conclusions: </strong>This study provided the first clinical vupanorsen data in China. In Chinese participants with elevated TG, PK and PD parameters were consistent with those reported previously in non-Chinese participants, including in Japanese individuals. No safety concerns were noted.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov identifier: NCT04916795.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"253-262"},"PeriodicalIF":2.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11315818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141471935","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":"The Importance of Patient Reported Outcomes in Oncology Clinical Trials and Clinical Practice to Inform Regulatory and Healthcare Decision-Making.","authors":"Stefania Bellino, Anna La Salvia","doi":"10.1007/s40268-024-00478-2","DOIUrl":"10.1007/s40268-024-00478-2","url":null,"abstract":"","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"123-127"},"PeriodicalIF":2.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11315859/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141635245","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":"Pharmacokinetics of a Fixed-Dose Combination Product of Amlodipine, Losartan, Ezetimibe, and Rosuvastatin and Its Comparison with Co-administration of Four Individual Components in Healthy Participants.","authors":"Jin-Woo Park, Hyewon Chung, Jong-Min Kim, Na Young Kim, Sung Hee Hong, Kyoung-Ah Kim, Ji-Young Park","doi":"10.1007/s40268-024-00460-y","DOIUrl":"10.1007/s40268-024-00460-y","url":null,"abstract":"<p><strong>Background and objective: </strong>This study aimed to assess and compare the pharmacokinetics, safety, and tolerability of a fixed-dose combination product (FDCP) comprising four different drugs (two antihypertensive drugs, amlodipine and losartan, and two lipid-lowering agents, ezetimibe and rosuvastatin) with their separate tablets.</p><p><strong>Methods: </strong>A total of 60 participants were enrolled in this open-label, randomized, single-dose crossover study. Each participant received a single dose of FDCP and individual tablets during each period, with a 14-day washout period between the periods. The pharmacokinetic parameters of amlodipine, losartan, EXP3174 (an active metabolite of losartan), rosuvastatin, free ezetimibe, and total ezetimibe were evaluated and compared.</p><p><strong>Results: </strong>The pharmacokinetic profiles of amlodipine, losartan, rosuvastatin, and ezetimibe after administration of the individual products were similar to those of FDCP. The geometric mean ratios and 90% confidence intervals for maximum concentration (C_max) and area under the curve (AUC) of FDCP to individual tablets were within 0.8-1.25 for all six analytes. No clinically relevant changes were observed in the vital signs or physical, biochemical, hematological, electrocardiographic, or urinalysis findings during the study, and no serious adverse events were reported.</p><p><strong>Conclusion: </strong>This study demonstrated that a newly developed FDCP containing amlodipine, losartan, ezetimibe, and rosuvastatin exhibited pharmacokinetic equivalence with the individual products and met the regulatory criteria. Both formulations were well tolerated.</p><p><strong>Clinical trial registration: </strong>This trial (NCT04322266) was retrospectively registered on 9 September 2019.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"179-186"},"PeriodicalIF":2.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11315872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141077119","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":"Pharmacokinetic Bioequivalence and Safety Assessment of Two Venlafaxine Hydrochloride Extended-Release Capsules in Healthy Chinese Subjects Under Fed Conditions: A Randomized, Open-Label, Single-Dose, Crossover Study.","authors":"Yingxia He, Jie Wang, Fang Yao, Pan Lu, Yafang Xie, Xiuwen Li, Qiangwei Liu, Yang Liu, Dan Cao, Jun Liang, Dan Tian, Guan Liu","doi":"10.1007/s40268-024-00470-w","DOIUrl":"10.1007/s40268-024-00470-w","url":null,"abstract":"<p><strong>Background and objective: </strong>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.</p><p><strong>Methods: </strong>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 (AUC_0-t) and the maximum observed concentration (C_max).</p><p><strong>Results: </strong>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 AUC_0-t and C_max 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.</p><p><strong>Conclusions: </strong>Both the test and reference venlafaxine hydrochloride ER capsules were bioequivalent and showed a similar safety and tolerability profile in the population studied.</p><p><strong>Clinical trials registration: </strong>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.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"275-283"},"PeriodicalIF":2.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11315838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141749422","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":"Unveiling the Influence of a High-Fat Meal on the Pharmacokinetics of Oral Globalagliatin, A Glucokinase Activator, in Healthy Chinese Volunteers.","authors":"Maodi Xu, Yaqin Wang, Xiaohu Wang, Zhichen Pu, Ya Liu, Cuilian Jiang, Xiaokun Shen, Hua Sun, Haitang Xie","doi":"10.1007/s40268-023-00448-0","DOIUrl":"10.1007/s40268-023-00448-0","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Glucokinase (GK) plays a pivotal role in maintaining glucose homeostasis; globalagliatin, a newly developed drug, is a GK activator (GKA). This study constitutes a randomized, open-label, two-cycle, two-crossover, single-dose, phase I clinical trial conducted at a single center with healthy Chinese volunteers, aiming to examine the influence of a high-fat meal on the pharmacokinetics (PK) of orally administered globalagliatin.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Twenty-four healthy volunteers were randomly divided into two groups, with a washout period of 16 days between the two cycles. The first cycle involved Group 1 volunteers who were orally administered globalagliatin 80 mg with 240 mL of water while fasting on Day 1. In contrast, Group 2 volunteers began oral administration of globalagliatin 80 mg with 240 mL of water, 30 min after consuming a high-fat meal (where high-fat content contributed to 54% of the total calories; the high-calorie meal amounted to 988.4 kcal). After the washout period, both groups of volunteers entered the second cycle of drug administration, with meals and medication being swapped on Day 17. Each volunteer collected blood samples at the following time points: 0 h (within 1 h before administration), and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, and 168 h after administration on both trial Day 1 and Day 17. The primary and secondary PK parameters were collected. The validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was used to determine the concentration of globalagliatin in collected plasma samples, and the results were analyzed using Phoenix WinNonlin software. Safety evaluation was conducted by detecting or observing various adverse events (AEs) and serious AEs (SAEs).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;All 24 healthy Chinese volunteers enrolled completed the study and underwent PK analysis. The maximum concentration (C&lt;sub&gt;max&lt;/sub&gt;; ng/mL), area under the plasma concentration-time curve (AUC) from time zero to time of the last quantifiable concentration (AUC&lt;sub&gt;t&lt;/sub&gt;; h·ng/mL), and AUC from time zero extrapolated to infinity (AUC&lt;sub&gt;∞&lt;/sub&gt;; h·ng/mL) of fasting administration were 22.35 ± 7.02, 725.74 ± 303.04, and 774.07 ± 343.89, respectively, while the C&lt;sub&gt;max&lt;/sub&gt;, AUC&lt;sub&gt;t&lt;/sub&gt;, and AUC&lt;sub&gt;∞&lt;/sub&gt; administered after a high-fat meal were 28.95 ± 12.60, 964.84 ± 333.99, and 1031.28 ± 392.80, respectively. The geometric mean ratios of C&lt;sub&gt;max&lt;/sub&gt;, AUC&lt;sub&gt;t&lt;/sub&gt;, and AUC&lt;sub&gt;∞&lt;/sub&gt; for high-fat meal/fasting administration of globalagliatin were 124.81%, 135.24%, and 135.42%, respectively, with 90% confidence intervals of 109.97-141.65, 124.24-147.20, and 124.42-147.39, respectively. Compared with the fasting state, healthy volunteers who consumed a high-fat meal showed a 24.8% increase in C&lt;sub&gt;max&lt;/sub&gt;, a 35.2% increase in AUC&lt;sub&gt;t&lt;/sub&gt;, and a 35.4% increase in AUC&lt;sub&gt;∞&lt;/sub&gt;. The geometric mean of T&lt;sub&gt;max&lt;/sub&gt; was 4.69 h unde","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"41-50"},"PeriodicalIF":3.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11035525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138177641","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":"Pharmacokinetic and Safety Study of Bismuth Potassium Citrate Formulations in Healthy Subjects.","authors":"Hong-Yu Luo, Shuo-Guo Xu, Li-Chen Gao, Hui-Zhi Long, Zi-Wei Zhou, Feng-Jiao Li, Shang-Ming Dai, Jin-Da Hu, Yu Su, Yan Cheng","doi":"10.1007/s40268-024-00455-9","DOIUrl":"10.1007/s40268-024-00455-9","url":null,"abstract":"<p><strong>Background: </strong>Potassium bismuth citrate is a gastric mucosal protector and a key drug for treating peptic ulcers.</p><p><strong>Objective: </strong>To evaluate the pharmacokinetic characteristics and safety of 120-mg bismuth potassium citrate formulations administered orally under fasting conditions in healthy Chinese subjects.</p><p><strong>Method: </strong>A single-center open two-cycle trial was conducted on 12 healthy subjects who received a single oral dose of 120 mg of bismuth potassium citrate. The plasma concentration of bismuth was determined using a validated inductively coupled plasma mass spectrometry (ICP‒MS) method. The pharmacokinetic parameters, including maximum serum concentration (C_max) and area under the curve concentration-time curve (AUC_0-t and AUC_0-∞), and safety were evaluated via noncompartment analysis.</p><p><strong>Results: </strong>The ratios of the least square geometric mean ratio between the test (T) and reference (R) formulations for C_max, AUC_0-t, and AUC_0-∞ were 44.8%, 55.5%, and 64.4%, respectively; the bilateral 95% confidence intervals (Cis) for these parameters were 20.2-99.6%, 24.1-127.5%, and 23.7-175.0%, respectively, and the non-inferior limits for these parameters were 169.4%, 198.8%, and 200.5%, respectively. The upper limits of the one-sided 97.5% confidence interval for the least squares geometric mean ratio (T/R) were lower than the non-inferior limits. No serious adverse reactions or adverse reactions leading to detachment were observed among the subjects.</p><p><strong>Conclusion: </strong>The concentration of bismuth in the blood of healthy subjects in the T formulation was not greater than that in the R formulation. Similarly, the safety of oral administration of 120 mg of bismuth potassium citrate formulations to healthy subjects was good. The trial registration number (TRN) was [2018] 013, 6 December 2018.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"81-87"},"PeriodicalIF":3.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11035504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139724623","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":"Linezolid-Induced Thrombocytopenia in Patients with Renal Impairment: A Case Series, Review and Dose Advice.","authors":"S R E Laarhuis, C H M Kerskes, M R Nijziel, R J A van Wensen, D J Touw","doi":"10.1007/s40268-024-00458-6","DOIUrl":"10.1007/s40268-024-00458-6","url":null,"abstract":"<p><strong>Background and objective: </strong>Oral linezolid is often used as alternative therapy for intravenous vancomycin. According to the current guidelines, no dose adjustment has to be made in case of renal impairment. Nevertheless, in our hospital we have seen several patients with renal impairment who developed linezolid-induced thrombocytopenia when linezolid was taken in the standard dose. In this case series and review we want to emphasize the necessity of reviewing the Dutch and international guidelines.</p><p><strong>Methods: </strong>We describe five cases with renal impairment that developed linezolid-induced thrombocytopenia in our hospital. A PubMed literature review was conducted to identify other cases and find the optimal dosing regimen for these patients.</p><p><strong>Results: </strong>Our cases join a long list of cases and available literature about linezolid-induced thrombocytopenia in patients with renal impairment. Less linezolid-induced thrombocytopenia was found, both in our cases and in the literature, after dose reduction of 50%. High linezolid trough concentrations were associated with a higher risk of linezolid-induced thrombocytopenia. Besides renal impairment, other risk factors for developing linezolid-induced thrombocytopenia were also identified, such as low body weight, high daily dose/kg, higher age, longer duration of therapy, low baseline count, malignity, low-dose aspirin and interacting co-medication.</p><p><strong>Conclusion: </strong>Re-evaluation of the current dose advice is necessary. We advocate for a standard dose reduction to 50% after 2 days of standard dosing for all patients with an estimated glomerular filtration of <60 mL/min/1.73 m². Besides this, therapeutic drug monitoring and thrombocytes monitoring may be executed weekly when patients have renal impairment or other risk factors for developing linezolid-induced thrombocytopenia.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"109-115"},"PeriodicalIF":3.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11035510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140121197","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":"Application of Transthoracic Echocardiography for Cardiac Safety Evaluation in the Clinical Development Process of Vaccines Against Streptococcus pyogenes.","authors":"Usman Nakakana, Alimamy Serry-Bangura, Bassey Effiom Edem, Pietro Tessitore, Leonardo Di Cesare, Danilo Gomes Moriel, Audino Podda, Iris Sarah De Ryck, Ashwani Kumar Arora","doi":"10.1007/s40268-024-00452-y","DOIUrl":"10.1007/s40268-024-00452-y","url":null,"abstract":"<p><p>Superficial infections with Streptococcus pyogenes (Strep A), pharyngitis and impetigo can induce acute rheumatic fever, an autoimmune sequela manifesting mostly with arthritis and rheumatic carditis. Valvular heart damage can persist or advance following repeated episodes of acute rheumatic fever, causing rheumatic heart disease. Acute rheumatic fever and rheumatic heart disease disproportionately affect children and young adults in developing countries and disadvantaged communities in developed countries. People living with rheumatic heart disease are at risk of experiencing potentially fatal complications such as heart failure, bacterial endocarditis or stroke. Transthoracic echocardiography plays a central role in diagnosing both rheumatic carditis and rheumatic heart disease. Despite the obvious medical need, no licensed Strep A vaccines are currently available, as their clinical development process faces several challenges, including concerns for cardiac safety. However, the development of Strep A vaccines has been recently relaunched by many vaccine developers. In this context, a reliable and consistent safety evaluation of Strep A vaccine candidates, including the use of transthoracic echocardiography for detecting cardiac adverse events, could greatly contribute to developing a safe and efficacious product in the near future. Here, we propose a framework for the consistent use of transthoracic echocardiography to proactively detect cardiac safety events in clinical trials of Strep A vaccine candidates.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"1-12"},"PeriodicalIF":2.2,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11035538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140144443","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 Daridorexant on the Pharmacokinetics of Midazolam, and on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Male Subjects.","authors":"Isabelle Zenklusen, Jasper Dingemanse, Christian Reh, Martine Gehin, Priska Kaufmann","doi":"10.1007/s40268-024-00456-8","DOIUrl":"10.1007/s40268-024-00456-8","url":null,"abstract":"<p><strong>Background and objectives: </strong>Daridorexant, a dual orexin receptor antagonist was recently approved for the treatment of insomnia at doses up to 50 mg once per night. This study investigated the effect of single-dose and multiple-dose daridorexant 50 mg at steady state on the pharmacokinetics (PK) of the cytochrome P450 (CYP) 3A4-sensitive substrate midazolam, and the effect of single-dose daridorexant 50 mg on the PK and pharmacodynamics (PD) of the CYP2C9-sensitive substrate warfarin.</p><p><strong>Methods: </strong>In this prospective, single-center, open-label, fixed-sequence, phase I, drug-drug interaction study, 18 healthy male subjects sequentially received Treatment A, B, and C in three periods. Treatment A consisted of a single oral concomitant administration of midazolam 2 mg and warfarin 25 mg on day 1 of the first period. Treatment B consisted of one oral administration of daridorexant 50 mg followed 1 h later by a single oral dose of midazolam 2 mg concomitantly with a single oral dose of warfarin 25 mg on day 1 and a once-daily oral administration of daridorexant 50 mg for 6 days of the second period. Treatment C consisted of a single oral administration of daridorexant 50 mg at steady state followed 1 h later by a single oral administration of midazolam 2 mg on day 1 of the third period. Blood samples were assessed for midazolam and S-warfarin PK, and PD (international normalized ratio and factor VII). Noncompartmental  PK parameters and PD variables were evaluated with geometric mean ratios and 90% confidence intervals of Treatment B/A versus C/A for midazolam, and treatment B/A for warfarin. Safety and tolerability of each treatment were also assessed.</p><p><strong>Results: </strong>Midazolam maximum plasma concentration (C_max) and area under the plasma concentration-time curve from 0 to 24 h (AUC_0-24) were 1.13- and 1.42-fold higher, respectively, after single-dose administration of daridorexant 50 mg compared to administration of midazolam alone, while C_max and AUC_0-24 were 1.12- and 1.35-fold higher, respectively, after administration of daridorexant 50 mg once daily at steady state. Terminal half-life and time to maximum plasma concentration were comparable between treatments. Daridorexant had no influence on the PK and PD of warfarin. All treatments were safe and well tolerated.</p><p><strong>Conclusions: </strong>Daridorexant at 50 mg is classified as a weak CYP3A4 inhibitor after single- and multiple-dose administration once daily at steady state. Daridorexant 50 mg did not induce CYP3A4 activity or inhibit CYP2C9 activity.</p><p><strong>Clinical trial registration: </strong>This trial (NCT05480488) was registered on 29 July, 2022.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"97-108"},"PeriodicalIF":3.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11035509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140111947","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}