Drugs in Research & Development最新文献

{"title":"An Exploratory Pharmacogenetic Pilot Study of Two Reverse Transcriptase Inhibitors, Tenofovir Alafenamide Fumarate and Tenofovir Disoproxil Fumarate.","authors":"Derek E Murrell, Benjamin C Kennard, Maria E Bertoni, David B Cluck, Jonathan P Moorman, Stacy D Brown, Kesheng Wang, Michelle M Duffourc, Sam Harirforoosh","doi":"10.1007/s40268-025-00509-6","DOIUrl":"10.1007/s40268-025-00509-6","url":null,"abstract":"<p><strong>Background and objectives: </strong>The nucleoside reverse transcriptase inhibitors tenofovir alafenamide fumarate and tenofovir disoproxil fumarate are frequently employed in treating human immunodeficiency virus. Further, each form of tenofovir requires laboratory monitoring to determine efficacy and tolerability among patients. This study sought to investigate the relationship, if any, of single nucleotide polymorphisms (SNPs) and selected clinical parameters.</p><p><strong>Methods: </strong>The study population, predominantly Caucasian males with a median age of 53.0 years [interquartile range 46.0-59.0], was assayed for genetic variations using an iPLEX ADME PGx Pro v1.0 Panel.</p><p><strong>Results: </strong>Although several SNP relationships were found with both forms of tenofovir, many of the reported SNPs were displayed only in the comprehensive regimen grouping, making it difficult to distinguish between the two prodrug forms.</p><p><strong>Conclusions: </strong>Being an exploratory study, the findings of this substudy serve as potential avenues for further research.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"153-160"},"PeriodicalIF":2.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12185805/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143971","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":"Correction: Damoctocog Alfa Pegol, a PEGylated B-domain Deleted Recombinant Extended Half-life Factor VIII for the Treatment of Hemophilia A: A Product Review.","authors":"Mark T Reding, Shadan Lalezari, Gili Kenet, Giovanni Di Minno, Jonathan Ducore, Alexander Solms, Anita Shah, Pål André Holme, Lone H Poulsen, Karina Meijer, Mindy Simpson, Maria Elisa Mancuso","doi":"10.1007/s40268-024-00494-2","DOIUrl":"10.1007/s40268-024-00494-2","url":null,"abstract":"","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"89-98"},"PeriodicalIF":2.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12011687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865661","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":"Evaluation of BCRP-Related DDIs Between Methotrexate and Cyclosporin A Using Physiologically Based Pharmacokinetic Modelling.","authors":"Stephan Schaller, Ingrid Michon, Vanessa Baier, Frederico Severino Martins, Patrick Nolain, Amit Taneja","doi":"10.1007/s40268-024-00495-1","DOIUrl":"10.1007/s40268-024-00495-1","url":null,"abstract":"<p><strong>Background and objective: </strong>This study provides a physiologically based pharmacokinetic (PBPK) model-based analysis of the potential drug-drug interaction (DDI) between cyclosporin A (CsA), a breast cancer resistance protein transporter (BCRP) inhibitor, and methotrexate (MTX), a putative BCRP substrate.</p><p><strong>Methods: </strong>PBPK models for CsA and MTX were built using open-source tools and published data for both model building and for model verification and validation. The MTX and CsA PBPK models were evaluated for their application in simulating BCRP-related DDIs. A qualification of an introduced empirical uniform in vitro scaling factor of K_i values for transporter inhibition by CsA was conducted by using a previously developed model of rosuvastatin (sensitive index BCRP substrate), and assessing if corresponding DDI ratios were well captured.</p><p><strong>Results: </strong>Within the simulated DDI scenarios for MTX in the presence of CsA, the developed models could capture the observed changes in PK parameters as changes in the area under the curve ratios (area under the curve during DDI/area under the curve control) of 1.30 versus 1.31 observed and the DDI peak plasma concentration ratios (peak plasma concentration during DDI/peak plasma concentration control) of 1.07 versus 1.28 observed. The originally reported in vitro K_i values of CsA were scaled with the uniform qualified scaling factor for their use in the in vivo DDI simulations to correct for the low intracellular unbound fraction of the CsA effector concentration. The resulting predicted versus observed ratios of peak plasma concentration and area under the curve DDI ratios with MTX were 0.82 and 0.99, respectively, indicating adequate model accuracy and choice of a scaling factor to capture the observed DDI.</p><p><strong>Conclusions: </strong>All models have been comprehensively documented and made publicly available as tools to support the drug development and clinical research community and further community-driven model development.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"1-17"},"PeriodicalIF":2.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12011704/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142883520","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 Real-World Data Analysis of Alglucosidase Alfa in the FDA Adverse Event Reporting System (FAERS) Database.","authors":"Yi Yin, Jie Jiang, Youpeng Jin","doi":"10.1007/s40268-024-00502-5","DOIUrl":"10.1007/s40268-024-00502-5","url":null,"abstract":"<p><strong>Background and objective: </strong>Alglucosidase alfa for injection is used as an enzyme replacement therapy for the treatment of Pompe disease. The safety profile of alglucosidase alfa-associated adverse events requires a comprehensive evaluation. In this study, we aimed to identify drug safety alert signals and investigate the real-world safety of alglucosidase alfa to guide clinical decision making and optimize the risk-benefit balance.</p><p><strong>Methods: </strong>The adverse event reports from the first quarter of 2006 to the fourth quarter of 2023 were selected by exploring the Food and Drug Administration Adverse Event Reporting System (FAERS) database. The new and unexpected potential adverse event signals were detected using a disproportionality analysis, including the reporting odds ratio, the proportional reporting ratio, the Bayesian confidence propagation neural network, and the empirical Bayes geometric mean. Then, the Medical Dictionary for Regulatory Activities was used to systematically classify the results.</p><p><strong>Results: </strong>After analyzing 16,945,027 adverse event reports, a total of 4326 cases of adverse events related to alglucosidase alfa were identified, spanning 27 system organ classes. A total of 359 preferred terms of adverse events for glucosidase alpha were detected. Pyrexia ranked first, followed by pneumonia, dyspnea, respiratory failure, and disease progression according to occurrence frequency. The top three system organ classes were general disorders and administration-site conditions (n = 2466), respiratory, thoracic, and mediastinal disorders (n = 1749), and infections and infestations (n = 1551). In addition to adverse effects mentioned in the product label, our study also discovered rare but high signal intensity adverse events such as chronic recurrent multifocal osteomyelitis.</p><p><strong>Conclusions: </strong>There are many adverse events associated with the clinical use of alglucosidase alfa, which should be closely monitored in the FAERS database. As the most effective enzyme replacement therapy for Pompe disease, it is crucial to closely monitor these adverse events. Ensuring patient safety while balancing drug effectiveness is particularly important.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"57-66"},"PeriodicalIF":2.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12011682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014846","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":"Analysis of Sirolimus Blood Concentration and Influencing Factors in Pediatric Patients: Implications for Individualized Drug Therapy.","authors":"Xiaolin Xu, Xueting Mao, Bo Liu, Yixin Sun, Xiaoling Cheng, Xiaoling Wang, Huawei Mao","doi":"10.1007/s40268-025-00506-9","DOIUrl":"https://doi.org/10.1007/s40268-025-00506-9","url":null,"abstract":"<p><strong>Background and objective: </strong>The purpose of this study is to investigate the status of blood concentration of sirolimus (SRL), explore the factors influencing SRL drug blood concentration, and provide guidance for the appropriate utilization of clinical medications.</p><p><strong>Methods: </strong>A single-center retrospective cohort study encompassed 1535 blood drug concentration observations obtained from 249 children from August 2018 to June 2023. Participants were categorized into four groups (A, B, C, and D) on the basis of their blood concentration levels at various time intervals. The analysis focused on identifying the factors that influenced blood concentration in the short- and long-term posttreatment. The primary endpoint was factors affecting the sirolimus blood concentration. The effect of physiopathological indicators on the corrected blood drug concentration (C/D value) was analyzed to avoid the effect of differences in the dose of SRL used in patients on SRL blood concentrations. The multiple linear regression model was used to examine the impact of factors influencing pharmacokinetics and pharmacodynamics on the C/D.</p><p><strong>Results: </strong>Analysis of SRL blood concentration monitoring indicated that a majority (60.43%) of patients demonstrated a trough sirolimus concentration (C₀) below the level of the recommended threshold of 5 ng/mL, while approximately 17.7% of patients exceeded 15 ng/mL. The results indicated a noteworthy association between weight and body surface area (BSA) and the C/D of SRL in groups A, B, and D (P < 0.05). Additionally, aspartate transaminase (AST), alanine aminotransferase (ALT), and albumin (ALB) in group A; ALB in group B; and platelet count (PLT) in group C demonstrated a statistically significant correlation with the C/D of SRL (P < 0.05).</p><p><strong>Conclusions: </strong>Clinicians should optimize medication plans by considering the child's weight, BSA, ALT, AST, PLT, ALB, and relevant factors. These findings may serve as a valuable resource for clinicians.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"25 1","pages":"79-88"},"PeriodicalIF":2.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12011663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143994424","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":"Characterization for the Similarity Assessment Between the Proposed Biosimilar SB17 and Ustekinumab Reference Product Using State-of-the-Art Analytical Methods.","authors":"Sung-Yong Yang, Changsoo Lee, Keumbi Hwang, Jungmin Lee, Jaell Lee, Juyong Hong, Seongyoung Jung","doi":"10.1007/s40268-024-00501-6","DOIUrl":"10.1007/s40268-024-00501-6","url":null,"abstract":"<p><strong>Background: </strong>SB17 is being developed as a biosimilar to ustekinumab reference product (RP), a human monoclonal antibody (IgG1 kappa immunoglobulin) that binds to the common p40 subunit of cytokines interleukin (IL)-23 and IL-12. Binding to this subunit prevents interaction with their receptor, resulting in modulation in the immune system responses that play a key role in inflammatory disease.</p><p><strong>Objective: </strong>The objective of this study was to demonstrate structural, physicochemical, and biological similarity between ustekinumab RP and SB17 using various state-of-the-art analytical methods.</p><p><strong>Methods: </strong>Comprehensive analytical characterization was conducted by the quality range and side-by-side comparison approach for SB17 versus the European Union (EU) and US ustekinumab RP using various analytical methods. Comparisons included purity, product-related impurity, charge heterogeneity, primary structure, posttranslational modification, higher-order structure, quantity, Fab-related biological activities (potency and binding activity), and Fc-related biological activities.</p><p><strong>Results: </strong>On the basis of the analytical similarity assessment, the structural, physicochemical, and biological characterization results demonstrated that SB17 is comparable to the ustekinumab RP. In the structural aspects, it was confirmed that there is no clinically meaningful difference between posttranslational modification profiles and higher-order structures of SB17 compared with the ustekinumab RP. Product-related impurities in the form of aggregates were also confirmed to be similar. SB17 has lower acidic and basic variants compared with ustekinumab RP, owing to the difference in the producing cell line. Ustekinumab RP is expressed in an Sp2/0 cell line, whereas SB17 is expressed in CHO cell line. However, the difference between SB17 and ustekinumab RP in the charge variants is not considered to be clinically meaningful, since equivalent biological activity was observed. In the case of mechanism of action (MoA)-related biological activities, SB17 is highly similar to the EU and US ustekinumab RP with respect to overall critical and noncritical quality attributes analyzed. Moreover, similarity or lack of activity in Fc-related biological activities was also confirmed. On the basis of these results, SB17 is expected to have comparable safety and efficacy as compared with ustekinumab RP.</p><p><strong>Conclusion: </strong>In summary, the overall analytical characterization and similarity assessment results show that SB17 is comparable to the EU and US ustekinumab RP in terms of structural, physicochemical, biophysical, and biological attributes.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"19-34"},"PeriodicalIF":2.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12011669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014903","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 Preclinical Evaluation of Tuznue Versus Referent Herceptin: A Registered Trastuzumab Biosimilar.","authors":"Herve Bischoff, Neil K O'Connor, Jamie Kim, Bogdan V Popescu, Cecile Bigot, Sumita Pradhan, Rusha Chakraborty, Litha Jaison, Fathima Majeed, Lisa S Park, Lotfi Boudali, Alexandre Detappe, Xavier Pivot, Pierre Coliat","doi":"10.1007/s40268-025-00505-w","DOIUrl":"10.1007/s40268-025-00505-w","url":null,"abstract":"<p><strong>Introduction: </strong>The high cost of trastuzumab (Herceptin^®) limits its accessibility for patients worldwide. Biosimilars, such as Tuznue^® (HD201), represent a promising alternative to improve access to this essential therapy for HER2-positive breast cancer. This study aims to assess the similarity of Tuznue^® with the reference product Herceptin^® through comprehensive analytical and biofunctional evaluations, ensuring similar quality, safety, and efficacy profiles.</p><p><strong>Methods: </strong>Multiple analytical methods were performed to assess key quality attributes of Tuznue^® and Herceptin^®. Physicochemical properties, HER2 binding, anti-proliferative activity, antibody-dependent cellular cytotoxicity, complement dependent cytotoxicity, and Fc receptor binding were evaluated through various bioassays. Statistical analyses were conducted according to a risk-based tiered approach (Tiers 1-3) to demonstrate biosimilarity. The equivalence margin for critical quality attributes (Tier 1) was set at ±1.5 standard deviations from the reference product's mean.</p><p><strong>Results: </strong>Tuznue^® showed highly comparable results to Herceptin^® across all evaluated biofunctional assays. HER2 binding affinity, inhibition of cellular proliferation, and antibody-dependent cellular cytotoxicity activity were equivalent between Tuznue^® and Herceptin^®, with 90% confidence intervals within predefined equivalence margins. No complement dependent cytotoxicity activity was observed for either product. Differences in glycosylation profiles were identified but did not affect critical biofunctional properties. Fc receptor binding remained consistent across all tested lots.</p><p><strong>Conclusions: </strong>The comprehensive analytical characterization confirms the biosimilarity of Tuznue^® to Herceptin^®. This supports Tuznue^® as a safe and effective alternative, offering a more affordable option for patients and healthcare systems. Biosimilar development requires overcoming inherent challenges, particularly when reference products exhibit variability in quality attributes over time. Regulatory guidance and scientific rigor are essential to ensuring biosimilar similarity, facilitating broader patient access to life-saving therapies.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"67-77"},"PeriodicalIF":2.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12011664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143773977","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":"Analyses of Adverse Drug Reactions to Fluoroquinolones in Spontaneous Reports Before and After the Referral and in Clinical Routine Cases.","authors":"Diana Dubrall, Julia Wicherski, Maike Below, Jan Görtzen-Patin, Matthias Schmid, Sven Zenker, Britta Haenisch, Bernhardt Sachs","doi":"10.1007/s40268-024-00499-x","DOIUrl":"10.1007/s40268-024-00499-x","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;In November 2018, the European Medicines Agency (EMA) restricted the use of fluoroquinolones (used by mouth, injections or inhalation) in the context of a referral due to long-lasting and potentially irreversible adverse drug reactions (ADRs). Fluoroquinolones should no longer be used to treat mild or moderate bacterial infections unless other antibacterials cannot be used.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objectives: &lt;/strong&gt;The first aim of our study was to analyze whether in the period before compared with after the referral the characteristics of spontaneous ADR reports related to fluoroquinolones differed and whether specific ADRs were more frequently reported for fluoroquinolones compared with cotrimoxazole. Secondly, we analyzed whether the ADR profile differed between individual fluoroquinolones. Finally, the number of fluoroquinolone reports was considered in relation to the number of outpatient drug prescriptions.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;All spontaneous ADR reports from Germany received before the referral (01/2014-12/2019) and after the referral (01/2020-12/2022) for adults in which fluoroquinolones (n = 2575; n = 967) or cotrimoxazole (n = 299, n = 275) were reported as suspected/interacting were identified in the European ADR database, EudraVigilance. The ADR reports were descriptively analyzed concerning the reported characteristics. Odds ratios (ORs) and their 95% confidence intervals (CIs) were estimated by logistic regression analyses, which were performed to investigate whether aortic aneurysms, retinal detachments, cardiac arrhythmias, peripheral polyneuropathies, nervous system disorders, toxic liver diseases and non-traumatic injuries of muscles, tendons and synovialis were more frequently reported for fluoroquinolones compared with cotrimoxazole. Stratified analyses between fluoroquinolones were conducted by calculating ORs and their 95% CIs by using two-by-two tables. Reporting rates were calculated by dividing the number of fluoroquinolone reports by the number of fluoroquinolone prescriptions.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Reporting rates of fluoroquinolones clearly increased until 2019 and decreased afterward. Only minor differences in the characteristics of fluoroquinolone reports (e.g., regarding the indications) were observed in reports received before and after the referral. In both periods, peripheral neuropathies, nervous system, and muscle and tendon disorders were more often reported for fluoroquinolones than cotrimoxazole. In the pooled fluoroquinolone-stratified analyses, (i) peripheral neuropathies and nervous system disorders were more frequently reported for ciprofloxacin, (ii) non-traumatic injuries of muscle, tendon, and synovialis were more often reported for levofloxacin, and (iii) cardiac arrhythmias and toxic liver diseases were more frequently reported for moxifloxacin compared with the other fluoroquinolones.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;In accordance with a reminder s","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"35-55"},"PeriodicalIF":2.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12011694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014880","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, 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":"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":"505-515"},"PeriodicalIF":2.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11652471/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses of Pegcetacoplan in Patients with Paroxysmal Nocturnal Hemoglobinuria.","authors":"Ryan L Crass, Brandon Smith, Sven Adriaens, Sunny Chapel, Grant Langdon","doi":"10.1007/s40268-024-00500-7","DOIUrl":"10.1007/s40268-024-00500-7","url":null,"abstract":"<p><strong>Background and objective: </strong>Paroxysmal nocturnal hemoglobinuria is a rare blood disorder characterized by life-threatening hemolysis and thrombosis. Complement C5 inhibitor therapy improves symptoms and life prognosis; however, it can result in insufficient hemolysis control, with residual intravascular hemolysis and extravascular hemolysis in some patients. Pegcetacoplan, the first complement C3 inhibitor approved for patients with paroxysmal nocturnal hemoglobinuria, targets both intravascular and extravascular hemolysis. This analysis evaluated population pharmacokinetic/pharmacodynamic profiles of pegcetacoplan.</p><p><strong>Methods: </strong>Pooled clinical study data were used to predict pegcetacoplan concentrations and biomarker responses indicative of hemolysis (hemoglobin and lactate dehydrogenase) over time, including the impact of patient characteristics and prior or concurrent complement C5 inhibitor treatment, to support the approved dose of subcutaneous pegcetacoplan 1080 mg twice weekly.</p><p><strong>Results: </strong>The population pharmacokinetoc analysis included 284 subjects, and the pharmacokinetic/pharmacodynamic analysis included 165 subjects. Subcutaneous pegcetacoplan 1080 mg twice weekly resulted in rapid serum exposures and robust biomarker response within 4 weeks after treatment initiation. Steady-state serum concentrations demonstrated consistent exposure (median ≥ 600 µg/mL) with minimal peak-to-trough variation. The median effective half-life was 8.6 days in patients with paroxysmal nocturnal hemoglobinuria. Body weight significantly impacted pegcetacoplan exposure, and other covariates impacted hemoglobin (sex and creatinine clearance) or lactate dehydrogenase (prior or concurrent complement C5 inhibitor treatment); however, effects were not clinically meaningful.</p><p><strong>Conclusions: </strong>The approved dose of pegcetacoplan is predicted to produce rapid and sustained exposure and robust hemoglobin and lactate dehydrogenase responses in adult patients with paroxysmal nocturnal hemoglobinuria, with no initial dose adjustments required for any specific patient population.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"563-573"},"PeriodicalIF":2.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11652457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142752151","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}