Drugs in Research & Development最新文献

{"title":"Network Meta-Analysis of Pharmacological Therapies for Long-Term Prophylactic Treatment of Patients with Hereditary Angioedema.","authors":"Sarah Walsh, Meaghan Bartlett, Elizabeth M Salvo-Halloran, John Sears, Yinglei Li, Maebh Kelly, Simona Gavata-Steiger, Chiara Nenci, Iris Jacobs, Ingo Pragst, Neelanjana Ray, Imtiaz A Samjoo","doi":"10.1007/s40268-025-00511-y","DOIUrl":"https://doi.org/10.1007/s40268-025-00511-y","url":null,"abstract":"<p><strong>Background and objectives: </strong>Several treatments for long-term prophylaxis (LTP) of hereditary angioedema (HAE) are in clinical use, such as garadacimab, lanadelumab, subcutaneous C1 esterase inhibitor (C1INH), and berotralstat. In the absence of head-to-head comparative evidence, indirect comparison methods are needed to compare LTP treatments in patients with HAE. The objective of this analysis was to estimate the comparative efficacy, safety, and impact on quality of life of LTP treatments for patients with HAE through NMAs.</p><p><strong>Methods: </strong>A systematic literature review was conducted to identify randomized controlled trials (RCTs) investigating LTP treatments in patients (at least 12 years old) with HAE (PROSPERO protocol #CRD42022359207). A network meta-analysis (NMA) feasibility assessment evaluated trial suitability and Bayesian NMAs were conducted for evaluable efficacy, safety, and quality of life (QoL) outcomes.</p><p><strong>Results: </strong>The results of these NMAs show improved efficacy, QoL, and reduced rate of adverse events with garadacimab (200 mg once monthly), lanadelumab (300 mg every two or four weeks), subcutaneous C1INH (60 IU/kg twice weekly), and berotralstat (150 mg once daily) compared to placebo in the treatment of patients with HAE. For the primary outcome of time-normalized number of HAE attacks, garadacimab statistically significantly reduced the rate of attacks compared to lanadelumab Q4W and berotralstat. A similar statistically significant reduction was shown for HAE attacks treated with on-demand treatment. Garadacimab showed statistically significant reduction in the rate of moderate and/or severe HAE attacks compared to lanadelumab Q2W. Garadacimab also showed statistical improvements in change from baseline in AE-QoL total score as compared to berotralstat.</p><p><strong>Conclusions: </strong>Overall, garadacimab ranked as the most probable effective treatment among all comparators assessed, with lanadelumab Q2W or subcutaneous C1INH ranking second, across most outcomes.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144163333","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":"Opinion of the Italian Association of Myology on Ataluren for the Treatment of Nonsense Mutation Duchenne Muscular Dystrophy.","authors":"Luca Bello, Pietro Riguzzi, Emilio Albamonte, Guja Astrea, Roberta Battini, Andrea Barp, Angela L Berardinelli, Enrico S Bertini, Noemi Brolatti, Claudio Bruno, Stefania Corti, Adele D'Amico, Maria Grazia D'Angelo, Gianfranco Dallavalle, Rocco Liguori, Lorenzo Maggi, Francesca Magri, Michelangelo Mancuso, Riccardo Masson, Eugenio Mercuri, Carlo Minetti, Sonia Messina, Tiziana Mongini, Olimpia Musumeci, Vincenzo Nigro, Marika Pane, Chiara Panicucci, Marina Pedemonte, Antonella Pini, Luisa Politano, Stefano Previtali, Federica Ricci, Giulia Ricci, Lucia Ruggiero, Valeria Sansone, Gabriele Siciliano, Antonio Trabacca, Federica Trucco, Daniele Velardo, Elena Pegoraro, Giacomo P Comi","doi":"10.1007/s40268-025-00512-x","DOIUrl":"https://doi.org/10.1007/s40268-025-00512-x","url":null,"abstract":"<p><p>The Italian Duchenne muscular dystrophy expert clinicians, gathered in the Italian Association of Myology (AIM), intend to express a position against the suspension of the Marketing Authorization of ataluren (Translarna^®) for the treatment of nonsense mutation Duchenne muscular dystrophy. The marketing authorization has been recently withdrawn by the European Commission following a recommendation from the Committee for Medicinal Products for Human Use of the European Medicines Agency. This negative recommendation was based on the fact that three randomized controlled trials of ataluren in nonsense mutation Duchenne muscular dystrophy (007, 020, and 041) have failed to show statistically significant differencs in favor of the treatment in the selected primary outcomes for each individual study, i.e., 6-min walk distance, in the intent-to-treat population for 007 and 020 and in a subgroup for 041. However, observed differences always favored treatment, and several clinically meaningful secondary outcomes were positive and statistically significant across studies. Importantly, the largest and longest phase III study (041) showed a statistically significant effect in favor of ataluren in the wider intent-to-treat population. Furthermore, a long-term registry of \"real-world\" ataluren treatment data (Strategic Targeting of Registries and Database of Excellence, STRIDE), in addition to confirming a reassuring safety profile, suggested a prolonged maintenance of ambulatory, upper limb, and respiratory function. We deem that a withdrawal of ataluren from the European market would harm not only patients with nonsense mutation Duchenne muscular dystrophy, but the whole neuromuscular field, in which clinical trials are challenging because of the heterogenous complex slow-progressing nature of the disorders.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144163374","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":"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":"https://doi.org/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":""},"PeriodicalIF":2.2,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of Anti-SARS-CoV-2 IgG Responses in a Clinical Study of a Biosimilar Candidate to Denosumab Using Singlicate Analysis.","authors":"Sandra Ribes, Natalia Krivtsova, Celine Schelcher, Ana Villalba-Izquierdo, Falko Reiss, Mandy Richter, Katrin Reisinger, Johann Poetzl","doi":"10.1007/s40268-025-00510-z","DOIUrl":"https://doi.org/10.1007/s40268-025-00510-z","url":null,"abstract":"<p><strong>Background and objectives: </strong>During the coronavirus disease-2019 (COVID-19) pandemic there was the uncertainty that the long-term immune response generated upon natural infection or triggered by available severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) vaccines could impact the clinical endpoints of ongoing clinical trials, in particular, whether the immunogenicity of biotherapeutics could be affected.</p><p><strong>Methods: </strong>Here, we describe the different stages to build an adequate COVID-19 serology testing strategy to ultimately assess whether the presence of anti-SARS-CoV-2 antibodies could impact the immunogenicity data of a clinical trial supporting the approval of GP2411 (Jubbonti^®/Wyost^®; a denosumab biosimilar to Prolia/XGeva) conducted during the pandemic. We first assessed the sensitivity and specificity of US Food and Drug Administration Emergency Use Authorization (FDA EUA)-approved commercial SARS-CoV-2 anti-IgG enzyme-linked immunosorbent (ELISA) assay. Then, we validated the assay in accordance with bioanalytical guidelines and demonstrated that the analysis of validation parameters as singlicates met all bioanalytical acceptance criteria and showed comparable results to those of duplicate analyses. Lastly, we report data on anti-SARS-CoV-2 IgG antibody responses in healthy participants treated with a single dose of a biotherapeutic.</p><p><strong>Results: </strong>SARS-CoV-2 serology was assessed in 1970 serum samples collected from 499 healthy participants who were dosed throughout a clinical study that was conducted during the COVID-19 pandemic. Anti-SARS-CoV-2 IgG antibodies triggered by natural infection and/or vaccination were detected in 1165 serum samples from 82% of the study participants. Anti-SARS-COV-2 IgG responses were of comparable magnitude in study participants who were vaccinated during the course of the study or had a confirmed COVID-19 infection. A total of 6408 serum samples from the same study were evaluated for the presence of anti-drug antibodies (ADAs), with 64% of the participants being positive. Independent of the presence of anti-SARS-CoV-2 IgG antibodies, all ADA-positive study participants showed ADAs of very low magnitude. Neutralizing ADAs were detected in less than 1% of study participants without an association to anti-SARS-CoV-2 IgG responses.</p><p><strong>Conclusions: </strong>The established bioanalytical strategy allowed the reliable detection of COVID-19 adaptive responses in study participants. The development of anti-SARS-CoV-2 IgG responses (triggered by either a natural infection or a vaccine) did not have any clinically meaningful impact on the immunogenicity of the biotherapeutic administered in the study.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144129410","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":"Safety Evaluation of Contezolid (MRX-I) Versus Linezolid in Sprague-Dawley Rats.","authors":"Liping Wei, Min Hong, Min Lu, Yimin Qian, Qingmei Li, Naping Tang, Hua Li, Yan Chang, Yunliang Qiu","doi":"10.1007/s40268-025-00504-x","DOIUrl":"https://doi.org/10.1007/s40268-025-00504-x","url":null,"abstract":"<p><strong>Background & objectives: </strong>Contezolid (MRX-I) is a novel ortho-fluorophenyl dihydropyridone developed by MicuRx Pharmaceuticals, Inc. It has been approved for the treatment of drug-resistant Gram-positive bacterial infections with relatively lower toxicity than other oxazolidinones such as linezolid. However, the toxicity profile has not yet been completely revealed. The aim of this study was to disclose the toxicity of contezolid in Sprague-Dawley (SD) rats and compare its toxicity profile with linezolid in a standard 4-week toxicity study.</p><p><strong>Methods: </strong>In this study, SD rats were orally administered with contezolid at doses of 20, 100, or 200/300 mg/kg/day for 28 consecutive days followed by a 28-day recovery period. Linezolid at doses of 100 or 200 mg/kg/day served as a comparator. Clinical observations, body weight, food consumption, hematology, clinical chemistry, urinalysis, and histopathological examinations were conducted.</p><p><strong>Results: </strong>All females in the 200 mg/kg/day linezolid group were subjected to unscheduled death due to myelosuppression within the first 2 weeks. No abnormalities were noted in the 200 mg/kg/day contezolid group, and the dose level was escalated to 300 mg/kg/day from day 15. Myelosuppression or myelosuppression-associated effects were comparable between the 300-mg/kg/day contezolid group and the 100-mg/kg/day linezolid group. The 'no observed adverse effect level' (NOAEL) of contezolid was determined to be 100 mg/kg/day (with an average AUC_0-24 h of 268.4 μg*h/mL). At the same dose levels, the toxicity of contezolid was significantly lower than that of linezolid.</p><p><strong>Conclusion: </strong>These findings demonstrate that contezolid exhibits a favorable safety profile compared with linezolid in this 4-week repeated-dose toxicity study in rats.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143992192","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 and Safety of Two Amisulpride Formulations in Healthy Chinese Subjects Under Fasting and Fed Conditions: A Randomized, Open‑Label, Single‑Dose, Crossover Study.","authors":"Min Wang, Yu Peng, Hegui Yan, Zhixiang Pan, Ronghui Du, Guan Liu","doi":"10.1007/s40268-025-00508-7","DOIUrl":"https://doi.org/10.1007/s40268-025-00508-7","url":null,"abstract":"<p><strong>Background and objectives: </strong>Amisulpride is a second-generation antipsychotic drug that selectively binds to D2 and D3 dopaminergic receptors in the limbic system. In this study, the bioequivalence of an amisulpride formulation manufactured in China with the original formulation Solian® was evaluated under fasting and fed conditions in healthy Chinese subjects.</p><p><strong>Methods: </strong>A single-centre, randomized, open, two-preparation, single-dose, two-period crossover trial in healthy adult subjects was conducted under fasting and fed conditions. A total of 42 and 36 eligible healthy subjects were enrolled in the fasting and fed studies, respectively. The subjects were randomly assigned to receive either the test or the reference formulation with a washout period of 7 days. The concentration of amisulpride in plasma was determined by liquid chromatography‒tandem mass spectrometry (LC‒MS/MS), and the pharmacokinetic (PK) parameters of amisulpride were calculated via the noncompartmental method.</p><p><strong>Results: </strong>The geometric mean ratios (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 93.83, 101.90, and 102.35, respectively, with corresponding 90% confidence intervals (CIs) of 83.93-104.89, 97.58-106.42, and 98.24-106.63. The GMRs of C_max, AUC_0-t, and AUC_0-∞ under fed conditions were 102.23, 106.09, and 101.87, respectively, with corresponding 90% CIs of 92.49-112.99, 102.44-109.87, and 97.49-106.44. These data all satisfied the bioequivalence criteria (90% CIs in the range of 80-125%). In terms of safety, no serious adverse events were observed.</p><p><strong>Conclusions: </strong>The test and reference amisulpride formulations were bioequivalent under fasting and fed conditions. Both formulations showed similar safety and tolerability in the population studied.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018613","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":"Patient-Reported Outcome Measures in Patients with Rheumatoid Arthritis, Psoriasis, or Psoriatic Arthritis Treated with GP2015, an Etanercept Biosimilar: Results from Two Phase III Studies (EGALITY and EQUIRA).","authors":"Diamant Thaçi, Sascha Gerdes, Hendrik Schulze-Koops, Yannick Allanore, Arthur Kavanaugh, Charlotte Both, Sreekanth Gattu, Sohaib Hachaichi, Marco Matucci-Cerinic","doi":"10.1007/s40268-025-00507-8","DOIUrl":"https://doi.org/10.1007/s40268-025-00507-8","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objective: &lt;/strong&gt;GP2015 is an etanercept biosimilar. Equivalent efficacy and comparable safety of GP2015 to reference etanercept (ref-ETN) was demonstrated in two phase III studies, one in patients with moderate-to-severe chronic plaque-type psoriasis (PsO; EGALITY study) and the other in patients with rheumatoid arthritis (RA; EQUIRA study). EGALITY also included patients with reported psoriatic arthritis (PsA). Here, patient-reported outcome (PRO) data from both studies are presented.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;EGALITY included 531 patients with PsO and EQUIRA included 376 patients with RA. In EGALITY, patients who had achieved ≥ 50% improvement in Psoriasis Area and Severity Index (PASI) at week 12 either continued the initial treatment or underwent three treatment switches between GP2015 and ref-ETN starting at week 12. In EQUIRA, patients with at least moderate European League Against Rheumatism response at week 24 received GP2015 up to week 48. Assessed PROs included Dermatology Life Quality Index (DLQI) and EuroQol five-dimension health status questionnaire (EQ-5D-5L) in EGALITY, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score in EQUIRA, and Health Assessment Questionnaire-Disability Index (HAQ-DI) in both studies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In EGALITY, mean DLQI decreased from baseline in the GP2015 and ref-ETN groups, and the mean (standard deviation [SD]) percent reductions from baseline in DLQI were comparable between groups at week 12 (GP2015, - 67.7 [40.7]; ref-ETN, - 67.3 [30.6]), and were sustained after the switch at week 52 ('continued GP2015,' - 77.3 [36.5]; 'continued ref-ETN,' - 72.8 [33.7]; 'switched GP2015,' - 73.9 [37.0]; 'switched ref-ETN,' - 78.1 [30.9]). The proportion of patients with EQ-5D-5L scores of 1 ('no problems') improved from baseline to week 52 for all five dimensions and was comparable between treatment groups. In EGALITY, in patients with reported PsA at baseline, mean (SD) HAQ-DI scores decreased from baseline, and scores were comparable between treatment groups at week 12 (GP2015, 0.6 [0.7]; ref-ETN, 0.6 [0.6]) and after switching at week 52 ('continued GP2015,' - 0.4 [0.6]; 'continued ref-ETN,' - 0.4 [0.6]; 'switched GP2015,' - 0.4 [0.6]; 'switched ref-ETN,' - 0.1 [0.4]). In EQUIRA, the proportion of patients achieving HAQ-DI in normal range (≤ 0.5) was comparable between treatment groups up to week 48 ('continued GP2015,' 36.7%; 'switched to GP2015,' 39.9%). The mean FACIT-Fatigue scores increased from baseline and the mean (SD) percent change from baseline in FACIT-Fatigue score at week 24 was 9.6 (9.5) in the 'continued GP2015' and 11.4 (9.7) in the 'switched to GP2015' groups; the scores were sustained after switching until week 48.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Treatment with GP2015 and ref-ETN resulted in similar improvements in PROs and quality-of-life scores across the three diseases, namely RA, PsA, and PsO. These improvements wer","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144056591","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":"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":"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}