Clinical Drug Investigation最新文献

{"title":"Insulin Aspart-szjj: An Insulin Aspart Biosimilar.","authors":"Aisling McGuigan","doi":"10.1007/s40261-026-01523-5","DOIUrl":"10.1007/s40261-026-01523-5","url":null,"abstract":"<p><p>Insulin aspart-szjj (MERILOG^™) is a biosimilar of the reference rapid-acting insulin analog, insulin aspart, and is approved for the same indication as reference insulin aspart: to improve glycemic control in adult and pediatric patients with diabetes mellitus. The physicochemical characteristics of insulin aspart-szjj were similar to reference insulin aspart, and the pharmacodynamic and pharmacokinetic equivalence of the agents has been shown in patients with type 1 diabetes. Insulin aspart-szjj demonstrated clinical efficacy similar to that of reference insulin aspart in patients with type 1 or type 2 diabetes and was generally well tolerated in this population. The tolerability, safety, and immunogenicity profiles of insulin aspart-szjj were similar to those of reference insulin aspart. The role of insulin aspart in the management of diabetes mellitus is well established, and insulin aspart-szjj provides an effective biosimilar alternative for patients with diabetes mellitus requiring reference insulin aspart.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"353-357"},"PeriodicalIF":3.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Single-Center, Randomized, Open-Label, Two-Formulation, Two-Sequence, Two-Period Crossover Study to Evaluate the Bioequivalence of Two Eltrombopag Olamine Tablets (25 mg) in Healthy Chinese Subjects in the Fed State.","authors":"Keyi Wu, Qin Ren, Yanli Wang, Yannan Zhou, Zhengzhi Liu, Yang Cheng, Qiaohuan Deng, Yingzi Cui, Haimiao Yang","doi":"10.1007/s40261-026-01528-0","DOIUrl":"10.1007/s40261-026-01528-0","url":null,"abstract":"<p><strong>Background and objective: </strong>Eltrombopag is an orally active thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia. The purpose of this randomized study is to evaluate the bioequivalence of test and reference eltrombopag olamine tablets in healthy Chinese subjects after consuming a low-calcium, high-fat, high-calorie breakfast.</p><p><strong>Methods: </strong>This was a single-center, randomized, open-label, two-sequence, two-period crossover study. Enrolled subjects were randomly divided into two groups at a 1:1 ratio, with each group randomly receiving either the test or reference eltrombopag olamine tablets per period. The washout period was set to 14 days. The concentration of eltrombopag in plasma was quantified using validated liquid chromatography-tandem mass spectrometry. Safety assessments were conducted throughout the entire trial.</p><p><strong>Results: </strong>This study ultimately included 36 healthy subjects. The geometric mean ratio for maximum plasma concentration between the test or reference eltrombopag olamine tablets was 92.68%; the geometric mean ratio for the area under the concentration-time curve from the time zero to the last measurable concentration was 97.15%; for the area under the concentration-time curve from the time zero to infinity, the geometric mean ratio was 97.30%. The geometric mean ratios and their 90% confidence intervals for the key pharmacokinetic parameters fell within the range of 80.00-125.00%. Within the safety data set of 36 subjects, adverse events were reported in nine subjects, totaling 14 occurrences. All reported adverse events were Grade 1, and no serious adverse events occurred.</p><p><strong>Conclusions: </strong>These findings indicate that a single oral administration of the test eltrombopag is bioequivalent to the reference eltrombopag in healthy subjects after consuming a low-calcium, high-fat, high-calorie breakfast, with both formulations exhibiting a favorable safety profile. These results support the therapeutic interchangeability of the test formulation with the reference product, offering a reliable alternative for clinical use.</p><p><strong>Clinical trial registration: </strong>This trial was registered at the Drug Clinical Trial Registration and Information Disclosure Platform ( http://www.chinadrugtrials.org.cn , CTR20230598) and ClinicalTrials.gov ( https://clinicaltrials.gov , NCT06768619).</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"321-330"},"PeriodicalIF":3.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mazindol Immediate-Release/Sustained-Release (IR/SR): A 50-Year Legacy of Multifaceted Mechanisms and Emerging Therapeutic Potential.","authors":"Eric Konofal, Isabelle Arnulf, Jean-Charles Bizot, Bruce C Corser, Bruno Figadère, Clete A Kushida, Jeffrey H Newcorn, Michel Lecendreux, Christelle Peyron, Michael J Thorpy, Sharon B Wigal, Tim L Wigal","doi":"10.1007/s40261-025-01510-2","DOIUrl":"10.1007/s40261-025-01510-2","url":null,"abstract":"<p><p>Mazindol, an imidazo[2,1-a]-isoindole anorectic from the 1970s, has recently re-emerged as a candidate therapy for disorders of arousal and reward dysregulation, due to its unique multimodal receptor profile. Despite its 1999 withdrawal from US/EU markets, off-label narcolepsy efficacy spurred immediate-release/sustained-release (IR/SR) development. Clinical trials demonstrate mazindol IR/SR efficacy, reducing excessive daytime somnolence and cataplexy in narcolepsy and attention-deficit/hyperactivity disorder (ADHD) severity symptomatology, with mild adverse events (e.g., dry mouth). Preclinical studies demonstrate potent monoamine transporter inhibition (dopamine, norepinephrine, serotonin) with minimal dopamine release, reducing abuse liability compared with amphetamines. Novel interactions orexin-2, 5-HT_1A, and mu-opioid receptors suggest reward modulation, low abuse potential, and utility in polydrug dependence (e.g., fentanyl-cocaine co-use). This review, covering the period 1970-2025, emphasizes the potential for repositioning mazindol, including its potential utility in managing opioid-stimulant co-dependence and attention-related disorders, and underscores its relevance for future therapeutic repurposing. Although this is a narrative review, we conducted targeted searches of PubMed, Scopus, and ClinicalTrials.gov from this period of time, using terms including \"mazindol,\" \"narcolepsy,\" \"ADHD,\" and \"substance use disorder.\"</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"259-280"},"PeriodicalIF":3.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146156335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of the Efficacy of Denosumab and Alendronate in Improving Bone Mineral Density in Osteoporosis Patients and High-Risk Populations: A Systematic Review and Meta-Analysis.","authors":"Kejia Zhu, Hang Li, Hui Zhang, Zongke Zhou, Bin Shen, Yong Nie","doi":"10.1007/s40261-025-01521-z","DOIUrl":"10.1007/s40261-025-01521-z","url":null,"abstract":"<p><strong>Background: </strong>Osteoporosis, a common condition of low bone mineral density (BMD), significantly increases fracture risk. Denosumab and alendronate are both established anti-resorptive therapies, yet their comparative effectiveness remains inconsistent across studies.</p><p><strong>Objective: </strong>The aim of this meta-analysis was to systematically evaluate the efficacy of denosumab versus alendronate for improving BMD at multiple skeletal sites in osteoporosis patients, aiming to provide evidence for clinical decision making.</p><p><strong>Methods: </strong>Multiple databases were searched for relevant randomised controlled trials published in English (as of November 2024). The primary outcomes were mean change of BMD at different skeletal sites. Data were pooled using fixed- or random-effects models to determine the mean differences (MDs) and 95% confidence intervals (CIs) for various BMD in patients treated with denosumab in comparison to patients treated with alendronate.</p><p><strong>Results: </strong>This meta-analysis included thirteen randomized controlled trials (RCTs) with a total of 3364 patients and follow-up periods ranging from 6 to 24 months, and the overall quality of the studies was relatively high. The results demonstrated that denosumab was more effective than alendronate in increasing BMD at the lumbar spine (LS), femoral neck (FN), distal radius (DR), and total hip (TH) in osteoporosis patients and high-risk populations. Subgroup analysis revealed that postmenopausal women experienced greater improvements in BMD at the LS (p < 0.001) at 6 months, and at the FN (p < 0.001) at 24 months, compared with non-postmenopausal  subjects.</p><p><strong>Conclusions: </strong>Denosumab was more effective than alendronate in increasing BMD. However, all the included randomised controlled trials (RCTs) carried a risk of bias, and the patient sample sizes were relatively small. Therefore, further studies with larger sample sizes and better methodological rigor are needed to confirm these findings.</p><p><strong>Prospero registration number: </strong>CRD420250655676.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"243-258"},"PeriodicalIF":3.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146060514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy of Brexpiprazole in Participants with Agitation Associated with Dementia Due to Alzheimer's Disease: Pooled Analysis of Randomized Controlled Trials.","authors":"Jeffrey L Cummings, Sanjeda R Chumki, Denise Chang, Zhen Zhang, Malaak Brubaker, Nanco Hefting, Pedro Such, David Wang, George T Grossberg","doi":"10.1007/s40261-025-01517-9","DOIUrl":"10.1007/s40261-025-01517-9","url":null,"abstract":"<p><strong>Objective: </strong>This analysis aimed to evaluate the efficacy of brexpiprazole 2 or 3 mg/day for the treatment of agitation associated with dementia due to Alzheimer's disease, on the basis of pooled clinical trial data.</p><p><strong>Methods: </strong>Data were pooled from two similarly designed, phase 3, 12-week, multicenter, randomized, double-blind, placebo-controlled trials of fixed-dose brexpiprazole in participants in care facilities or community-based settings who had agitation associated with dementia due to Alzheimer's disease. Efficacy outcomes included Cohen-Mansfield Agitation Inventory (CMAI) total score (which measures the frequency of 29 different agitation symptoms), Clinical Global Impression-Severity of illness (CGI-S) score, CMAI factor scores (aggressive behaviors, physically nonaggressive behaviors, and verbally agitated behaviors), and response rates. A sensitivity analysis included a third trial with flexible dosing.</p><p><strong>Results: </strong>In total, 621 participants were randomized (brexpiprazole, 368; placebo, 253), and completion rates were 320/368 (87.0%) and 225/253 (88.9%), respectively. Mean (SD) baseline CMAI total scores were: brexpiprazole 76.9 (17.2) points and placebo 75.5 (18.0) points. Over 12 weeks, CMAI total scores improved by least squares mean (SE) - 22.8 (0.8) points for brexpiprazole and - 18.3 (1.0) points for placebo, with a least squares mean difference between treatment arms of - 4.50 points (95% CI - 6.90 to - 2.10; p < 0.001; Cohen's d 0.30). CGI-S, CMAI factor, and response analyses also showed greater improvement with brexpiprazole versus placebo. The sensitivity analysis was supportive.</p><p><strong>Conclusions: </strong>Brexpiprazole 2 or 3 mg/day reduced agitation symptoms compared with placebo over 12 weeks in this large, pooled sample of participants with dementia due to Alzheimer's disease.</p><p><strong>Study registration: </strong>ClinicalTrials.gov identifiers: NCT01862640, NCT03548584, and NCT01922258.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"281-292"},"PeriodicalIF":3.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12950069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146050520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unexpected Clinical Drug-Drug Interaction of Fexinidazole on Midazolam Pharmacokinetics: Insights into Underlying Mechanisms from Clinical Phase I Study Results and Supporting In Vivo/Vitro Evidence.","authors":"Matthieu Gassiot, Priscilla Brun, Valerie Wauthier, Franck Da Silva, Olivier Nicolas, Sophie Hays, Eric Sultan","doi":"10.1007/s40261-025-01508-w","DOIUrl":"10.1007/s40261-025-01508-w","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Fexinidazole, a nitroimidazole antiparasitic, has been approved to treat human African trypanosomiasis (HAT) worldwide. In vitro studies have shown that fexinidazole inhibits and weakly induces CYP3A4/5. In silico predictions indicated that fexinidazole, which has a significant intestinal and liver first-pass metabolism, could increase the exposure of a sensitive probe substrate of CYP3A4 by two-fold. Therefore, this study investigated the potential clinical drug-drug interactions (DDIs) of fexinidazole with CYP3A4 substrates.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;To assess the effect of fexinidazole on the pharmacokinetics of midazolam, a well-recognised sensitive CYP3A4 substrate (and its metabolites 1-hydroxy-midazolam and N-glucuronide-midazolam) in humans and to elucidate the underlying mechanism of the in vivo DDI.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This was a phase I, open-label, single-centre, non-randomised, single-sequence, two-period, two-treatment crossover study. The study population consisted of 12 healthy male and female participants. The two treatment periods included Period 1, wherein a single midazolam dose was administered on Day 1, and Period 2, wherein fexinidazole was administered once daily from Day 1 to Day 5, with a single midazolam dose co-administered on Day 4. Key pharmacokinetic parameters of midazolam and its main metabolites, including the maximum plasma concentration (C&lt;sub&gt;max&lt;/sub&gt;), area under the curve (AUC), and elimination half-life (t&lt;sub&gt;1/2z&lt;/sub&gt;), were evaluated. Additionally, in vitro assessments (protein-binding and CYP enzyme induction studies) were conducted to investigate potential mechanisms contributing to the observed interaction.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Contrary to the in vitro predictions, fexinidazole significantly reduced midazolam exposure in vivo, resulting in a reduction of 39% in C&lt;sub&gt;max&lt;/sub&gt;, 57% in AUC, and 33% in t&lt;sub&gt;1/2z&lt;/sub&gt;, without significant changes in t&lt;sub&gt;max&lt;/sub&gt;. Mechanistic studies ruled out reduced absorption and plasma protein displacement as potential causes. At clinically relevant concentrations, fexinidazole and M1 exhibited weak induction potential on CYP3A4/5 and no significant induction on other enzymes. Further, in vivo investigations on midazolam metabolites confirmed that CYP3A4/5 induction by fexinidazole was the primary mechanism, increasing the first-pass metabolism and clearance of midazolam. The metabolic ratios of 1-hydroxy-midazolam and N-glucuronide-midazolam were increased by 1.63-fold and 1.24-fold, respectively. Steady-state exposures of fexinidazole and its metabolites M1 and M2 were consistent with those previously assessed in other clinical studies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;While in vitro studies showed weak induction by fexinidazole and its metabolite M1, the clinical pharmacokinetic data provided stronger evidence, supporting the conclusion that fexinidazole is a moderate inducer of CYP3A4/5 in viv","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"221-236"},"PeriodicalIF":2.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12872618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145773791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Bumetanide Nasal Spray: First Approval.","authors":"Hannah A Blair","doi":"10.1007/s40261-025-01514-y","DOIUrl":"10.1007/s40261-025-01514-y","url":null,"abstract":"","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"241-242"},"PeriodicalIF":2.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bumetanide Nasal Spray: First Approval.","authors":"Hannah A Blair","doi":"10.1007/s40261-025-01503-1","DOIUrl":"10.1007/s40261-025-01503-1","url":null,"abstract":"<p><p>Bumetanide nasal spray (ENBUMYST^™) is a loop diuretic developed by Corstasis Therapeutics for the treatment of oedema. It is designed as a short-term therapeutic option, with absorption via the nasal mucosa potentially offering more consistent or predictable bioavailability than oral administration, particularly in patients with gastrointestinal impairment. Bumetanide nasal spray received its first approval on 12 September 2025 in the USA for the treatment of oedema associated with congestive heart failure (CHF), and hepatic and renal disease, including nephrotic syndrome in adults. This article summarizes the milestones in the development of bumetanide nasal spray leading to this first approval for the treatment of oedema.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"237-240"},"PeriodicalIF":3.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145494845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Absorption, Metabolism, Distribution and Excretion (ADME) and Absolute Bioavailability Assessment of Zongertinib in Healthy Male Volunteers.","authors":"Rolf Grempler, David Joseph, Guanfa Gan, Adam M Auclair, Renger G Tiessen, Hlaing H Maw, Ralf Laux, Sven Wind, Philipp M Roessner, Behbood Sadrolhefazi, Fabian Müller, David Minich","doi":"10.1007/s40261-025-01509-9","DOIUrl":"10.1007/s40261-025-01509-9","url":null,"abstract":"<p><strong>Background and objectives: </strong>Zongertinib is an irreversible tyrosine kinase inhibitor that selectively inhibits human epidermal growth factor receptor 2 (HER2) while sparing epidermal growth factor receptor (EGFR), minimizing related toxicities. This non-randomized, open-label, Phase I study evaluated the absorption, distribution, metabolism and excretion (ADME) of zongertinib (Part A) and its absolute bioavailability (F) (Part B) in healthy male volunteers.</p><p><strong>Methods: </strong>In Part A, eight subjects received a single oral 60 mg dose of zongertinib (C-14)-solution containing radiolabeled [¹⁴C]zongertinib [3.7 MBq] and unlabeled drug. In Part B, seven subjects received an oral unlabeled zongertinib 60-mg film-coated tablet after fasting, followed by a 15-min intravenous (IV) infusion of 100 μg zongertinib solution (C-14), consisting of 10 μg [¹⁴C]zongertinib [~ 0.03 MBq] and 90 μg unlabeled drug. Plasma pharmacokinetics, excretion pathways, metabolism, and bioavailability were assessed. Safety was evaluated in both study parts.</p><p><strong>Results: </strong>After oral dosing in Part A, peak plasma concentration occurred at a median of 1-h post-dose (range 0.5‒2.0 h). Mean recovery of the radioactive dose was 93.8%, primarily in feces (92.5%) and minimally in urine (1.30%). Unchanged zongertinib accounted for most circulating radioactivity (74.6%) in plasma and was the most abundant component in feces (31.4% of the dose) and urine (0.18% of dose). In vitro metabolism involved oxidation (48-62%), glucuronidation (13-25%), and glutathione conjugation (13-25%). In part B, the mean F of the oral tablet was 76.2%. Following IV administration, zongertinib showed low plasma clearance (106 mL/min) and a moderate volume of distribution of 138 L. Zongertinib had a manageable safety profile in both study parts.</p><p><strong>Conclusions: </strong>Zongertinib was rapidly absorbed with high absolute bioavailability. The unchanged zongertinib was the predominant form in plasma and excreta, with fecal excretion as the main elimination pathway. Metabolism occurred primarily through oxidation, with minor contributions from glucuronidation and glutathione conjugation.</p><p><strong>Clinical trial registration: </strong>Registered under identifier NCT05879991 (25 May 2023).</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"115-125"},"PeriodicalIF":2.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12872673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145676323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and Pharmacokinetics of Repeat Dosing of Long-Acting SARS-CoV-2 Antibodies Tixagevimab/Cilgavimab (AZD7442): Results from the PROVENT Sub-study.","authors":"Andrew Ustianowski, Myron J Levin, Stephane De Wit, Odile Launay, Bernard Veekmans, Tommy Rampling, James G Sullivan, Mark Vishnepolsky, Priyantha Wijewardane, Yousef Fawadleh, Huixia Zhang, Meng Li, Dilki Wickramarachchi, Audrey Sharbaugh, Rohini Beavon, Jesse Thissen, Lauren Hirao, Vitalina Dzutseva, Seth Seegobin, Katie Streicher, Alexandre Kiazand, Mark T Esser, Lee-Jah Chang, John L Perez, Taylor S Cohen","doi":"10.1007/s40261-025-01515-x","DOIUrl":"10.1007/s40261-025-01515-x","url":null,"abstract":"<p><strong>Background and objectives: </strong>The PROVENT study demonstrated the efficacy and safety of a single 300-mg dose of AZD7442 (tixagevimab/cilgavimab) for pre-exposure prophylaxis of COVID-19 in at-risk individuals. Here we report an analysis of repeat dosing of intramuscular AZD7442 300 and 600 mg from the PROVENT sub-study.</p><p><strong>Methods: </strong>The sub-study enrolled eligible participants from the parent study, creating four sub-study groups. Group 1 received AZD7442 300 mg in PROVENT followed by one 300-mg dose in the sub-study (10-14 months apart). Group 2 received placebo in PROVENT followed by two AZD7442 300-mg doses 6 months apart in the sub-study. Group 3a received AZD7442 300 mg in PROVENT followed by one 300-mg dose and two 600-mg doses 6 months apart in the sub-study. Group 3b received placebo in PROVENT followed by one 300-mg dose and two 600-mg doses 6 months apart in the sub-study. The primary endpoint was safety. Secondary endpoints included pharmacokinetics and anti-drug antibody (ADA) responses.</p><p><strong>Results: </strong>Adverse events (AEs) and serious AEs (SAEs) were reported in 75.7-81.5% and 13.2-16.8% of participants, respectively. AZD7442-related AEs, SAEs, and AEs of special interest occurred in 1.4-5.3%, 0-0.2%, and 0-5.3% of participants, respectively, and 3.9-6.7% experienced ≥ 1 cardiac and/or thromboembolic SAE. AZD7442 serum concentrations were dose-dependent with minimal accumulation following redosing, and 4.1-10.7% had treatment-emergent ADAs to AZD7442.</p><p><strong>Conclusions: </strong>AZD7442 safety, pharmacokinetic, and ADA response profiles were similar regardless of repeat dosing schedule, and consistent with single-dose study data. These results may support future use of long-acting antibodies.</p><p><strong>Clinicaltrials: </strong></p><p><strong>Gov registration: </strong>NCT04625725.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"207-219"},"PeriodicalIF":3.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12872691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}