Clinical Drug Investigation最新文献

{"title":"Economic Model of Uridine Triacetate Versus Supportive Care for the Treatment of Patients with Life-Threatening Early-Onset Severe Toxicity.","authors":"Jorge J Garcia, Alice Beers, Paige Reid, Salvatore Miragliotta, Suzanne Ward, Setareh A Williams, Michelle Barnard, Megan Bourque, Chantal Trepanier, Amanda Griffin","doi":"10.1007/s40261-025-01426-x","DOIUrl":"10.1007/s40261-025-01426-x","url":null,"abstract":"<p><strong>Background: </strong>Early-onset severe toxicity following the administration of 5-fluorouracil (5-FU) or capecitabine occurs in approximately 10-30% of patients receiving fluoropyrimidine therapy in the USA and is fatal to at least 0.5% of patients treated. Supportive care measures used to manage symptoms of toxicity are associated with extended hospital length of stay, high cost of care, and poor survival. Uridine triacetate is indicated as an emergency treatment for patients who exhibit early-onset, severe or life-threatening toxicity, and has been shown to significantly improve clinical outcomes. Despite its life-saving capability to reverse early-onset severe toxicity, uridine triacetate may be underutilized.</p><p><strong>Purpose: </strong>This study aims to evaluate the economic impact of uridine triacetate as a rescue therapy for adult patients from the US hospital payer perspective for early-onset severe toxicity, who are expected to die without treatment.</p><p><strong>Methods: </strong>A decision tree model was developed to compare inpatient survival, hospital length of stay, and inpatient healthcare resource utilization for patients treated with and without uridine triacetate. Costs associated with hospitalization, including supportive care measures and monitoring were evaluated, considering medications and procedures commonly used to manage various severe toxicities experienced (e.g., gastrointestinal, hematological, etc.). The model compared the hypothetical current practice, in which approximately half of patients expected to die from early-onset severe toxicity receive uridine triacetate in addition to supportive care, with the proposed future practice in which all eligible patients receive uridine triacetate during their hospital stay. Hypothetical practical scenarios for US institutions were also considered.</p><p><strong>Results: </strong>For each adult patient hospitalized for early-onset severe or life-threatening toxicity who would be expected to die without treatment, adoption of uridine triacetate as a rescue treatment was associated with clinical benefits, including increased inpatient survival (48.5%) and a 7.3-day reduction in total hospital length of stay per patient. Treatment of each additional patient with uridine triacetate was associated with an incremental cost of US$25,247 per patient. Seventy percent of the drug cost was offset by reduction in inpatient healthcare resources utilization. This cost offset is likely underestimated as it does not include additional savings from potential reimbursements associated with changes in hospital length of stay, readmissions and discounting. Hypothetical scenarios demonstrated that model outputs were most sensitive to changes in length of stay and hospitalization costs.</p><p><strong>Conclusion: </strong>Optimal treatment with uridine triacetate for all hospitalized patients in the USA expected to die from early-onset severe toxicity has the potential to improve ","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"111-123"},"PeriodicalIF":2.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476333","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":"Dose-Dependent Relationship Between Long-Term Metformin Use and the Risk of Diabetic Retinopathy: A Population-Based Cohort Study.","authors":"Yu-Ching Li, Kuang-Hua Huang, Yih Yang, Shuo-Yan Gau, Tung-Han Tsai, Chien-Ying Lee","doi":"10.1007/s40261-025-01421-2","DOIUrl":"10.1007/s40261-025-01421-2","url":null,"abstract":"<p><strong>Background and objective: </strong>Recent research has raised concerns about the association between metformin treatment in patients with diabetes mellitus (DM) and an increased risk of diabetic retinopathy. We sought to investigate this relationship, specifically examining if metformin use affects diabetic retinopathy risk in a dose-dependent manner.</p><p><strong>Methods: </strong>This study was a secondary data analysis based on a nationwide population database in Taiwan. Patients with new-onset DM, an age of 20 years or older, and a diagnosis of type 2 DM received at any time during 2002-2013 were included in the study. Patients diagnosed with new-onset type 2 DM between 2002 and 2013 were enrolled as the study population. We divided them into two groups: those treated with metformin and those treated with sulfonylureas. A Cox proportional hazards model was employed to estimate the risk of diabetic retinopathy after 5 years of follow-up, including cumulative defined daily dose and intensity of metformin treatment.</p><p><strong>Results: </strong>A total of 241,231 patients received treatment with metformin, while 152,617 patients were treated with sulfonylureas. Compared with patients treated with sulfonylureas, patients who received metformin treatment, at a cumulative defined daily dose < 30, had a lower risk of diabetic retinopathy (adjusted hazard ratio = 0.77; 95% confidence interval 0.60-0.98). However, those with varying defined daily doses, especially at a higher metformin treatment level (> 25 defined daily dose), had a 2.43 times higher risk of diabetic retinopathy (95% confidence interval 1.37-4.30) compared with patients treated with sulfonylureas.</p><p><strong>Conclusions: </strong>Patients with DM treated with a lower cumulative dosage of metformin showed beneficial effects that were associated with a lower risk of diabetic retinopathy. In contrast, a higher intensity of metformin use had a greater risk of diabetic retinopathy.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"125-136"},"PeriodicalIF":2.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406078","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":"Dihydropyrimidine Dehydrogenase Deficiency (DPYD) Genotyping-Guided Fluoropyrimidine-Based Adjuvant Chemotherapy for Breast Cancer. A Cost-Effectiveness Analysis.","authors":"Dina Abushanab, Shaban Mohamed, Rania Abdel-Latif, Diala Alhaj Moustafa, Wafa Marridi, Shereen Elazzazy, Radja Badji, Wadha Al-Muftah, Said I Ismail, Salha Bujassoum, Asma Al-Thani, Daoud Al-Badriyeh, Moza Al Hail","doi":"10.1007/s40261-024-01413-8","DOIUrl":"10.1007/s40261-024-01413-8","url":null,"abstract":"<p><strong>Background and objective: </strong>While standard doses of adjuvant fluoropyrimidine-based chemotherapies are generally safe for most patients, the risk of severe adverse drug reactions (ADRs) is increased for those with dihydropyrimidine dehydrogenase deficiency (DPYD), a genetic variation that affects drug metabolism. The objective of this study was to examine the cost effectiveness of offering DPYD pharmacogenetic-guided care, where genetic testing informs personalized dosing versus the current standard of care (SoC), which involves administering fluoropyrimidine-based therapies without prior genetic screening, for local or metastatic breast cancer patients in Qatar.</p><p><strong>Methods: </strong>We developed a two-stage decision analysis, with an analytic tree model over a 6-month period, followed by a life-table Markov model over a lifetime horizon. We compared the current SoC with the alternate strategy of DPYD genetic screening in patients living in Qatar with local or metastatic breast cancer who were eligible for adjuvant fluoropyrimidine therapy. Clinical outcomes and utilities were obtained from published studies, while healthcare costs were estimated from Hamad Medical Corporation, Qatar. The short-term outcome included the incremental cost-effectiveness ratio (ICER), defined as cost per success (survival without grade III/IV ADRs) at 6 months. The long-term outcome was the ICER, defined as cost per quality-adjusted life year (QALY) gained, with a 3% annual discount rate. The study adopted a public healthcare perspective in Qatar. Sensitivity analyses were conducted to explore the impact of key input parameters on the robustness of the model.</p><p><strong>Results: </strong>In the short-term model, at its base case, DPYD genomic screening was dominant over SoC with a mean cost-saving of QAR84,585 (95% confidence interval [CI], 45,270-151,657). This cost saving reflects the overall economic benefits associated with the implementation of DPYD genomic screening. In the long-term model, compared to the current SoC, DPYD genetic screening would result in an ICER of QAR21,107 (95% CI -59,382-145,664) per QALY gained.</p><p><strong>Conclusion: </strong>Based on our model, implementing DPYD genetic screening to detect DPYD mutations in breast cancer patients before therapy initiation seems to be a cost-saving and cost-effective strategy in Qatar.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"151-163"},"PeriodicalIF":2.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064127","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, Tolerability, and Pharmacokinetics of a Novel Anti-obesity Agent, S-309309, in Healthy Adults with or Without Obesity.","authors":"Toru Ishibashi, Hideki Tanioka, Tatsuya Ikehara, Safwan Kezbor, Takuhiro Sonoyama","doi":"10.1007/s40261-024-01418-3","DOIUrl":"10.1007/s40261-024-01418-3","url":null,"abstract":"<p><strong>Background: </strong>Anti-obesity medications are recommended for patients who do not achieve and maintain weight loss despite lifestyle interventions. S-309309 is a novel oral inhibitor of monoacylglycerol O-acyltransferase 2 being developed as a treatment for obesity.</p><p><strong>Objective: </strong>The objective of the study was to investigate the safety, clinical pharmacology, pharmacokinetics and pharmacodynamic biomarker of S-309309.</p><p><strong>Methods: </strong>A phase I, single-center, two-part, randomized, double-blind, placebo-controlled study of S-309309 following oral administration of a single-ascending dose (part 1) and a multiple dose (part 2) in healthy adults with or without obesity was conducted. We also assessed the effect of food on the pharmacokinetics of S-309309 and the effect of S-309309 on electrocardiogram parameters, the pharmacokinetics of midazolam (a cytochrome P450 3A substrate), and the pharmacodynamic biomarker of monoacylglycerol O-acyltransferase 2 inhibition.</p><p><strong>Results: </strong>In part 1 (N = 50), a single-ascending dose of S-309309 in healthy adults demonstrated dose proportionality and comparable exposure of S-309309 between the fasted and fed states. In part 2 (N = 24), no clinically meaningful difference was observed in the pharmacokinetics of multiple doses between healthy adults with or without obesity. S-309309 did not affect the pharmacokinetics of the cytochrome P450 3A substrate. The pharmacodynamic biomarker of monoacylglycerol O-acyltransferase 2 inhibition, dicarboxylic acid (18:1), was significantly increased after S-309309 administration in healthy adults with or without obesity. Overall, S-309309 demonstrated acceptable safety and tolerability without any serious adverse events or discontinuations because of adverse events, and did not have a clinically relevant effect on the heart rate or cardiac conduction. An effect on the placebo-corrected change-from-baseline corrected QT interval, corrected for heart rate using the Fridericia method, exceeding 10 ms can be excluded.</p><p><strong>Conclusions: </strong>S-309309 was well tolerated as single-dose (up to 300 mg) and multiple-dose (50 mg once daily for 14 days) oral administration. The pharmacokinetic characteristics remained unaffected by obesity and food intake. S-309309 did not affect the pharmacokinetics of the cytochrome P450 3A substrate. Overall, S-309309 had an acceptable safety profile and favorable pharmacokinetic and pharmacodynamic characteristics.</p><p><strong>Clinical trial registration: </strong>NCT05247970, date of registration: 8 February, 2022.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"85-99"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11802679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001235","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":"The Cost-Effectiveness of CDK4/6 Inhibitors in Treating HR+/HER2- Metastatic Breast Cancer Patients in the USA: When Non-medication Expenses are Considered.","authors":"Asal Pilehvari, Wen You, Gretchen Kimmick, Fabian Camacho, Gloribel Bonilla, Roger Anderson","doi":"10.1007/s40261-024-01416-5","DOIUrl":"10.1007/s40261-024-01416-5","url":null,"abstract":"<p><strong>Background and objective: </strong>Cyclin-dependent kinase (CDK)4/6 inhibitors in combination with endocrine therapy (ET) significantly enhance progression-free survival and overall survival in patients diagnosed with HR+/HER2- metastatic breast cancer (MBC). However, they are highly expensive, and their economic impact has not been fully evaluated. This is a retrospective secondary analysis evaluating the cost effectiveness of these drugs, differentiating between medication-related and non-medication costs from a healthcare perspective.</p><p><strong>Methods: </strong>We identified 3879 patients diagnosed with MBC who received either CDK4/6i+ET (N = 2137) or ET alone (N = 1742) as first-line treatment between February 2015 and November 2021 using a USA-wide electronic health record-derived de-identified database. SEER-Medicare claims spending data were used to quantify monthly costs as a supplement to the database. Relevant costs included prescribed medications (ET and/or CDK4/6i) and overall other costs. The effectiveness was measured as progression-free duration in months. The incremental cost effectiveness ratio (ICER) analysis was conducted to examine the cost effectiveness of first-line CDK4/6i as compared with first-line ET alone.</p><p><strong>Results: </strong>For medication costs, CDK4/6i+ET (mean cost: $240,723.7; mean effect: 19.2 months of delayed progression) compared with ET alone (mean cost: $5159.7; mean effect: 16 months without progression) resulted in an ICER of $73,098 per month of delayed progression. For non-medication costs, CDK4/6i+ET (mean cost: $43,656.6) compared with ET alone (mean cost: $66,083.5) resulted in an ICER of - $7178 per month of delayed progression.</p><p><strong>Conclusion: </strong>The cost of treating HR+/HER2- MBC is driven by the cost of CDK4/6i. Using CDK4/6i+ET reduces non-medication costs compared to ET alone, but these savings are offset by high CDK4/6i medication costs. Lowering the market cost of CDK4/6i or targeting those who can benefit the most could improve the cost effectiveness of CDK4/6i from Medicare perspective.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"59-68"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964049","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":"Evaluating the Real-World Safety of Icosapent Ethyl Versus Omega-3 Polyunsaturated Fatty Acid in Nationwide US Veterans Cohort: Examining Atrial Fibrillation and Bleeding Endpoints.","authors":"Tanvi Patil, Michael Gregory, Natalie Savona, Nabil Jarmukli, Charles E Leonard","doi":"10.1007/s40261-024-01417-4","DOIUrl":"10.1007/s40261-024-01417-4","url":null,"abstract":"<p><strong>Purpose: </strong>The REDUCE-IT randomized trial demonstrated a cardiovascular benefit of icosapent ethyl (IPE) but also raised potential safety signals for atrial fibrillation (AF) and serious bleeding. We aimed to evaluate the real-world safety of IPE versus mixed omega-3 polyunsaturated fatty acid (OM-3) formulations.</p><p><strong>Methods: </strong>This retrospective active comparator new-user cohort study compared rates of new-onset AF and major bleeding (MB) among adult new users of IPE versus OM-3 in 2020-2024 US Veterans Affairs data. Daily drug exposure was determined via prescription dispensing dates. AF and MB outcomes were identified via validated algorithms based on the International Statistical Classification of Diseases and Related Health Problems, 10th revision, clinical modification. Confounding was accounted for via nearest-neighbor pairwise propensity score (PS) matching. The PS, constructed via logistic regression, was informed by expert-identified variables meeting the disjunctive cause criterion. Cox regression was used to estimate adjusted hazard ratios (aHRs), interpretable as average treatment effects for the treated.</p><p><strong>Results: </strong>Cohorts for analyses of AF and MB endpoints included 1927 and 2015 people, respectively, in each of the IPE and OM-3 exposure groups. The median age was 70 years, and the groups exhibited a predominance of white (80%) males (93%). The median follow-up time was 1.29 years per person. Baseline covariates were well balanced by treatment arm after PS matching. Incidence rates for AF were 7.29 versus 7.48 per 100 person-years among new users of IPE versus OM-3. The aHR for AF was 1.15 (95% confidence interval 0.82-1.63). Incidence rates for MB were 3.27 versus 3.35 per 100 person-years among new users of IPE versus OM-3. The aHR for MB was 1.22 (95% confidence interval 0.87-3.02).</p><p><strong>Conclusions: </strong>Our measures of association were consistent with the null, but we were unable to rule out harms from IPE (vs. OM-3) more modest than a 63% increased rate of AF and threefold increased rate of MB.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"69-84"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964047","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 Pharmacokinetics of Long-Acting Local Analgesics: CPL-01, a Novel Extended-Release Ropivacaine, Demonstrates Consistent and Predictable Exposure Compared with Liposomal Bupivacaine.","authors":"Stevie Pope, Christopher Crean, Sarah Thrasher, Hanghang Xu, P J Chen, Lee Chen, DeeDee Hu, Erol Onel","doi":"10.1007/s40261-025-01419-w","DOIUrl":"10.1007/s40261-025-01419-w","url":null,"abstract":"<p><strong>Background and objective: </strong>There is a significant medical need for improved long-acting local anesthetics to decrease postsurgical pain and reduce postoperative opioid use. While ropivacaine is considered a safer local anesthetic than bupivacaine, no long-acting ropivacaine formulation is currently marketed. Available formulations of bupivacaine show inconsistent pharmacokinetics (PK) among different surgical models, and inconsistency in PK may lead to a reluctance to use the medication owing to fear of local anesthetic systemic toxicity (LAST) or unreliable efficacy. CPL-01 is a novel extended-release formulation of ropivacaine. This analysis used existing published literature to compare the PK of CPL-01 and liposomal bupivacaine (LB) across five surgical models.</p><p><strong>Methods: </strong>Published results of LB PK were used to construct dose-normalized curves in total knee arthroscopy, hemorrhoidectomy, and bunionectomy after a 200 mg dose, which were compared with a 200 mg dose of CPL-01 in abdominoplasty, herniorrhaphy, and bunionectomy.</p><p><strong>Results: </strong>The shape of the CPL-01 systemic concentration curves was consistent across multiple surgical models; however, in LB it was not. The median time to peak concentration (T_max) of CPL-01 was 8-12 h and the median T_max of LB varied from < 1 to 36 h. CPL-01 showed tighter ranges in average peak concentration (C_max) compared with average concentration (C_avg) ratios (less \"swing\") throughout 72 h, suggesting a more predictable and consistent release over time compared with the biphasic release in LB, with two distinct T_max peaks.</p><p><strong>Conclusions: </strong>CPL-01 demonstrates a more predictable and consistent release of ropivacaine over time, in contrast to LB's erratic and biphasic release of bupivacaine. If approved, the predictability of CPL-01 PK may give physicians greater confidence in more consistent efficacy and less fear of inadvertent LAST.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"51-58"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11802670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064124","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":"Assessment of Reperfusion Efficacy of Altelyse Versus Actilyse in Patients with Acute Myocardial Infarction: A Phase 3, Randomized, Double-Blinded, Non-inferiority Clinical Trial.","authors":"Mohammad Reza Beyranvand, Mohammad Asadpour Piranfar, Masoud Solaymani-Dodaran, Nahid Mohebbi, Reyhaneh Taati, Mehdi Sheibani, Mohammadreza Shahami, Safdar Masoumi, Saeid Shahraz, Hootan Manhoobi","doi":"10.1007/s40261-025-01420-3","DOIUrl":"10.1007/s40261-025-01420-3","url":null,"abstract":"<p><strong>Background: </strong>Primary percutaneous coronary intervention (PPCI) and fibrinolytic or thrombolytic therapy are common treatments for ST-elevation myocardial infarction (STEMI). Primary percutaneous coronary intervention is more effective than thrombolytic therapy, but fibrinolytic therapy is still a preferable option for patients with limited access to healthcare. Alteplase is a tissue plasminogen activator (tPA) used to treat acute myocardial infarction, acute ischemic stroke, and pulmonary embolism.</p><p><strong>Objective: </strong>This study aims to compare the efficacy and safety of Altelyse (bio-similar Alteplase, Arena Life Science Company, Tehran, IRAN) versus the brand name Actilyse^® (Boehringer Ingelheim, GERMANY) in patients with STEMI.</p><p><strong>Methods: </strong>In this phase 3, double-blind, randomized trial, we assigned patients with STEMI to receive Altelyse or Actilyse, an intravenous bolus of 15 mg followed by an infusion of 0.75 mg/kg over 30 min (with a maximum dose of 50 mg) and continued with 0.50 mg/kg over 60 min (with a maximum dose of 35 mg). The primary endpoint was total ST-segment resolution (STR) in all leads with ST-segment elevations after 90 min of receiving fibrinolytic therapy.</p><p><strong>Results: </strong>A total of 153 STEMI patients received Actilyse (79 patients) or Altelyse (74 patients). The mean total STR in all leads with ST elevation after 90 min was - 45.89 ± 32.92% and - 37.11 ± 35.28% in the Altelyse and Actilyse groups, respectively (the mean difference [95% confidence interval]: - 8.77 [- 19.92, 2.36]; p-value for non-inferiority: 0.0004).</p><p><strong>Conclusions: </strong>Among patients with STEMI, Altelyse was non-inferior to Actilyse with respect to STR after 90 min.</p><p><strong>Trial registry: </strong>Trial Registration Number, Date: IRCT20190729044366N1, 2019-05-25.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"101-110"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051694","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":"Evaluation of NUN-004, a Novel Engineered Ephrin Antagonist, in Healthy Volunteers and Patients with Amyotrophic Lateral Sclerosis: A Phase I/Ib, Open-Label, Escalating Dose and Extended Access Study.","authors":"Michael Gerometta, Robert D Henderson, Richard Friend, Leanne T Cooper, Jing Zhao, Andrew W Boyd, Perry F Bartlett","doi":"10.1007/s40261-024-01410-x","DOIUrl":"10.1007/s40261-024-01410-x","url":null,"abstract":"<p><strong>Background: </strong>Erythropoietin-producing hepatocellular carcinoma A4 (EphA4) is implicated in the pathophysiology of amyotrophic lateral sclerosis. EphA4 fusion protein (EphA4-Fc) inhibits EphA4 function in vivo but is too short-lived for prolonged therapy. NUN-004 (mEphA4-Fc) is a modified EphA4-Fc engineered for an extended half-life.</p><p><strong>Objective: </strong>This first-in-human phase I/Ib study evaluated the safety, tolerability, pharmacokinetics, immunogenicity and efficacy of NUN-004 in healthy volunteers and patients with amyotrophic lateral sclerosis.</p><p><strong>Methods: </strong>In this open-label study, Part 1 enrolled 20 healthy volunteers in five single ascending dose cohorts (1, 3, 10, 20 and 30 mg/kg), followed by Part 2, which enrolled eight patients with amyotrophic lateral sclerosis in two multiple ascending dose cohorts (cycle 1: 15 and 30 mg/kg) who could continue into an extended access phase (cycles 2-6: 15 mg/kg) for a total of 6 months' treatment. All participants received intravenous NUN-004; multiple dosing was administered weekly in 28-day cycles. Primary endpoints included safety assessments, single-dose and multiple-dose pharmacokinetics, and anti-drug antibodies. Efficacy assessments were Amyotrophic Lateral Sclerosis Function Rating Score Revised (ALSFRS-R) and forced vital capacity.</p><p><strong>Results: </strong>NUN-004 was well tolerated, with no serious adverse events or discontinuations. NUN-004 exposure generally increased with dose. Single-dose half-life was 111.7 (± 22.8) h in healthy volunteers (n = 20) and 74.4 (± 19.4) h in patients (n = 6). Steady state was observed in patients by day 8. Steady-state half-life (cycle 1 doses 2-4) was 83.7 (± 26.6) to 101.1 (± 46.0) h. No antibody response was observed. ALSFRS-R showed a slight improvement (+0.09 points/month) to cycle 4 and a slight decline (-0.35 points/month) over the whole study. Forced vital capacity trends were consistent with ALSFRS-R.</p><p><strong>Conclusions: </strong>This study supports the safety, tolerability and extended half-life of NUN-004, and provides preliminary evidence for its ability to ameliorate disease progression in an amyotrophic lateral sclerosis cohort.</p><p><strong>Clinical trial registration: </strong>Registered on ANZCTR under identifier ACTRN12621000514808 (3 May, 2021).</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"17-28"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766822","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":"Authors' Reply to Noguchi et al. Comment on: \"Differences in the Adverse Event Profiles of Sodium-Glucose Cotransporter 2 Inhibitors Used in Patients with Diabetes and Heart Failure: An Analysis Using the Japanese Adverse Drug Event Report Database\".","authors":"Toshiaki Sakamoto, Hirotaka Miyamoto, Junya Hashizume, Hayato Akamatsu, Tomoaki Akagi, Yukinobu Kodama, Hirofumi Hamano, Yoshito Zamami, Kaname Ohyama","doi":"10.1007/s40261-024-01414-7","DOIUrl":"10.1007/s40261-024-01414-7","url":null,"abstract":"","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"47-49"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881402","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}