Clinical Drug Investigation最新文献

{"title":"Assessment of Dose Proportionality and the Effect of Food on a Once-Daily Extended-Release Tablet Formulation of Deutetrabenazine in Healthy Participants.","authors":"Eva-Maria Sunzel, Giulia Ghibellini, Maria Gutierrez, Debra Ruffo, Shailendra Chavan, Nagnath G Birajdar, Frank Schneider, Pippa Loupe, Mark Forrest Gordon, Laura Rabinovich-Guilatt","doi":"10.1007/s40261-026-01566-8","DOIUrl":"10.1007/s40261-026-01566-8","url":null,"abstract":"<p><strong>Background and objective: </strong>Deutetrabenazine is approved as a treatment in adults for tardive dyskinesia and chorea associated with Huntington's disease. A once-daily tablet (Austedo XR^® Teva) was recently approved in addition to the twice-daily tablet (Austedo^®), and studies were conducted to evaluate dosage strength proportionality and food effect of the once-daily formulation.</p><p><strong>Methods: </strong>In a randomized cross-over study of dosage strength proportionality, healthy participants (n = 116) received single doses of the once-daily deutetrabenazine formulation and a power model was fitted to describe the relationship between dose and pharmacokinetic parameters (maximum observed plasma drug concentration [C_max], area under the plasma concentration-time curve from time 0 to 36 h [AUC_0-36h], and area under the plasma concentration-time curve from time 0 extrapolated to infinity [AUC_0-∞]). In the second cross-over study, a single 24-mg dose of the once-daily formulation was given in fasted and fed conditions to healthy participants (n = 84) and the effect of food was evaluated by constructing 90% confidence intervals of the geometric mean ratios for C_max, AUC_0-t, and AUC_0-∞. RESULTS: Dosage strength proportionality for the once-daily formulation was demonstrated for the dosage strengths 6 mg, 12 mg, and 24 mg; and across the approved dose range up to 48 mg for the pharmacokinetic parameters of all analytes (deutetrabenazine, and metabolites; deuterated alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine), individually and as a sum). In the food effect study, the C_max, AUC_0-t, and AUC_0-∞ geometric mean ratios for deutetrabenazine and deuterated metabolites all fell within the 90% confidence interval of 80-125.</p><p><strong>Conclusions: </strong>The once-daily formulation of deutetrabenazine exhibited dosage strength proportional pharmacokinetics for doses up to 48 mg and there was no observed effect of food.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"911-923"},"PeriodicalIF":3.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13356046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148283338","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":"Change in Adherence to Oral Antidiabetic Medications Before and After Prostate Cancer Diagnosis: A Group-Based Trajectory Modeling Approach.","authors":"Ahmed S Kenawy, James O Baffoe, Chanhyun Park","doi":"10.1007/s40261-026-01569-5","DOIUrl":"10.1007/s40261-026-01569-5","url":null,"abstract":"<p><strong>Background: </strong>Cancer diagnoses impact adherence to antidiabetic medications, but limited research has focused on patients with prostate cancer and type 2 diabetes (T2DM). We investigated adherence trajectories to oral antidiabetic medications one year before and after a prostate cancer diagnosis and identified risk factors.</p><p><strong>Methods: </strong>This retrospective cohort study used the 2011-2021 MarketScan Commercial and Medicare Supplemental databases. We included newly diagnosed prostate cancer patients with T2DM with continuous insurance enrollment. We applied group-based trajectory modeling with a beta distribution to evaluate adherence patterns before and after prostate cancer diagnosis. Model covariates included age, total number of medications, number of antidiabetic medications, the Charlson Comorbidity Index (CCI), cost, insurance type, and complicated diabetes from the year before diagnosis. Metastasis and cancer treatments were included in the model after diagnosis.</p><p><strong>Results: </strong>The study included 7864 patients (mean age = 74.5 ± 7.1). Three adherence trajectories were identified before diagnosis: consistently high adherence, steady decliners, and consistently low adherence. After diagnosis, a fourth trajectory revealing a moderate decline emerged. Over half (61.2%) changed adherence patterns after diagnosis. Among those with consistently high adherence before diagnosis, 57.8% transitioned to a lower adherence trajectory. In contrast, 58.5% of steady decliners and 57.6% of consistently low adherents transitioned to a higher adherence trajectory after diagnosis. Predictors of high adherence included older age, fewer antidiabetic medications, lower CCI, and complicated diabetes before diagnosis. After diagnosis, fewer antidiabetic medications and complicated diabetes remained predictive of high adherence.</p><p><strong>Conclusion: </strong>Patterns of adherence to oral antidiabetic medications undergo substantial changes after a prostate cancer diagnosis. Targeted interventions are needed to support and facilitate effective diabetes management in this population.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"897-909"},"PeriodicalIF":3.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13356077/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148216807","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":"Amyloid-Related Imaging Abnormalities in Anti-amyloid Therapy: Clinical Implications of Kinetics for Safer Use and Risk Stratification.","authors":"Ozlem Totuk","doi":"10.1007/s40261-026-01572-w","DOIUrl":"10.1007/s40261-026-01572-w","url":null,"abstract":"<p><p>Anti-amyloid monoclonal antibodies have emerged as disease-modifying therapies for Alzheimer's disease. However, their broader clinical adoption is limited by amyloid-related imaging abnormalities, a key safety concern. Traditionally viewed as an unavoidable and dose-dependent adverse effect, amyloid-related imaging abnormalities often lead to treatment interruption or the exclusion of high-risk patients from therapy. Emerging evidence now suggests that amyloid-related imaging abnormalities may instead reflect a transient modifiable cerebrovascular response, primarily influenced by the kinetics of amyloid clearance rather than the absolute magnitude of amyloid removal. Recent data from titration-based dosing strategies demonstrate that gradual amyloid mobilization can significantly reduce the incidence of amyloid-related imaging abnormalities without compromising amyloid positron emission tomography responses or downstream biomarkers. This kinetic perspective may support a more nuanced re-evaluation of patient groups previously deemed unsuitable for therapy, including APOE ε4 carriers, individuals with cerebral microbleeds, and patients on antithrombotic treatment. In this Current Opinion, we propose a pragmatic clinical framework that integrates amyloid clearance kinetics, magnetic resonance imaging-based risk stratification, and individualized protocols for treatment interruption and re-challenge. By reframing amyloid-related imaging abnormalities as a modifiable clinical decision-making challenge rather than an inherent toxicity, anti-amyloid therapies may be optimized for safer use; however, whether such approaches can enable broader and more inclusive treatment strategies remains to be established in prospective studies, particularly in high-risk populations.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"803-808"},"PeriodicalIF":3.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148223508","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":"Assessing the Impact on Health and Productivity Outcomes of Anti-PD-(L)1 Agents to Treat Early-Stage Cancers in Italy.","authors":"Andrea Marcellusi, Fabio Calabrò, Anna Maria Di Giacomo, Fabio Puglisi, Alessio Cortellini, Isobel Thornton, Yan Zhi Tan, Alessandro Catanzaro, Catarina Neves, Fabrizio Ascone, Matilde Franceschini, Mario Calandriello, Raquel Aguiar-Ibáñez, Yizhen Lai","doi":"10.1007/s40261-026-01567-7","DOIUrl":"10.1007/s40261-026-01567-7","url":null,"abstract":"<p><strong>Background: </strong>Anti-programmed cell death-(ligand) 1 (anti-PD-[L]1) agents are approved for advanced and early-stage cancers. While they may offer clinical and economic benefits in the neoadjuvant and/or adjuvant setting, their population-level impact in Italy has not been thoroughly evaluated.</p><p><strong>Objective: </strong>This study aims to estimate health and productivity outcomes of introducing anti‑PD‑(L)1 agents for neoadjuvant and/or adjuvant therapy in early‑stage cancers in Italy (melanoma Stage IIB/C, melanoma Stage III, renal cell carcinoma, triple‑negative breast cancer and resectable non‑small‑cell lung cancer) over a 10-year horizon.</p><p><strong>Methods: </strong>We developed a model synthesising outputs from five indication-specific Markov models comparing two worlds: one without anti-PD-(L)1 agents use in the neoadjuvant and/or adjuvant settings versus one with their use. Italian-specific population and incidence inputs were used, with clinical and quality-of-life data from individual trials, from a societal perspective with 3% annual discount. Outcomes included total life years (LYs), recurrence- free (RF)/event-free (EF)/disease-free (DF) LYs, quality-adjusted LYs (QALYs), number of recurrences/events, metastatic treatments, total deaths and deaths after first event/recurrence. Productivity gains were estimated using a human capital approach.</p><p><strong>Results: </strong>Between 2025 and 2034, 118,329 patients with early-stage cancer were estimated to be eligible for anti-PD-(L)1 agents in Italy. Compared with no early-stage use, neoadjuvant/adjuvant use was associated with increased total LYs (+ 20,458, + 5%), RF/EF/DF LYs (+ 60,631, + 19%), QALYs (+ 21,093, + 6%) and fewer recurrences/events (- 20,209, - 33%), metastatic treatments (- 25,220, - 38%), total deaths (- 7137, - 24%) and deaths after first event/recurrence (- 8021, - 32%). Productive years gained were 35,897 (+ 30%).</p><p><strong>Conclusions: </strong>Our study suggests that the use of anti-PD-(L)1 agents in early-stage cancers is associated with substantial health and societal gains in Italy. Expanding their use across approved indications translates trial benefits into fewer recurrences, deaths and productivity losses, informing national planning and access decision.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"869-881"},"PeriodicalIF":3.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13356081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148175511","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":"Pigmentary Changes Reported with Tyrosine Kinase Inhibitors: A Narrative Review of Mechanisms and Clinical Implications.","authors":"Mohammadsalman Parsapour, Navid Omidkhoda, Amir Hooshang Mohammadpour, Omid Arasteh","doi":"10.1007/s40261-026-01570-y","DOIUrl":"10.1007/s40261-026-01570-y","url":null,"abstract":"<p><p>Tyrosine kinase inhibitors are widely used targeted anti-cancer agents. They may induce pigmentary alterations that, although often benign, can have meaningful clinical and psychosocial implications. This study aimed to investigate pigmentation changes in the use of all tyrosine kinase inhibitors and to explain their underlying mechanisms. This narrative review is based on studies identified through searches of PubMed, Scopus, and Web of Science up to 1 September, 2025, encompassing clinical trials, case reports, original research articles, and relevant review articles on tyrosine kinase inhibitor-associated pigmentary changes. Tyrosine kinase inhibitor therapy was associated with a wide spectrum of pigmentary outcomes. Skin hypopigmentation and hair depigmentation were more frequently observed, largely attributed to direct inhibition of stem cell factor/c-Kit signaling and its downstream mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphoinositide 3-kinase/protein kinase B pathways, leading to reduced melanocyte survival and function. Conversely, hyperpigmentation, though rare and unpredictable, was reported in association with paradoxical mitogen-activated protein kinase activation, melanocortin 1 receptor reactivation, or drug-melanin-iron complex formation. Patient-specific factors, including genetic polymorphisms (c-KIT, melanocortin 1 receptor, microphthalmia-associated transcription factor), immune and cytokine milieu, ethnicity, and concomitant therapies, were identified as modifiers of clinical outcomes. Pigmentary alterations induced by tyrosine kinase inhibitors are multifactorial, patient dependent, and reflect the interplay of genetic, immunologic, environmental, and pharmacologic factors. While hypopigmentation predominates, hyperpigmentation remains an uncommon but clinically relevant phenomenon. Larger multicenter studies, functional experimental models, and pharmacogenetic investigations are needed to elucidate predictive factors, clarify molecular mechanisms, and develop preventive or therapeutic strategies. Understanding these pigmentary changes may also provide valuable insights into drug activity and pave the way toward personalized medicine.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"827-854"},"PeriodicalIF":3.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148204352","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":"Deuruxolitinib: New Approval.","authors":"Simon Fung","doi":"10.1007/s40261-026-01568-6","DOIUrl":"10.1007/s40261-026-01568-6","url":null,"abstract":"<p><p>Deuruxolitinib (LEQSELVI), a deuterated analogue of the Janus kinase (JAK) 1/2 inhibitor ruxolitinib, is being developed by Sun Pharmaceuticals Industries for the treatment of alopecia areata. In July 2024, deuruxolitinib received its first global approval for the treatment of severe alopecia areata in adults in the USA. Additionally, in March 2026, deuruxolitinib received approval in the same indication in the UK. This article summarizes the milestones in the development of deuruxolitinib leading to the approval for severe alopecia areata in adults.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"925-930"},"PeriodicalIF":3.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359588","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":"Ketamine and Evolving Neuroplasticity.","authors":"Angel Prabakar","doi":"10.1007/s40261-026-01565-9","DOIUrl":"10.1007/s40261-026-01565-9","url":null,"abstract":"<p><p>Ketamine has revolutionized the treatment of mood disorders by offering rapid antidepressant effects, particularly in individuals with treatment-resistant depression. Unlike traditional monoaminergic antidepressants, ketamine acts primarily through antagonism of the N-methyl-D-aspartate (NMDA) receptor, initiating a cascade of glutamatergic signaling that promotes synaptic plasticity, neurogenesis, and rapid symptom relief. However, while its mechanisms are increasingly understood, the temporal trajectory of these neuroplastic changes-and their behavioral correlates-remain poorly defined. This review synthesizes both preclinical and clinical evidence on the time-dependent effects of ketamine across molecular, cellular, and behavioral domains. Preclinical studies are examined to characterize rapid molecular and synaptic changes, including brain-derived neurotrophic factor (BDNF) signaling, activation of the mechanistic target of rapamycin (mTOR) pathway, and modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which collectively drive early phases of synaptic remodeling. In parallel, clinical studies are reviewed to evaluate how these biological processes correspond to changes in mood, motivation, cognition, and functional outcomes in patients, with particular emphasis on the timing of antidepressant response and durability of effects. Special attention is given to how ketamine-induced neuroplasticity unfolds over hours to days, and how this temporal progression links mechanistic findings from preclinical models with observed clinical recovery. By framing ketamine's action within a plasticity-centered model of antidepressant response, this review provides a novel perspective that integrates neuroscience and clinical psychiatry. It also identifies critical gaps in translational research and offers a roadmap for optimizing the therapeutic use of ketamine and future fast-acting antidepressants.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"855-868"},"PeriodicalIF":3.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148249620","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":"Effectiveness of Micronized Purified Flavonoid Fraction on Quality of Life in Patients with Chronic Venous Disease: A Systematic Review and Meta-analysis.","authors":"Fabricio Rodrigues Santiago, Denisa Celovska, Sarah Thomis, Vanessa Blanc-Guillemaud, Marie-Blanche Onselaer, Soumeya Serifou, Hurrem-Pelin Yaltirik, Mamuka Bokuchava","doi":"10.1007/s40261-026-01563-x","DOIUrl":"10.1007/s40261-026-01563-x","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objective: &lt;/strong&gt;Chronic venous disease (CVD) substantially impacts patients' quality of life (QoL) owing to leg symptoms such as pain, swelling, and discomfort. The aim of this meta-analysis was to evaluate the effects of micronized purified flavonoid fraction (MPFF) treatment on QoL in patients with CVD.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A systematic review conducted in December 2023 identified studies investigating the efficacy of oral MPFF treatment (1000 mg daily for at least 1 month) on QoL in patients with CVD. Eligible prospective studies included randomized controlled trials (RCTs) and non-RCTs (comparative, single-arm, and observational studies). Medline, Embase, and Cochrane databases were searched. Mean changes (MC) from baseline to the last postbaseline value in the global QoL score (0-100) were estimated using single-group random-effects meta-analysis. Secondary outcomes included all dimensions of QoL score (pain, physical, social, and psychological) and CVD symptom scores (using 10-cm visual analog scale [VAS]) and percentage of patients with complete resolution for heaviness and cramps. Risk of bias was assessed using the Cochrane tools.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In total, 10 of 317 studies were retained for the analysis. These studies conducted worldwide included 5654 patients allocated to MPFF treatment; nearly all (99.6%) were treated for at least 2 months. Mean (standard deviation [SD]) age was 45.6 (6.7) years, with mostly females (81.3%) and overweight (body mass index [BMI] of 25.9 [3.5] kg/m&lt;sup&gt;2&lt;/sup&gt;) patients. The distribution of Clinical, Etiology, Anatomy, and Pathophysiology (CEAP) classes was: 37.3% (C2), 24.0% (C3), 21.2% (C1), 14.1% (C4), and 3.2% (C0s). Two studies had low risk of bias, four had some concerns, and four had high risk. There was no strong evidence of publication bias (Egger's test P = 0.083). Patients' global QoL score significantly improved post treatment: MC of - 17.1 (95% confidence interval (CI) [- 20.0, - 14.1], I&lt;sup&gt;2&lt;/sup&gt; = 96.3%), with greater reductions observed over longer treatment durations, from - 13.0 (- 17.7, - 8.3) for 1-2 months to - 20.0 (- 24.6, - 15.5) for 6 months treatment (all P &lt; 0.001). Sensitivity analysis excluding studies with a high risk of bias showed consistent results with the main analysis. Subgroup analysis between RCTs and non-RCTs showed comparable reductions across both study designs. QoL dimensions showed improvements in pain, physical function, psychological well-being, and social engagement (all P &lt; 0.001). MPFF treatment also significantly alleviated CVD symptoms such as pain, heaviness, and discomfort, with improvements demonstrated by VAS scores (all P &lt; 0.001). A significant percentage of patients reported complete resolution of heaviness (78.7%) and cramps (95.3%), both P &lt; 0.001. Heterogeneity was high across studies (I&lt;sup&gt;2&lt;/sup&gt; &gt; 80% in most analyses).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;This meta-analysis showed ","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"809-825"},"PeriodicalIF":3.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13356061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148053058","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":"Pharmacokinetic Drug Interaction Studies of Limnetrelvir with Midazolam and Itraconazole in Healthy Participants.","authors":"Janki M Desai, Ekram Ahmed Chowdhury, Izna Ali, Christine M Lee, Jeffrey M Schmidt, Amelia Orejudos, Swarna L Yadlapalli, Shelly Gupta, Christopher Ocampo, Michael G Miller, Ahmed Hamed Salem, Nael M Mostafa","doi":"10.1007/s40261-026-01551-1","DOIUrl":"10.1007/s40261-026-01551-1","url":null,"abstract":"<p><strong>Background and objectives: </strong>Limnetrelvir is an oral inhibitor of the SARS-CoV-2 main protease (Mpro) and was developed with the aim of achieving broad-spectrum efficacy against SARS-CoV-2 and emerging variants. The aim of this work was to evaluate potential CYP3A4 drug-drug interactions (DDIs) of limnetrelvir.</p><p><strong>Methods: </strong>In two phase 1, open-label studies, limnetrelvir was evaluated for DDIs with midazolam (Study 1), a CYP3A4 substrate, and itraconazole (Study 2), a strong CYP3A4 inhibitor. Study 1 (N = 24) consisted of two parts (Studies 1A and 1B), each with two periods (Periods 1 and 2), and Study 2 (N = 12) consisted of one part with two periods. In Study 1A, 12 healthy adult participants received midazolam (1 mg) on Period 1 Day 1 and Period 2 Day 10 and limnetrelvir 400 mg once daily (QD) on Period 2 Days 1-10. In Study 1B, an additional 12 healthy adult participants received midazolam (1 mg) on Period 1 Day 1 and Period 2 Day 5 and limnetrelvir 200 mg QD on Period 2 Days 1-5. In Study 2, 12 participants received limnetrelvir (50 mg) and itraconazole (200 mg twice daily on Day 1 and QD on Days 2 to 6 in Period 2), with limnetrelvir administered as a single dose on Period 1 Day 1 and Period 2 Day 4. All study drugs were administered orally. Serial blood samples were collected and analyzed for drug concentrations. Pharmacokinetic parameters were determined with noncompartmental methods.</p><p><strong>Results: </strong>Coadministration of limnetrelvir increased the maximum concentration (C_max) and area under the concentration-time curve from time 0 to infinity (AUC_inf) of midazolam by ~ 2.4- to 2.6-fold and ~ 4.6- to 4.3-fold, respectively. The pharmacokinetics of the active metabolite, 1-OH-midazolam, demonstrated a decrease in C_max by ~ 0.66-fold at Day 5 and ~ 0.96-fold at Day 10, while overall AUC remained stable at both time points. No clinically significant differences in CYP3A4 inhibition after 5 days and 10 days of limnetrelvir administration were observed. Limnetrelvir C_max and AUC_inf increased by ~ 1.7- and ~ 3.6-fold, respectively, when coadministered with itraconazole, suggesting that limnetrelvir is a moderately sensitive substrate of CYP3A4.</p><p><strong>Conclusions: </strong>Limnetrelvir was found to be a moderate CYP3A4 inhibitor and substrate, suggesting that dosing adjustment or careful monitoring may be necessary when coadministered with medications highly metabolized by CYP3A4 or with strong CYP3A4 inhibitors to ensure safe and effective treatment.</p><p><strong>Trial registration number (trn): </strong>NCT05691699, NCT05895266. Date of registration: 01/09/2023, 05/31/2023.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"759-769"},"PeriodicalIF":3.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13332963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147940102","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":"Topical Antibiotic Monotherapy Only Provides Mild Benefit for Patients with Acne Vulgaris: A Systematic Review and Network Meta-analysis.","authors":"Meng Lyu, Wenxin Fan, Haihui Yang, Xufei Luo, Gang Wang, Guannan Zhu, Christos C Zouboulis","doi":"10.1007/s40261-026-01553-z","DOIUrl":"10.1007/s40261-026-01553-z","url":null,"abstract":"<p><strong>Background and objectives: </strong>Topical antibiotics have long been used in acne management owing to their antibacterial and anti-inflammatory properties. However, the comparative efficacy and safety profiles of antibiotic monotherapy have not been systematically synthesized. The network meta-analysis aims to determine the relative efficacy and safety of topical antibiotics for acne vulgaris.</p><p><strong>Methods: </strong>We searched MEDLINE via PubMed, Embase, Cochrane Library, Web of Science, Google Scholar, and ClinicalTrials.gov from 1 January, 2000, to 22 August, 2023, with an updated search on 21 October, 2025. Randomized controlled trials comparing topical antibiotic monotherapy with placebo or other topical antibiotics in patients with acne vulgaris were included. Efficacy outcomes include mean absolute reduction in inflammatory lesions, non-inflammatory lesions, and total lesions, and treatment success (defined as a 2-grade reduction in the Investigator's Global Assessment). The primary safety outcome was discontinuation because of adverse events.</p><p><strong>Results: </strong>This review included 32 studies comprising 34 randomized controlled trials with 22,645 patients. Compared with placebo, only dapsone 5% [- 29.8 (95% confidence interval [CI] - 55.4 to - 4.1)] and erythromycin 2% [- 24.0 (95% CI - 45.7 to - 2.1)] significantly reduced inflammatory lesion counts. For non-inflammatory lesion counts, azithromycin 2% [- 58.9 (95% CI - 85.5 to - 31.7)], erythromycin 2% [- 42.0 (95% CI - 69.8 to - 14.0)], metronidazole 2% [- 14.6 (95% CI - 20.8 to - 8.6)], and minocycline 4% [- 5.1 (95% CI - 9.2 to - 2.2)] showed a significant reduction. However, no treatment showed a significant improvement in total lesion counts compared to placebo. Regarding Investigator's Global Assessment improvement, analysis was limited to three drugs because of inconsistent reporting; results showed that clindamycin 1% [1.6 (95% CI 1.1 to 2.3)], GDC 268 lotion (clindamycin phosphate topical lotion 1%) [2.2 (95% CI 1.1 to 4.4)], and minocycline 4% [2.2 (95% CI 1.5 to 3.5)] were superior to placebo. Data on discontinuation because of adverse events showed significant heterogeneity, which needs cautious interpretation.</p><p><strong>Conclusions: </strong>Current evidence indicates that topical antibiotic monotherapies yield inconsistent efficacy and uncertain safety across different lesion types. Given the lack of robust evidence for consistent superiority over placebo and the global concern for antibiotic resistance, routine antibiotics monotherapy should be limited in the management of acne vulgaris.</p><p><strong>Clinical trial registration: </strong>PROSPERO registration number: CRD42022297060.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"691-700"},"PeriodicalIF":3.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863569","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}