Clinical Drug Investigation最新文献

{"title":"Efficacy and Safety of Ustekinumab Biosimilars in the Treatment of Moderate-to-Severe Plaque Psoriasis: A Systematic Review and Meta-analysis.","authors":"Mohsin Rashid, Awon Muhammad, Eeraj Saeed, Ali Akram Qureshi, Mohammad Maheer Mubashir, Mohammad Waqas Bin Waheed, Muhammad Abdullah Yasin, Muhammad Abdullah, Ahsan Rashid, Zainab Zubair","doi":"10.1007/s40261-026-01587-3","DOIUrl":"10.1007/s40261-026-01587-3","url":null,"abstract":"<p><strong>Background and objectives: </strong>Psoriasis is a chronic, debilitating disease affecting 1-3% of the global population. Ustekinumab has been established as an effective therapy for moderate-to-severe plaque psoriasis, but its high cost limits patient access. Biosimilars offer a promising avenue to reduce costs and improve availability. Therefore, this study aimed to assess the efficacy, safety, and immunogenicity of biosimilars in comparison with ustekinumab.</p><p><strong>Methods: </strong>We comprehensively searched PubMed, Cochrane Library, Embase, and clinical trial registries from their inception through August 2025 for phase III randomized controlled trials (RCTs) that directly compared ustekinumab biosimilars with the reference product in patients with moderate-to-severe plaque psoriasis. Data on efficacy, safety, and immunogenicity were extracted. The primary outcome was the mean percent change in Psoriasis Area and Severity Index (PASI) from baseline at 12 weeks. Secondary outcomes included mean percent change in PASI from baseline at 28 and 52 weeks, mean change in Dermatology Life Quality Index (DLQI) score from baseline at 12 and 28 weeks, proportion of participants achieving a Physician's Global Assessment (PGA) score of 0 or 1 at 12 and 28 weeks, proportion of participants developing anti-drug antibodies (ADAs), and proportion of participants experiencing treatment-related adverse events (TRAEs). Risk ratios (RRs) and mean differences (MDs) were calculated using the random-effects models.</p><p><strong>Results: </strong>The meta-analysis included nine RCTs reported across ten studies (nine publications and one trial registry record). Nine RCTs (n = 4,532 total; n = 2,169 experimental; n = 2,363 control) contributed data on the primary outcome. The pooled mean difference (MD) was 0.44 (95% CI - 0.99 to 1.88, p = 0.54), indicating no statistically significant difference in PASI at 12 weeks between biosimilars and ustekinumab. Across all efficacy and safety outcomes, biosimilars demonstrated no statistically significant differences from ustekinumab except for three outcomes: the mean percent change in PASI at 28 weeks, the mean change in DLQI score at 28 weeks, and the presence of ADAs. Although the differences in PASI and DLQI at 28 weeks reached statistical significance, they were not considered clinically meaningful. For ADA development, the pooled RR was 0.68 (95% CI 0.55-0.85; p = 0.0005). However, this finding was associated with substantial heterogeneity (I<sup>2</sup> = 71%) and very low-certainty evidence, warranting cautious interpretation. Additionally, the relatively short follow-up duration (≤ 52 weeks) and industry funding of all included trials are important limitations of this review.</p><p><strong>Conclusion: </strong>Ustekinumab biosimilars demonstrated no clinically meaningful differences across the outcomes and sustained comparable efficacy across all time points. These findings suggest that ustekinumab","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"1105-1120"},"PeriodicalIF":3.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148720054","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":"Pharmacokinetics and Tolerability of Fexinidazole in Subjects with Hepatic Impairment.","authors":"Matthieu Gassiot, Jean Pierre Beaucire, Sophie Hays, Sarah Lezzar, Céline Beauchard, Eric Sultan","doi":"10.1007/s40261-026-01588-2","DOIUrl":"10.1007/s40261-026-01588-2","url":null,"abstract":"<p><strong>Background: </strong>Human African trypanosomiasis (HAT), also known as sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei species. Fexinidazole, an oral treatment for HAT, has shown efficacy in both hemo-lymphatic and meningo-encephalitic stages of the disease. After oral administration, only a small fraction of fexinidazole is eliminated unchanged via the renal route; therefore, hepatic metabolic clearance represents a significant portion of the total clearance of fexinidazole. Consequently, in patients with hepatic impairment (HI), total clearance may be decreased, potentially resulting in overexposure of fexinidazole and could lead to modification of the exposures of its two metabolites. This study aims to evaluate the effect of mild and moderate HI on the pharmacokinetics (PK) of fexinidazole and its active metabolites compared with that in participants with normal hepatic function.</p><p><strong>Methods: </strong>This Phase I, multicentric, open-label, non-randomised study included 21 participants divided into three groups: mild HI (n = 7), moderate HI (n = 7) and normal hepatic function (n = 7). Each participant received a single oral dose of 1200 mg fexinidazole under fed conditions. PK parameters, including the maximum plasma concentration (C<sub>max</sub>), area under the plasma concentration-time curve (AUC<sub>inf</sub>) and terminal half-life (t<sub>½z</sub>), of fexinidazole and its metabolites M1 (sulfoxide metabolite) and M2 (sulfone metabolite) were assessed. Safety and tolerability were evaluated through adverse events, laboratory tests and vital signs.</p><p><strong>Results: </strong>In participants with mild HI, the mean C<sub>max</sub> and AUC<sub>inf</sub> of fexinidazole, M1 and M2 were similar to or slightly higher (up to 1.40-fold; 90% confidence interval [CI]: 0.78-2.53) than those of healthy controls. In participants with moderate HI, the mean C<sub>max</sub> and AUC<sub>inf</sub> of fexinidazole and M1 were similar or slightly higher (up to 1.46-fold; 90% CI 0.86-2.48), whereas the mean C<sub>max</sub> and AUC<sub>inf</sub> of M2 were lower (0.44-fold for C<sub>max</sub> [90% CI 0.29-0.65] and 0.65-fold for AUC<sub>inf</sub> [90% CI 0.46-0.90]). The t<sub>½z</sub> of fexinidazole, M1 and M2 was longer in subjects with moderate HI (up to 1.77-fold). The unbound fraction of fexinidazole remained unchanged in both the mild- and moderate-HI groups. Six mild treatment-emergent adverse events (TEAEs) (one each in the mild- and moderate-HI groups and four in participants with normal hepatic function), not related to the study drug as per the investigator, were reported. All TEAEs had resolved by the end of the study. No serious adverse events or deaths occurred.</p><p><strong>Conclusions: </strong>A single oral dose of 1200 mg of fexinidazole showed a good safety profile and was well-tolerated in participants with mild and moderate HI and matched healthy controls. These slight PK modifi","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"1187-1195"},"PeriodicalIF":3.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148789119","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":"Effect of Hepatic Impairment on the Pharmacokinetics of Single-Dose Viloxazine Extended-Release Capsules (Qelbree^®) in Adults.","authors":"Zhao Wang, Toyin Adewole, Lilian W Adeojo, Peibing Qin, Stefan Schwabe, Azmi Nasser","doi":"10.1007/s40261-026-01580-w","DOIUrl":"10.1007/s40261-026-01580-w","url":null,"abstract":"<p><strong>Background and objectives: </strong>Viloxazine (extended-release [ER] capsules) is a nonstimulant medication approved for the treatment of pediatric (aged ≥ 6 years) and adult attention deficit hyperactivity disorder. This study assessed the effect of hepatic impairment (HI) on the pharmacokinetics, safety, and tolerability of viloxazine ER.</p><p><strong>Methods: </strong>In this open-label, multicenter study, adults (18-78 years) with mild (n = 8), moderate (n = 8), or severe (n = 8) HI (Child-Pugh classification) and a demographically matched control cohort with normal hepatic function received a single oral dose of viloxazine ER (200 or 400 mg), following a ≥ 10-h overnight fast. Blood samples were collected for 72 h post-administration and analyzed for viloxazine and its primary metabolite 5-hydroxy-viloxazine glucuronide. The potential for HI to impact pharmacokinetics was evaluated using relative bioavailability analysis of viloxazine maximum measured plasma concentration (C_max) and area under the concentration-time curve (AUC) parameters and comparison of time to C_max (T_max) and terminal elimination half-life (t_1/2). Safety and tolerability were also evaluated.</p><p><strong>Results: </strong>In adults with versus without HI (any severity), there were no significant differences in viloxazine C_max (mean ± standard deviation [SD] for mild HI, 3.1 ± 1.0 µg/mL versus 2.4 ± 0.4 µg/mL; moderate HI, 2.5 ± 0.8 µg/mL versus 2.5 ± 0.6 µg/mL; severe HI, 1.3 ± 0.4 µg/mL versus 1.5 ± 0.2 µg/mL) and AUC (from time 0 to infinity; mean ± SD for mild HI, 70.5 ± 19.3 h·µg/mL versus 56.8 ± 8.6 h·µg/mL; moderate HI, 62.8 ± 28.9 h·µg/mL versus 60.4 ± 20.5 h·µg/mL; severe HI, 42.0 ± 16.4 h·µg/mL versus 33.1 ± 9.7 h·µg/mL), and mean exposure for those with HI was within 25% of matched control values. Increased t_1/2 was observed in moderate and severe HI versus controls (mean ± SD for mild HI, 7.6 ± 3.1 h versus 6.7 ± 2.5 h; moderate HI, 9.3 ± 3.1 h versus 6.0 ± 1.7 h; severe HI, 14.2 ± 5.8 h versus 7.1 ± 2.7 h). No adverse event (AE) was reported by ≥ 2 study participants with HI. The most common AEs were headache (n = 1 mild HI, n = 2 healthy controls) and somnolence (n = 2 healthy controls).</p><p><strong>Conclusions: </strong>Mild-to-severe HI showed minimal impact on viloxazine ER exposure. The single dose of viloxazine ER was well-tolerated with no identified safety concerns.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"1121-1135"},"PeriodicalIF":3.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148590847","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":"Statin Use and Arterial Calcification in the General Population: A Longitudinal Analysis and a Negative Control Population.","authors":"Mitra Nekouei Shahraki, Jeremy A Labrecque, Fariba Ahmadizar, Bruno H Stricker, Maryam Kavousi, Daniel Bos","doi":"10.1007/s40261-026-01589-1","DOIUrl":"10.1007/s40261-026-01589-1","url":null,"abstract":"<p><strong>Background and objectives: </strong>Statins can increase arterial calcification by directly affecting the vessel wall. Insufficient evidence on long-term effects may reflect short follow-up and confounding by indication. We used long-term population-based cohort data to examine the effect of statin use, cumulative duration, and duration-response association with calcification volume across multiple key arteries. The robustness of the findings was evaluated using a negative control population.</p><p><strong>Methods: </strong>Rotterdam Study participants with computed tomography (CT)-assessed calcification volume in coronary arteries (CAC), aortic arch (AAC), and extra/intracranial carotid arteries (ECAC, ICAC) were linked to pharmacy records (n = 2,399) to identify statin prescriptions; those with repeat CT (after 13.6 years) were included as follow-up (n= 815). Associations were estimated using multivariable linear and mixed regressions with varying exposure and covariate specifications, with calcification volume as the outcome. The negative control compared associations between statin transporter function and calcification in statin users vs. never-users.</p><p><strong>Results: </strong>Cumulative duration until second CT (n = 588, mean 8 years) was statistically significantly associated with increased CAC (β = 0.02; 95% CI 0.01-0.03), AAC (0.01; 0.00-0.02), and ECAC (0.02; 0.01-0.03), but not ICAC. Effect sizes increased across quartiles of duration, reaching statistical significance in the highest quartile. In the negative control analysis, decreasing statin transporter function among statin users was generally associated with higher effect estimates for calcification volume, with statistically significant trends in CAC and ECAC; no such trend was observed in never-users.</p><p><strong>Conclusions: </strong>Prolonged statin use is associated with increased arterial calcification, most notably in CAC and ECAC, and least in ICAC, with the negative control supporting the robustness of these findings. Future studies using causal inference approaches, such as target trial emulation in large longitudinal datasets with detailed information on time-varying statin exposure and cardiovascular risk factors and longitudinal assessment of arterial calcification, are needed to strengthen causal interpretation.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"1197-1208"},"PeriodicalIF":3.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817851","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":"Healthcare Cost Patterns in CDK4/6 Inhibitor-Treated HR+/HER2- Metastatic Breast Cancer.","authors":"Munenobu Kashiwa, Kensuke Moriwaki","doi":"10.1007/s40261-026-01591-7","DOIUrl":"https://doi.org/10.1007/s40261-026-01591-7","url":null,"abstract":"<p><strong>Background and objectives: </strong>Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are standard first-line treatment for hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer, yet the cost architecture across the full treatment trajectory remains poorly characterized. This study aimed to characterize phase-specific healthcare costs using a Japanese nationwide claims database.</p><p><strong>Methods: </strong>We conducted a retrospective cohort study using the DeSC-IQVIA integrated Claims data (April 2014-May 2025). Patients with HR+/HER2- metastatic breast cancer who initiated first-line CDK4/6i were identified. Healthcare costs were decomposed into drug, non-drug inpatient, and non-drug outpatient components across eight treatment phases. Death-anchored analysis evaluated cost structure over the final 12 months of life among decedents.</p><p><strong>Results: </strong>Among 5435 patients (median age 72.3 years), active treatment phases showed drug-dominated cost structures: first-line per-patient per-month (PPPM) cost was 482,936 Japanese yen (JPY) (drug 85%-90%), second-line 361,615 JPY (81%), and extended chemotherapy 255,922 JPY (66%). A marked inversion occurred in the palliative phase (PPPM 233,824 JPY; drug 11%, inpatient 70%) and terminal phase (PPPM 412,149 JPY; drug 17%, inpatient 69%). Death-anchored analysis of 1111 decedents identified a transition 2 months before death, when inpatient costs first exceeded drug costs. Individual fixed-effects models estimated the CDK4/6i-associated cost increment at 239,815 JPY/month (p  < 0.001), corresponding to a total treatment-associated cost of 2.99 million JPY per patient.</p><p><strong>Conclusions: </strong>The cost architecture of CDK4/6i-treated metastatic breast cancer follows a predictable trajectory from drug-dominated active treatment to hospitalization-dominated end-of-life care, with a structural transition approximately 2 months before death. These findings support phase-specific healthcare resource allocation and economic modeling.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073729","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":"Symptomatic Interventions for Allergic Rhinitis Without Comorbid Asthma: A Dose-Stratified Network Meta-analysis.","authors":"Sajjad Salimi, Arezoo Hamidi, Mohammad Mahdi Babajani, Amirreza Mohammadnejad, Alireza Rezaiemanesh","doi":"10.1007/s40261-026-01597-1","DOIUrl":"https://doi.org/10.1007/s40261-026-01597-1","url":null,"abstract":"<p><strong>Background: </strong>Allergic rhinitis (AR) is a prevalent chronic condition with a substantial global burden. Although numerous therapeutic interventions exist, their comparative efficacy and safety remain unclear. The objective was to evaluate symptomatic interventions for seasonal and perennial AR without comorbid asthma via a systematic review and dose-stratified network meta-analysis (NMA).</p><p><strong>Methods: </strong>We systematically searched Web of Science, Cochrane Library, Scopus, PubMed, and Embase for randomized controlled trials. Studies evaluating immunotherapy, alternative medicine, or primarily enrolling patients with comorbid asthma were excluded. A frequentist random-effects NMA compared interventions at class and dose-specific levels. Primary outcomes were total nasal symptom score (TNSS), total ocular symptom score, quality of life, and adverse events. Treatment rankings were derived using the surface under the cumulative ranking curve (SUCRA), and the certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation for Network Meta-Analysis for the TNSS outcome. The protocol was registered in PROSPERO (CRD42024507281). Global and local inconsistencies were evaluated.</p><p><strong>Results: </strong>From 36,669 records, 175 randomized controlled trials (RCTs) encompassing over 90,000 participants were included. In the network meta-analysis, treatment rankings varied across outcomes, and no single regimen consistently outperformed others; the observed heterogeneity and significant inconsistency in several networks precluded firm conclusions regarding comparative effectiveness. Intra-class differences in effect sizes were observed across several drug classes. Certain higher-dose intranasal corticosteroid monotherapies appeared among the top-ranked interventions in SUCRA analyses. Still, these rankings should be interpreted cautiously given the substantial heterogeneity and inconsistency in some networks. The certainty of evidence for the TNSS outcome was moderate to very low in most comparisons.</p><p><strong>Discussion: </strong>Despite sensitivity analyses, significant statistical incoherence persisted in several comparisons, particularly for TNSS in seasonal AR. The analysis was limited to patients without comorbid asthma. Overall, no universally superior regimen could be identified. Given the remaining heterogeneity and inconsistency, the findings should be regarded as exploratory and hypothesis-generating rather than as definitive evidence of comparative effectiveness. These findings raise the possibility that treatment selection may benefit from an individualized approach, although confirmatory studies are needed.</p><p><strong>Registration: </strong>PROSPERO CRD42024507281.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149007801","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":"Real-World Treatment Patterns, Healthcare Resource Use, and Costs in Patients with Follicular Lymphoma, Waldenström Macroglobulinemia, and Marginal Zone Lymphoma: A Claims-Based Study in the USA.","authors":"Mahek Garg, Ambika Satija, Yan Song, Benjamin Meade, James Signorovitch, Shravanthi Gandra","doi":"10.1007/s40261-026-01592-6","DOIUrl":"https://doi.org/10.1007/s40261-026-01592-6","url":null,"abstract":"<p><strong>Background and objectives: </strong>Indolent non-Hodgkin's lymphomas (NHL) are associated with relapses necessitating recurrent treatment and lifelong care. However, contemporary real-world evidence of the disease burden among patients with indolent NHLs remains limited. This study describes treatment patterns, healthcare resource use (HRU), and costs among patients with follicular lymphoma (FL), Waldenström macroglobulinemia (WM), and marginal zone lymphoma (MZL) in the USA.</p><p><strong>Methods: </strong>Adults with newly diagnosed FL, WM, and MZL were identified in claims data (October 2015-June 2021). The study period spanned from the index date (first observed diagnosis code) until end of continuous enrollment or data availability. Treatment patterns were described during the study period by lines of therapy (LOTs). HRU and costs per-patient-per-month (PPPM) were described overall and by LOTs.</p><p><strong>Results: </strong>This study included 2805 patients with FL, 791 with WM, and 2207 with MZL with a median follow-up of > 20 months each. Bendamustine-based therapies and rituximab monotherapy were most common. In later lines, bendamustine-based therapies declined while rituximab monotherapy and ibrutinib-based therapies increased. Mean all-cause total costs were US $12,402, US $8445, and US $9580 PPPM for patients with FL, WM, and MZL, respectively. Disease-related medical costs constituted > 50% of all-cause total costs, with most hospitalization costs being disease-related. In FL, HRU and costs tended to increase by LOT, driven by FL-related hospitalizations. Trends in HRU and costs across LOTs were less clear for WM and MZL.</p><p><strong>Conclusions: </strong>Our study suggests that indolent NHLs are associated with a significant economic burden that tends to increase across LOTs in FL, highlighting the need for better therapeutic options.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149007820","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":"Dose-Dependent Association of Long-Term Metformin Use and Diabetic Nephropathy Risk in Patients with Type 2 Diabetes Mellitus: A Nationwide Population-Based Study in Taiwan.","authors":"Kuang-Hua Huang, Shuo-Yan Gau, Yu-Chia Chang, Zong-Han Lin, Tung-Han Tsai, Ya-Lan Chang, Chien-Ying Lee","doi":"10.1007/s40261-026-01594-4","DOIUrl":"https://doi.org/10.1007/s40261-026-01594-4","url":null,"abstract":"<p><strong>Background: </strong>Diabetic nephropathy (DN) is one of the most serious chronic microvascular complications of diabetes. Animal and clinical studies on the renoprotective effects of metformin have reported inconsistent results.</p><p><strong>Objective: </strong>This study investigated the relationship between long-term metformin use and DN risk in patients with type 2 diabetes mellitus (T2DM), to determine whether this relationship exhibits a dose-dependent pattern.</p><p><strong>Methods: </strong>This was a retrospective cohort study using data from a nationally representative database in Taiwan. Patients given a diagnosis of new-onset T2DM between 2002 and 2013 were divided into 2 groups: metformin and sulfonylurea treatment. We evaluated DN risk after a 5-year follow-up period. Using the Cox proportional hazard model, we estimated DN risk in correlation with the cumulative defined daily dose (cDDDs) of metformin, with adjustment for sex, age, income, urbanization level, diabetes severity, and various comorbidities.</p><p><strong>Results: </strong>In the metformin-treated group, the DN incidence rates were 7.02%, 8.09%, 9.24%, and 10.75% for metformin administered at cDDDs of < 3 0, 30 to 120, 120 to 240, and > 240, respectively. After adjustments for relevant variables, relative to sulfonylurea-treated patients, patients who received metformin at cDDDs of < 30, 30 to 120, 120 to 240, and > 240 exhibited adjusted hazard ratios (95% CIs) for DN of 1.06 (1.03-1.09), 1.24 (1.21-1.27), 1.45 (1.41-1.49), and 1.72 (1.65-1.80), respectively.</p><p><strong>Conclusions: </strong>In patients with T2DM, metformin treatment exhibited a dose-dependent relationship with an increased DN risk after 5 years of follow-up. Further large-scale prospective studies are warranted to confirm these findings and elucidate the biological mechanisms underlying this observed association.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955118","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 Randomized Four-Period Cross-Over Phase I Study to Assess Bioavailability, Bioequivalence, and Tolerability of IHL-42X Compared with the Reference Drugs in Healthy Volunteers.","authors":"George Williams Mbogo, Amanda Sallama, Parisa Asvadi, Natalie May, Emir Redzepagic, Philip Ryan, Mark Robert Bleackley","doi":"10.1007/s40261-026-01595-3","DOIUrl":"https://doi.org/10.1007/s40261-026-01595-3","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objectives: &lt;/strong&gt;Obstructive sleep apnea (OSA) is a poorly diagnosed, serious, and potentially life-threatening condition that is estimated to impact the lives of up to a billion patients globally. Untreated OSA poses multiple, varied, and serious health risks involving cardiovascular, hepatic, metabolic, endocrine, neurological, and mental health indications. Effective management of OSA currently relies on device-based positive airway pressure (PAP), but poor adherence significantly affects clinical management and long-term use. The preliminary proof-of-concept study demonstrated the combination of dronabinol (DRN) and acetazolamide (ACZ) for treatment of OSA. IHL-42X is a proprietary formulation comprised of a solid, film coated ACZ tablet contained within a DRN-sesame oil solution gel cap. Each IHL-42X gel cap contained 5 mg of DRN and 250 mg of ACZ. This study assessed the bioavailability, food effect, and bioequivalence of IHL-42X compared with the reference listed drugs for DRN and ACZ.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;The study was a four-period crossover study in healthy volunteers (HVs) at two sites in Australia. A total of 125 participants were recruited and assigned to one of four treatment sequences (A-B-C-D, B-D-C-A, C-A-D-B, and D-C-B-A: A = DRN 5 mg, fasted; B = ACZ 250 mg, fasted; C = IHL-42X (5 mg DRN + 250 mg ACZ), fasted; and D = IHL-42X (5 mg DRN + 250 mg ACZ), fed), with a minimum 7-day washout period between doses. Safety assessments included vital signs, electrocardiogram (ECG) parameters, and clinical laboratory parameters. Plasma concentrations of ACZ and tetrahydrocannabinol (THC) plus major metabolites of THC, carboxy-THC (COOH-THC), and hydroxy-THC (OH-THC) were conducted on blood samples taken pre-dose and post-dose at 0.08, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 16, 24, 36, and 48 were determined using liquid chromatography-tandem mass spectrometry. Analysis of variance (ANOVA) with Dunnet's adjustment was used on log-transformed PK variables with sequence, treatment, period, and participants nested within a sequence as fixed effects to determine bioequivalence. Bioequivalence (BE) for ACZ, THC, OH-THC, and COOH-THC for IHL-42X relative to reference listed drugs (RLDs) was concluded if the 90% CI around the geometric least squares (LS) mean ratio fell within the predefined limits (0.80 and 1.25) for the maximum plasma concentration (C&lt;sub&gt;max&lt;/sub&gt;), area under curve from zero to last measurable concentration (AUC&lt;sub&gt;0-last&lt;/sub&gt;), and AUC from zero extrapolated to infinity (AUC&lt;sub&gt;0-inf&lt;/sub&gt;). All adverse events (AE) terms were coded using MedDRA&lt;sup&gt;®&lt;/sup&gt; Version 26.0.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Overall IHL-42X was well tolerated in both fasted and fed states with no serious adverse events (SAEs) reported during the study. At least one treatment-emergent adverse event (TEAE) was reported in 70 (57.4%), 63 (52.1%), and 45 (37.8%) subjects in the IHL-42X, DRN, and ACZ g","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955184","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":"The Great Transatlantic Divide: The Case of Experimental Neuropharmacology.","authors":"Carlo Colosimo","doi":"10.1007/s40261-026-01593-5","DOIUrl":"https://doi.org/10.1007/s40261-026-01593-5","url":null,"abstract":"<p><p>Despite substantial agreement between the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) on new drug approval in the past decades, a few new drugs for the treatment of some of the most prevalent and severe neurological disorders, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as much rarer neurogenetic disorders, were handled differently by the two regulatory agencies. The possible reasons for the differing behaviors of the FDA and EMA are several and wide-ranging, and they will be examined in this opinion-based analysis. How patients' perceptions of the complex approaches to drug approval and commercialization may create disappointment and confusion will also be reappraised.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148911063","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}