Clinical Drug Investigation最新文献

{"title":"Overall Survival Benefit with Sacituzumab Govitecan in Metastatic Breast Cancer: A Post Hoc Interaction Analyses of a Randomized Controlled Trail.","authors":"Yu-Wei Qiao, Guo Yu, Guo-Fu Li","doi":"10.1007/s40261-024-01367-x","DOIUrl":"10.1007/s40261-024-01367-x","url":null,"abstract":"","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"455-457"},"PeriodicalIF":2.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247798","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":"Drug-Drug Interactions and Their Association with Adverse Health Outcomes in the Older Community-Dwelling Population: A Prospective Cohort Study.","authors":"John E Hughes, Kathleen E Bennett, Caitriona Cahir","doi":"10.1007/s40261-024-01369-9","DOIUrl":"10.1007/s40261-024-01369-9","url":null,"abstract":"<p><strong>Background: </strong>Evidence on associations between drug-drug interactions (DDIs) and health outcomes in the older community-dwelling population is limited.</p><p><strong>Objective: </strong>We estimate potentially clinically important DDI prevalence and examine the association between DDIs and (1) adverse drug events (ADEs), (2) emergency hospital attendance and (3) health-related quality of life (HRQoL) in an older community-dwelling population in Ireland.</p><p><strong>Methods: </strong>This is a prospective cohort study of community-dwelling older adults (N = 904) aged ≥ 70 years from 15 general practices in Ireland recruited in 2010 (wave-1) and followed-up over 2 years (wave-2; 2012-2013), with linked national pharmacy claims data. Individuals dispensed two or more drugs (wave-1: N = 842; wave-2: N = 763) were included. DDI prevalence at baseline, follow-up and 6 months prior to each health outcome was estimated. Multi-level regression was used to model the association between DDI-exposure and health outcomes at follow-up. DDI prevalence, adjusted incidence-rate ratios (aIRR), adjusted odds ratios (aOR), β coefficients and robust standard error (RSE) from multi-level regression analyses, and 95% confidence intervals (CIs) are reported.</p><p><strong>Results: </strong>At wave-1, n = 196 (23.3% [95% CI 20.5-26.3]), individuals were potentially exposed to ≥ 1 DDI, increasing to n = 345 (45.2% [41.7-48.9]) at wave-2. At 2-year follow-up, the median number of ADEs was 3 (interquartile range [IQR 2-5]); 229 (30.1%) had ≥ 1 emergency hospital attendance, and the mean EQ-5D was 0.74 (± 0.23). Evidence for the association between DDI-exposure and emergency hospital attendance at follow-up was lacking (aOR = 1.38 [0.42-4.53]). DDI-exposure was associated with an increasing number of ADEs (aIRR = 1.26 [1.03-1.55]), and decreasing EQ-5D utility (β = - 0.07, [-0.11 to -0.04], RSE = 0.02). Aspirin-warfarin, clarithromycin-prednisolone, amiodarone-furosemide, clarithromycin-salbutamol, rosuvastatin-warfarin, amiodarone-bisoprolol, and aspirin-nicorandil were common DDIs 6 months preceding these health outcomes.</p><p><strong>Conclusions: </strong>We found a two-fold increase in DDI prevalence between wave 1 and 2. DDI exposure was associated with increasing ADEs and declining HRQoL at 2-year follow-up. Common DDIs involved anticoagulants, cardiovascular and antimicrobial drugs, which should be targeted for medicine optimisation.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"439-453"},"PeriodicalIF":2.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11196341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327297","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":"Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Oral AL01211 in Healthy Chinese Volunteers.","authors":"Lei Dong, Jianxing Xiang, Michael Babcock, Yuanzhi Cheng, Yan Wang, Yuqiao Shen, Li Li, Liping Tan, Marvin Garovoy, Wei Hu, Jianhong Zheng","doi":"10.1007/s40261-024-01362-2","DOIUrl":"10.1007/s40261-024-01362-2","url":null,"abstract":"<p><strong>Background and objective: </strong>Aberrant accumulation of glycosphingolipids (GSLs) in the lysosome leads to GSL storage diseases. Glucosylceramide synthase inhibitors (GCSi) have the potential to treat several GSL storage diseases by reducing the synthesis of the disease-causing GSLs. AL01211 is a potent oral GCSi under investigation for Type 1 Gaucher disease and Fabry disease. Here, we evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of AL01211 in healthy Chinese volunteers.</p><p><strong>Methods: </strong>AL01211 was tested in a Phase 1, single-center, randomized, double-blind, placebo-controlled study with single-dose (15 and 60 mg) and multiple-dose (30 mg) arms.</p><p><strong>Results: </strong>Results of AL01211 demonstrated dose-dependent pharmacokinetics, rapid absorption (median time to maximum plasma concentration [t_max] 2.5-4 hours), relatively slow clearance rate (mean apparent total clearance from plasma [CL/F] 88.3-200 L/h) and the mean terminal half-life above 30 hours. Repeated once-daily oral administration of AL01211 for 14 days had an approximately 2-fold accumulation, reaching steady-state levels between 7 and 10 days, and led to a 73% reduction in plasma glucosylceramide (GL1) on Day 14. AL01211 was safe and well tolerated, with no identified serious adverse events.</p><p><strong>Conclusion: </strong>AL01211 showed a favorable pharmacokinetic, pharmacodynamics, safety, and tolerability profile in healthy Chinese volunteers. These data support the further clinical development of AL01211 as a therapy for GSL storage diseases.</p><p><strong>Clinical trial registry: </strong>Clinical Trial Registry no. CTR20221202 ( http://www.chinadrugtrials.org.cn ) registered on 6 June 2022 and ChiCTR2200061431 ( http://www.chictr.org.cn ) registered on 24 June 2022.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"387-398"},"PeriodicalIF":2.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140854768","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":"An Early Cost-Utility Model of mRNA-Based Therapies for the Treatment of Methylmalonic and Propionic Acidemia in the United Kingdom","authors":"Pablo E. Bretos-Azcona, Matthew Wallace, Murvin Jootun, Guanyi Jin, Ion Agirrezabal, Agota Szende","doi":"10.1007/s40261-024-01363-1","DOIUrl":"https://doi.org/10.1007/s40261-024-01363-1","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background and Objective</h3><p>Novel messenger RNA (mRNA)-based therapies, currently in development, are emerging as a promising potential treatment modality for a broad range of life-threatening and life-limiting inherited liver diseases, including methylmalonic acidemia (MMA) and propionic acidemia (PA). However, owing in part to their complexity, they are likely to come at considerable financial cost to healthcare systems. The objective of this research was to synthesize available evidence on the costs and clinical consequences associated with MMA and PA for the purpose of exploratory economic evaluation of novel mRNA-based therapies using an early cost-utility model from the United Kingdom payer perspective.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>A Markov model was constructed to simulate the costs and outcomes associated with novel mRNA therapies, compared with a combination of dietary management and organ transplantation (standard of care) among hypothetical cohorts of new-born patients with MMA and PA. Key model drivers were identified, and a price threshold analysis was performed to estimate value-based price ranges for future mRNA therapies given willingness-to-pay thresholds for orphan diseases.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>mRNA therapy was associated with an additional 5.7 and 1.3 quality-adjusted life-years (QALYs) gained per patient lifetime among patients with MMA and PA, respectively. Key drivers of cost-effectiveness were relative improvement in utility among patients who receive mRNA-based therapy and transplantation, and the cost of mRNA therapy. Assuming a willingness to pay range of £100,000–£300,000 per QALY gained, the model demonstrated mRNA therapy to be cost-effective in MMA and PA at an annual treatment cost of £70,452–£94,575 and £31,313–£36,695, respectively.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>Despite the lack of a strong evidence base in MMA and PA, this model provides a useful tool to estimate the cost-effectiveness, and inform value-based pricing, of new mRNA-based therapies. Our analyses also identified areas for research that will have the greatest value in reducing uncertainty in future health economic evaluations of such treatments.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":"20 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141153173","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":"PB006: A Natalizumab Biosimilar","authors":"Matt Shirley","doi":"10.1007/s40261-024-01360-4","DOIUrl":"https://doi.org/10.1007/s40261-024-01360-4","url":null,"abstract":"<p>PB006 (Tyruko^®) is the first biosimilar of the reference monoclonal anti-α4-integrin antibody natalizumab. It is approved for use in the same indications for which reference natalizumab is approved, as a single disease-modifying therapy in adults with highly active relapsing-remitting multiple sclerosis (RRMS). PB006 has similar physicochemical and pharmacodynamic properties to those of reference natalizumab, and the pharmacokinetic similarity of the agents has been demonstrated in a study in healthy subjects. PB006 demonstrated clinical efficacy similar to that of reference natalizumab in patients with RRMS, and was generally well tolerated in this population. The tolerability, safety and immunogenicity profiles of PB006 were similar to those of reference natalizumab, and switching from reference natalizumab to PB006 appeared to have no impact on tolerability or immunogenicity. The role of reference natalizumab in the management of RRMS is well established and PB006 provides an effective biosimilar alternative for patients requiring natalizumab therapy.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":"135 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140828436","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":"Prediction Model for Severe Thrombocytopenia Induced by Gemcitabine Plus Cisplatin Combination Therapy in Patients with Urothelial Cancer","authors":"Noriaki Matsumoto, Tomohiro Mizuno, Yosuke Ando, Koki Kato, Masanori Nakanishi, Tsuyoshi Nakai, Jeannie K. Lee, Yoshitaka Kameya, Wataru Nakamura, Kiyoshi Takahara, Ryoichi Shiroki, Shigeki Yamada","doi":"10.1007/s40261-024-01361-3","DOIUrl":"https://doi.org/10.1007/s40261-024-01361-3","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Chemotherapy-induced thrombocytopenia is often a use-limiting adverse reaction to gemcitabine and cisplatin (GC) combination chemotherapy, reducing therapeutic intensity, and, in some cases, requiring platelet transfusion.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>A retrospective cohort study was conducted on patients with urothelial cancer at the initiation of GC combination therapy and the objective was to develop a prediction model for the incidence of severe thrombocytopenia using machine learning.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We performed receiver operating characteristic analysis to determine the cut-off values of the associated factors. Multivariate analyses were conducted to identify risk factors associated with the occurrence of severe thrombocytopenia. The prediction model was constructed from an ensemble model and gradient-boosted decision trees to estimate the risk of an outcome using the risk factors associated with the occurrence of severe thrombocytopenia.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Of 186 patients included in this study, 46 (25%) experienced severe thrombocytopenia induced by GC therapy. Multivariate analyses revealed that platelet count ≤ 21.4 (×10⁴/µL) [odds ratio 7.19, <i>p</i> &lt; 0.01], hemoglobin ≤ 12.1 (g/dL) [odds ratio 2.41, <i>p</i> = 0.03], lymphocyte count ≤ 1.458 (×10³/µL) [odds ratio 2.47, <i>p</i> = 0.02], and dose of gemcitabine ≥ 775.245 (mg/m²) [odds ratio 4.00, <i>p</i> &lt; 0.01] were risk factors of severe thrombocytopenia. The performance of the prediction model using these associated factors was high (area under the curve 0.76, accuracy 0.82, precision 0.68, recall 0.50, and F-measure 0.58).</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>Platelet count, hemoglobin level, lymphocyte count, and gemcitabine dose contributed to the development of a novel prediction model to identify the incidence of GC-induced severe thrombocytopenia.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":"9 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140828569","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":"Safety, Tolerability, and Pharmacokinetics of Oral BI 1358894 in Healthy Japanese Male Volunteers","authors":"Jangsoo Yoon, Vikas Sharma, Akiko Harada","doi":"10.1007/s40261-024-01357-z","DOIUrl":"https://doi.org/10.1007/s40261-024-01357-z","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background and Objectives</h3><p>BI 1358894, a novel small-molecule inhibitor of transient receptor potential canonical ion channels, is under development for treatment of major depressive disorder. Phase I trials assessing the safety and pharmacokinetics of BI 1358894 in Caucasian male healthy volunteers (HVs) have been performed. This Phase I, double-blind, placebo-controlled, parallel-group trial assessed the safety, tolerability and pharmacokinetics of BI 1358894 in Japanese male HVs.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Male HVs were randomized to receive oral BI 1358894 (<i>n</i> = 18) or placebo (<i>n</i> = 6) after a high-fat, high-calorie meal within three dose groups (50 mg, 100 mg, 200 mg), administered sequentially in dose-ascending order. The primary endpoint was number of HVs with drug-related adverse events (DRAEs). Secondary endpoints were the pharmacokinetic parameters of BI 1358894.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Overall, 24 male HVs entered the trial [mean (standard deviation) age: 30.0 (7.6) years]. DRAEs occurred in 3/18 HVs (BI 1358894 100 mg group: one HV experienced dizziness and headache; BI 1358894 200 mg group: one HV experienced headache, another reported sleep disorder). BI 1358894 exposure increased dose dependently and proportionally, peaking 4–6 h after administration before declining in a multiphasic manner with a terminal elimination half-life of ~70 h in the 50 mg and 100 mg dose groups, and 203 h in the 200 mg dose group.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>BI 1358894 was well tolerated with a favorable pharmacokinetic profile in Japanese male HVs, similar to findings from a previous study in Caucasian male HVs.</p><h3 data-test=\"abstract-sub-heading\">Trial Registration</h3><p>ClinicalTrials.gov (NCT03875001; 08-Mar-2019).</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":"19 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140804833","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":"Risk of Cardiovascular Events in Schizophrenic Patients Treated with Paliperidone Palmitate Once-Monthly Injection (PP1M): A Population-Based Retrospective Cohort Study in Taiwan","authors":"Shih-Pei Shen, Li Yan, Tao Wu, Min-Wei Huang, Kuan-Chih Huang, Hong Qiu, Yongjing Zhang, Chao-Hsiun Tang","doi":"10.1007/s40261-024-01358-y","DOIUrl":"https://doi.org/10.1007/s40261-024-01358-y","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Schizophrenia is one of the leading causes of disability. Paliperidone palmitate once-monthly injection (PP1M) was developed to provide consistent drug delivery and improve medication adherence for maintenance treatment. It is well known that patients with schizophrenia have higher cardiovascular risks, however little is known about the cardiovascular risks of patients with schizophrenia treated with PP1M in Asia.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>This study aimed to estimate the incidence of cardiovascular events after initiating PP1M treatment and evaluate the cardiovascular risk associations compared with oral second-generation antipsychotics (SGAs).</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Data from Taiwan’s National Health Insurance Research Database were used to identify a cohort of adult patients with schizophrenia who received any SGAs from 1 March 2012 to 31 December 2018. Patients who initiated PP1M treatment were enrolled for descriptive analysis of incidence rates. PP1M patients were propensity matched 1:1 to patients initiating a new oral SGA, for comparative analysis based on demographics, clinical characteristics and treatment history at baseline, in three-step matching procedures, following the prevalent new-user design to enhance comparability. Follow-up ended at the end of the treatment episode of index drug, death, last record available, or end of the study (31 December 2019). Study endpoints included serious cardiovascular events (including severe ventricular arrhythmia and sudden death), expanded serious cardiovascular events (which further included acute myocardial infarction and ischemic stroke), and cardiovascular hospitalizations. Risks of study endpoints between matched cohorts were compared using Cox regression.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Overall, 11,023 patients initiating PP1M treatment were identified (49.5% were females; mean age of 43.2 [12.2] years). Overall incidences for serious cardiovascular events, expanded serious cardiovascular events, and cardiovascular hospitalizations were 3.92, 7.88 and 51.96 per 1000 person-years, respectively. In matched cohort analysis (<i>N</i> = 10,115), the hazard ratios (HRs) between initiating PP1M and a new oral SGA for serious cardiovascular events, expanded serious cardiovascular events, and cardiovascular hospitalizations were 0.86 (95% confidence interval [CI] 0.55–1.36), 0.88 (95% CI 0.63–1.21), and 0.78 (95% CI 0.69–0.89), respectively.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>This study reported the population-based incidence of cardiovascular events in schizophrenic patients initiating PP1M treatment. PP1M was not associated with increased risks of serious cardiovascular events but was potentially associated with lower risks of cardiovascular hospitalizations compared with oral SGAs.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":"49 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140602541","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":"Pharmacokinetic Interactions Between Tegoprazan and the Combination of Clarithromycin, Amoxicillin and Bismuth in Healthy Chinese Subjects: An Open-Label, Single-Center, Multiple-Dosage, Self-Controlled, Phase I Trial","authors":"Yujing Du, Lixiu Yu, Bin Deng, Qinying Li, Junrui Hu, Linjie Li, Yusen Xu, Liangwei Song, Fang Xie, Yinghui Wang, Yuhao Chen, Chengxin Liu, Xuejia Zhai, Yongning Lu","doi":"10.1007/s40261-024-01359-x","DOIUrl":"https://doi.org/10.1007/s40261-024-01359-x","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Tegoprazan is a potassium-competitive acid blocker that inhibits gastric acid and which may be used for eradicating <i>Helicobacter pylori</i>. This study focuses on the pharmacokinetic interaction and safety between tegoprazan and the combination of clarithromycin, amoxicillin and bismuth in healthy Chinese subjects.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>An open-label, three-period, single-center, multiple-dosage, single-sequence, phase I trial was conducted in 22 healthy subjects. In period 1, the subjects took tegoprazan 50 mg twice daily for 7 days, and in period 2 they were administered clarithromycin 500 mg, amoxicillin 1000 mg and bismuth potassium citrate 600 mg twice daily for 7 days (days 14–20). Tegoprazan, clarithromycin, amoxicillin and bismuth potassium citrate were then administered in combination for 7 days (days 21–27) in period 3. Blood samples were collected up to 12 h after the last dose of each period. Safety assessments were performed in each period.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>The geometric mean ratios (GMRs) [90% confidence interval (CI)] of maximum plasma concentration at steady state (<i>C</i>_max,ss) and area under the plasma concentration–time curve over the dosing interval (AUC_τ) at steady state were 195.93% (175.52–218.71%) and 287.54% (263.28–314.04%) for tegoprazan and 423.23% (382.57–468.22%) and 385.61% (354.62–419.30%) for tegoprazan metabolite M1, respectively. The GMRs (90% CI) of <i>C</i>_max,ss and AUC_τ were 83.69% (77.44–90.45%) and 110.30% (102.74–118.41%) for clarithromycin, 126.25% (114.73–138.93%) and 146.94% (135.33–159.55%) for 14-hydroxyclarithromycin, 75.89% (69.73–82.60%) and 94.34% (87.94–101.20%) for amoxicillin, and 158.43% (125.43–200.11%) and 183.63% (156.42–215.58%) for bismuth, respectively. All reported adverse events were mild. The frequency of adverse events during the coadministration stage was not higher than that during the single- or triple-drug administration stages.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>The plasma exposure of tegoprazan, M1, 14-hydroxyclarithromycin and bismuth was increased after the coadministration of tegoprazan, clarithromycin, amoxicillin and bismuth. The coadministration exhibited favorable safety and tolerability.</p><h3 data-test=\"abstract-sub-heading\">Clinical Trials Registration</h3><p>CTR20230643.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":"93 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140581427","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":"Impact of Viloxazine Extended-Release Capsules (Qelbree®) on Select Cytochrome P450 Enzyme Activity and Evaluation of CYP2D6 Genetic Polymorphisms on Viloxazine Pharmacokinetics","authors":"Zhao Wang, Tesfaye Liranso, Zulane Maldonado-Cruz, Alisa R. Kosheleff, Azmi Nasser","doi":"10.1007/s40261-024-01356-0","DOIUrl":"https://doi.org/10.1007/s40261-024-01356-0","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background and Objective</h3><p>Viloxazine extended-release (ER) [Qelbree^®] is a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment. In vitro studies suggested potential for viloxazine to inhibit cytochrome 450 (CYP) enzymes 1A2, 2B6, 2D6 and 3A4. This clinical study therefore evaluated viloxazine ER effects on index substrates for CYP1A2, 2D6, and 3A4, and secondarily evaluated the impact of CYP2D6 polymorphisms on viloxazine pharmacokinetics.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Thirty-seven healthy subjects received a modified Cooperstown cocktail (MCC; caffeine 200 mg, dextromethorphan 30 mg, midazolam 0.025 mg/kg) on Day 1, viloxazine ER 900 mg/day on Days 3–5, and a combination of viloxazine ER 900 mg and MCC on Day 6. Viloxazine ER effects on MCC substrates were evaluated using analysis of variance. The impact of CYP2D6 genetic polymorphisms on steady-state viloxazine plasma concentrations was evaluated using Student’s <i>t</i> test assessing pharmacokinetic parameter differences between poor versus extensive metabolizers.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>The least squares geometric mean ratio [GMR%] (90% CI) of MCC substrate + viloxazine ER/MCC substrate alone for caffeine maximum concentration (<i>C</i>_max), area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC_<i>t</i>), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC_∞) was 99.11 (95.84–102.49), 436.15 (398.87–476.92), and 583.35 (262.41–1296.80), respectively; 150.76 (126.03–180.35), 185.76 (155.01–222.61), and 189.71 (160.37–224.42) for dextromethorphan <i>C</i>_max, AUC_t, and AUC_∞, respectively; and 112.81 (104.71–121.54), 167.56 (153.05–183.45), and 168.91 (154.38–184.80) for midazolam <i>C</i>_max, AUC_<i>t</i>, and AUC_∞, respectively. At steady state, viloxazine least squares GMR (90% CI) for poor/extensive CYP2D6 metabolizers were <i>C</i>_max 120.70 (102.33–142.37) and area under the plasme concentration-time curve from time 0 to 24 hours (AUC_0–24 125.66 (105.36–149.87)).</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>Viloxazine ER is a strong CYP1A2 inhibitor and a weak CYP2D6 and CYP3A4 inhibitor. CYP2D6 polymorphisms did not meaningfully alter the viloxazine ER pharmacokinetic profile.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":"38 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140581489","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}