Clinical therapeutics最新文献

{"title":"SGLT2 Inhibitors, but Not GLP-1 Receptor Agonists, Reduce Incidence of Gout in People Living With Type 2 Diabetes Across the Therapeutic Spectrum","authors":"Frank G. Preston ,&nbsp;Matthew Anson ,&nbsp;David R. Riley ,&nbsp;Gema H. Ibarburu ,&nbsp;Alexander Henney ,&nbsp;Gregory Y.H. Lip ,&nbsp;Daniel J. Cuthbertson ,&nbsp;Uazman Alam ,&nbsp;Sizheng S. Zhao","doi":"10.1016/j.clinthera.2024.06.021","DOIUrl":"10.1016/j.clinthera.2024.06.021","url":null,"abstract":"<div><h3>Purpose</h3><div>This study aimed to evaluate the relative association between sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1Ra) with the incidence of gout in patients with type 2 diabetes (T2D) using real-world data.</div></div><div><h3>Methods</h3><div>We conducted a cohort study using data from TriNetX (an international federated database). We included patients commenced on metformin or insulin, either alone or with an SGLT2i or GLP-1Ra, at least 2 years prior to date of analysis. We propensity score matched (PSM) (1:1) for 26 relevant characteristics. Time to event analysis was performed to assess the incidence of gout, all-cause mortality (positive control), and herpes zoster infection (negative control) at 5 years following drug initiation.</div></div><div><h3>Findings</h3><div>Prior to PSM, the cohort numbers were as follows: metformin control, 1,111,449; SGLT2i with metformin, 101,706; GLP-1Ra with metformin, 110,180, insulin control, 1,398,066; SGLT2i with insulin, 68,697; and GLP-1Ra with insulin, 99,693. SGLT2i with metformin demonstrated a statistically significant decreased incidence of gout at 5 years compared to the metformin control cohort (HR 0.75 [95% CI 0.69-0.82], <em>P &lt;</em> 0<em>.</em>0001). Similarly, SGLT2i with insulin demonstrated a statistically significant decreased incidence of gout at 5 years compared to the insulin control cohort (HR 0.83 [95% CI 0.74–0.92], <em>P</em> &lt; 0.0001). Conversely, no significant disparity in gout incidence was observed between the use of GLP-1Ra and matched controls. Subgroup analysis showed an associated reduced incidence of gout with SGLT2i use compared to GLP-1Ra, in groups using metformin (HR 0.77 [95% CI 0.70-0.86], <em>P</em> &lt; 0.0001) or insulin (HR 0.82 [95% CI 0.73-0.91)], <em>P</em> &lt; 0.0001).</div></div><div><h3>Implications</h3><div>In this large-scale real-world study, SGLT2i use was associated with a lower incidence of gout in patients with T2D compared to both insulin and metformin controls. These findings suggest the potential of SGLT2i as a promising therapeutic option for treating gout in this population.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 11","pages":"Pages 835-840"},"PeriodicalIF":3.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Randomized Placebo-Controlled Trial of Leronlimab in Mild-To-Moderate COVID-19","authors":"Harish Seethamraju MD ,&nbsp;Otto O. Yang MD ,&nbsp;Richard Loftus MD ,&nbsp;Onyema Ogbuagu MD ,&nbsp;Daniel Sammartino MD ,&nbsp;Ali Mansour MD ,&nbsp;Jonah B. Sacha PhD ,&nbsp;Sohita Ojha PhD ,&nbsp;Scott G. Hansen PhD ,&nbsp;Arvin Cyrus Arman PhD ,&nbsp;Jacob P. Lalezari MD","doi":"10.1016/j.clinthera.2024.08.019","DOIUrl":"10.1016/j.clinthera.2024.08.019","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Purpose&lt;/h3&gt;&lt;div&gt;Early in the course of the SARS-CoV-2 pandemic it was hypothesised that host genetics played a role in the pathophysiology of COVID-19 including a suggestion that the CCR5-Δ32 mutation may be protective in SARS-CoV-2 infection. Leronlimab is an investigational CCR5-specific humanized IgG4 monoclonal antibody currently in development for HIV-1 infection. We aimed to explore the impact of leronlimab on the severity of disease symptoms among participants with mild-to-moderate COVID-19.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;The TEMPEST trial was a randomized, double-blind, placebo-controlled study in participants with mild-to-moderate COVID-19. Participants were randomly assigned in a 2:1 ratio to receive subcutaneous leronlimab (700 mg) or placebo on days 0 and 7. The primary efficacy endpoint was assessed by change in total symptom score based on fever, myalgia, dyspnea, and cough, at end of treatment (day 14).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Findings&lt;/h3&gt;&lt;div&gt;Overall, 84 participants were randomized and treated with leronlimab (n = 56) or placebo (n = 28). No difference was observed in change in total symptom score (&lt;em&gt;P&lt;/em&gt; = 0.8184) or other pre-specified secondary endpoints between treatments. However, in a &lt;em&gt;post hoc&lt;/em&gt; analysis, 50.0% of participants treated with leronlimab demonstrated improvements from baseline in National Early Warning Score 2 (NEWS2) at day 14, compared with 20·8% of participants in the placebo group (&lt;em&gt;post hoc; p&lt;/em&gt; = 0.0223). Among participants in this trial with mild-to-moderate COVID-19 adverse events rates were numerically but not statistically significantly lower in leronlimab participants (33.9%) compared with placebo participants (50.0%).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Implications&lt;/h3&gt;&lt;div&gt;At the time the TEMPEST trial was designed although CCR5 was known to be implicated in COVID-19 disease severity the exact pathophysiology of SARS-CoV-2 infection was poorly understood. Today it is well accepted that SARS-CoV-2 infection in asymptomatic-to-mild cases is primarily characterized by viral replication, with a heightened immune response, accompanied by diminished viral replication in moderate-to-severe disease and a peak in inflammatory responses with excessive production of pro-inflammatory cytokines in critical disease. It is therefore perhaps not surprising that no differences between treatments were observed in the primary endpoint or in pre-specified secondary endpoints among participants with mild-to-moderate COVID-19. However, the results of the exploratory &lt;em&gt;post hoc&lt;/em&gt; analysis showing that participants in the leronlimab group had greater improvement in NEWS2 assessment compared to placebo provided a suggestion that leronlimab may be associated with a lower likelihood of people with mild-to-moderate COVID-19 progressing to more severe disease and needs to be confirmed in other appropriately designed clinical trials.&lt;/div&gt;&lt;div&gt;ClinicalTrials.gov number, NCT04343651 &lt;span&gt;&lt;span&gt;https://classi","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 11","pages":"Pages 891-899"},"PeriodicalIF":3.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extraglycemic Effects of SGLT2i/GLP1-ra: A Topic Update","authors":"Uazman Alam BSc, MPHe, FRCP, PhD","doi":"10.1016/j.clinthera.2024.10.005","DOIUrl":"10.1016/j.clinthera.2024.10.005","url":null,"abstract":"","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 11","pages":"Pages 826-827"},"PeriodicalIF":3.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Budget Impact Analysis of Dapagliflozin in Treating Patients With Heart Failure With Reduced Ejection Fraction From the Perspective of Malaysian Public Healthcare System","authors":"Yi Jing Tan MPharm, MSc ,&nbsp;Joo Zheng Low MSc ,&nbsp;Siew Chin Ong PhD","doi":"10.1016/j.clinthera.2024.08.008","DOIUrl":"10.1016/j.clinthera.2024.08.008","url":null,"abstract":"<div><h3>Purpose</h3><div>This is a budget impact analysis that compared the scenario of treating heart failure with reduced ejection fraction (HFrEF) using dapagliflozin plus standard of care (SoC) versus a scenario without dapagliflozin, from the perspective of Ministry of Health (MOH) Malaysia over a 5-year time horizon.</div></div><div><h3>Methods</h3><div>A Microsoft Excel-based cost calculator was developed for such comparison. The estimated size of eligible population, uptake rates for dapagliflozin, as well as costs related to drugs, clinical events, and adverse events were based on published data, official tariffs, and databases, and expert opinion. Clinical data from the DAPA-HF trial were used to inform efficacy and safety inputs (i.e., hospitalization for heart failure (hHF), cardiovascular death, and adverse events). Results were reported as total annual and cumulative costs (in 2023 Malaysian Ringgits [RM], United States Dollars [USD], and European Union Euros, [EUR]; with exchange rates of 1 USD = RM 4.40 and 1 EUR = RM 4.90]), as well as the number of clinical events. Sensitivity and scenario analyses were also conducted.</div></div><div><h3>Findings</h3><div>The base-case analysis estimated that over a five-year period, the adoption of dapagliflozin for HFrEF treatment would result in a cumulative cost-saving of RM 2.6 million (USD 0.6 million/EUR 0.5 million), representing a 0.3% reduction in costs, driven primarily by reduced expenditure on hHF. Moreover, dapagliflozin treatment would lead to 731 fewer hHF and 366 fewer cardiovascular deaths. Sensitivity and scenario analyses revealed that the results were most sensitive to assumptions regarding loop diuretic requirements and the cost of dapagliflozin. Although cost savings or a net-zero balance were projected for the first four years, an anticipated 2.5% annual increase in dapagliflozin uptake in the longer term would lead to additional costs for the MOH, starting from the fifth year.</div></div><div><h3>Implications</h3><div>Incorporating dapagliflozin into the SoC can improve health outcomes for HFrEF patients and may generate cost savings, potentially easing the economic strain of HFrEF management on Malaysia's public healthcare system in the short term. Nonetheless, a modest increase in budget should be anticipated as more patients gain access to the treatment over time.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 11","pages":"Pages e1-e9"},"PeriodicalIF":3.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Update on an Anti-Alzheimer Drug Candidate CT1812: A Sigma-2 Receptor Antagonist","authors":"Guramrit Kaur B.Pharm,&nbsp;Zahid Ahmad Dar M.Pharm,&nbsp;Ankit Bajpai M.Pharm,&nbsp;Ranjit Singh PhD,&nbsp;Ranju Bansal PhD","doi":"10.1016/j.clinthera.2024.08.013","DOIUrl":"10.1016/j.clinthera.2024.08.013","url":null,"abstract":"<div><h3>Purpose</h3><div>This review article summarizes the progress and latest findings related to the investigational drug candidate CT1812, which is currently in phase 2 clinical trials for Alzheimer's disease (AD). The article outlines the development of this promising molecule and provides insights into its mechanism of action as sigma-2 receptor (S2R) antagonist along with the positive outcomes of various clinical trials. Literature mentioning AD therapeutics that specifically target amyloid-beta (Aβ) oligomers is limited even though these oligomers are established as the most neurotoxic forms of the Aβ protein. This timely article highlights the potential of CT1812 as a breakthrough in AD therapeutics, providing a new avenue for addressing the neurotoxic forms of Aβ and advancing the field toward a potential cure for AD.</div></div><div><h3>Methods</h3><div>The literature includes articles searched from PubMed and Google Scholar along with a comprehensive discussion of all the clinical research trials undertaken for CT1812. The review includes 12 clinical trials; of the total citations identified, 10 have been used to support the results of published trials.</div></div><div><h3>Findings</h3><div>The positive outcomes in the multiple clinical trials conducted on CT1812 indicate the emergence of an effective and promising drug candidate for AD. The article mentions a gap in the literature regarding AD therapeutics specifically targeting Aβ oligomers, which reveals lack of established treatments addressing Aβ oligomers, making the novel approach of CT1812 noteworthy.</div></div><div><h3>Implications</h3><div>Clinical treatments available today provide symptomatic relief, however, any drug providing a potential cure for AD remains an unanswered question. S2Rs mediated oligomer binding in addition to synaptic toxicity suggest the potential usefulness of CT1812 in AD treatment. Efficacy and safety of CT1812 in further clinical trials could represent a significant advancement in the field, offering a potential treatment that goes beyond the symptomatic relief and aimed at addressing the core mechanisms associated with AD.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 11","pages":"Pages e21-e28"},"PeriodicalIF":3.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Intravenous Lidocaine on Postoperative Cognitive Dysfunction in Patients Undergoing General Anesthesia Surgery: A Systematic Review of a Randomized Controlled Trial.","authors":"Xian-Xue Wang, Jing Dai, Hui-Wei Deng, Qi Wang, Yun Liu, Hua-Jing Guo","doi":"10.1016/j.clinthera.2024.09.027","DOIUrl":"https://doi.org/10.1016/j.clinthera.2024.09.027","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Purpose: &lt;/strong&gt;Postoperative cognitive dysfunction (POCD) is a common neurologic complication that occurs after surgery, which prolongs the hospital stay of patients to a certain extent, increases the occurrence of complications, and even leads to the patient's death. Intravenous lidocaine can reduce perioperative inflammatory response in patients undergoing surgery, but its effect on postoperative cognitive function has not been systematically evaluated. Notably, prior findings regarding the impact of intravenous lidocaine on postoperative cognitive function have been variable. Therefore, on this basis, this study explored the effects of intravenous lidocaine on postoperative cognitive function of patients undergoing general anesthesia through a systematic review and meta-analysis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Pubmed, Cochrane Library, Embase, Medline, Wanfang Medical Database, China Biomedical Literature Database, and China Academic Journals Full-Text Database were searched from inception to February 2024 for relevant studies that investigated effect of intravenous lidocaine on POCD in patients undergoing general anesthesia surgery. Key data obtained from the referenced literature included the prevalence of POCD, scores from the Mini-Mental State Examination (MMSE), and perioperative serum concentrations of neuron-specific enolase (NSE) and central nervous specific protein (S-100β) protein, serving as biomarkers for central nervous system specificity. Meta-analysis of data was performed using RevMan5.3 software. The software Trial Sequential Analysis (version 0.9) (TSA) was used to analyze high-quality literature focusing on POCD outcome indicators to explore the reliability of the results of meta-analysis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;Twenty-five studies were included for quality evaluation and data analysis. The studies compared the effect of intravenous lidocaine on the incidence of POCD in patients undergoing surgery at different time points. Subgroup analysis was used to investigate the incidence of POCD at different time points. The results showed that intravenous lidocaine significantly reduced the incidence of POCD at 1, 3, 7, 9 days and 1 year after surgery compared with the control group (on the first day postoperatively: odds ratio (OR) = 0.48, 95% CI: 0.32-0.69, P &lt; 0.001; postoperative day 3: OR = 0.42, 95% CI: 0.25-0.72, P = 0.002; postoperative day 7: OR = 0.34, 95% CI: 0.21-0.55, P &lt; 0.001; postoperative day 9: OR = 0.32, 95% CI: 0.17-0.61, P &lt; 0.001; 1 year postoperatively: OR = 0.39, 95% CI: 0.28-0.54, P &lt; 0.001). The incidence of POCD in patients undergoing general anesthesia at postoperative day 1 with lidocaine was analyzed sequentially. The results showed that with the increase of the included sample size, the Z-curve still did not exceed the TSA boundary and did not reach the required information size. Fourteen studies compared MMSE scores before, 1, 2, 3, and 7 days after surgery between the 2 groups","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effectiveness of Remimazolam on Preventing Adverse Reactions Caused by Carboprost Tromethamine During Cesarean Section.","authors":"Jianjun Fan, Zhiguo Zhang, Jie Wang, Dianwei Han, Yongbo Zhen, Jinpei Fan, Shuai Wang, Fei Wang","doi":"10.1016/j.clinthera.2024.09.020","DOIUrl":"https://doi.org/10.1016/j.clinthera.2024.09.020","url":null,"abstract":"<p><strong>Purpose: </strong>To evaluate the effectiveness of remimazolam in preventing adverse reactions triggered by carboprost tromethamine during cesarean section procedures.</p><p><strong>Methods: </strong>A total of 200 parturients scheduled for cesarean sections at risk of postpartum hemorrhage in our hospital from October 2022 to July 2023 were included. The participants were assigned via random number table method to either a study group or a control group, resulting in 100 cases in each. All parturients received combined spinal and epidural anesthesia (CSEA) during cesarean section, followed by administration of carboprost tromethamine (250 µg) for preventing postpartum hemorrhage after childbirth. CSEA was performed with 1.8 to 2 mL of 0.5% bupivacaine and 7 to 10 mL of 2% lidocaine. The study group was given remimazolam via intravenous infusion at a rate of 0.3 mg/kg/h commencing at 1 minute prior to CSEA and concluding with a final dosage adjustment 20 minutes preceding the end of surgery, while the control group was given the same volume of saline within this time frame. Primary outcome measures were adverse reactions and sedative effects of the parturients.</p><p><strong>Findings: </strong>Nausea and vomiting were the only adverse reactions that exhibited significant differences between groups. The study group reported significantly fewer cases (32 cases) of nausea and vomiting when compared to the 48 cases observed in the control group. Moreover, the use of remimazolam appeared to alleviate the severity of nausea and vomiting, as evidenced by the significantly lower incidence of Grade III event and the higher risk of Grade I event in comparison with the control group (P < 0.05). The Apgar scores of newborns at birth and 5 minutes after birth were compared, and no statistically significant difference was found (P > 0.05). Parturients receiving remimazolam exhibited better effective sedation outcomes and were more satisfied with the treatment when compared with controls (P < 0.05). There were no significant differences in postpartum bleeding volume at 2 and 12 hours postpartum, as well as in the duration of postpartum bleeding between the two groups (P > 0.05).</p><p><strong>Implications: </strong>Intravenous administration of remimazolam effectively prevents adverse reactions induced by carboprost tromethamine during cesarean section performed under CSEA, thereby improving sedative effects.</p>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cost-effectiveness Analysis of Tumor Treating Fields Therapy Combined With Immune Checkpoint Inhibitor in Metastatic Non-small-cell Lung Cancer.","authors":"Mengwei Zhang, Ping Yue, Yuanying Feng, Yuan Gao, Chao Sun, Peng Chen","doi":"10.1016/j.clinthera.2024.09.022","DOIUrl":"https://doi.org/10.1016/j.clinthera.2024.09.022","url":null,"abstract":"<p><strong>Background: </strong>The LUNAR clinical trial revealed that incorporating Tumor Treating Fields (TTFields) therapy alongside immune checkpoint inhibitor (ICI) significantly prolonged the overall survival of patients with metastatic, platinum-resistant non-small-cell lung cancer (NSCLC). However, the cost of TTFields therapy is high and may further increase the financial burden for patients. Our research aims to evaluate the cost-effectiveness of TTFields therapy addition with ICI for metastatic NSCLC.</p><p><strong>Methods: </strong>We constructed a Markov model to evaluate the healthcare costs associated with TTFields therapy combined with ICI for the treatment of advanced NSCLC. In this model, the clinical data utilized came from the LUNAR trial, while drug costs and health state utility values were extracted from public databases and relevant scholarly publications. The major outcomes incorporated costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER).</p><p><strong>Results: </strong>Compared with ICI therapy alone, ICI combination with TTFields therapy resulted in 0.42 QALYs at the cost of $167,329, with an ICER of $398,402.38 per year. The calculated ICER surpassed the generally accepted US willingness-to-pay (WTP) threshold of 150,000 per QALY. One-way sensitivity analyses demonstrated that the utility of progression disease is the most influential factor, followed by the cost of TTFields therapy, the utility of progression-free survival, the cost of ICI, and the cost of adverse events in TTFields therapy combined with ICI. Only when the cost of TTFields therapy is reduced by approximately 80.48%, it would be cost-effective within the commonly accepted WTP threshold of $150,000/QALY.</p><p><strong>Conclusions: </strong>According to the US WTP, the combination of TTFields therapy with ICI does not currently represent a cost-effective strategy for metastatic NSCLC followed progression on platinum-resistant therapy. Considering its promising clinical outcomes for metastatic NSCLC, it is necessary to control the expenses of this therapeutic strategy in future applications.</p>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Medical Cannabis Dosing Trajectories of Patients: Evidence From Sales Data.","authors":"Alexandra F Kritikos, Myfanwy Graham, Dominic Hodgkin, Rosalie Liccardo Pacula","doi":"10.1016/j.clinthera.2024.09.004","DOIUrl":"https://doi.org/10.1016/j.clinthera.2024.09.004","url":null,"abstract":"<p><strong>Purpose: </strong>Medical cannabis use is rising with limited high-quality clinical trial data to guide dosing. This study relies on real-world, longitudinal medical cannabis purchase data to provide information on Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) dosing trends for patients with qualifying medical conditions.</p><p><strong>Methods: </strong>A retrospective study of purchases by 16,727 patients obtaining medical cannabis from dispensaries located in New York between 2016 and 2019, recorded in point-of-sale data. Group-based trajectory modeling was used to identify clusters of patients following similar progressions in dosing of THC and CBD over time. χ² tests were performed to identify which patient characteristics and qualifying medical conditions were associated with membership in each trajectory group.</p><p><strong>Findings: </strong>Six trajectory groups were identified that described different patterns in the THC and CBD doses that patients purchased over the whole time period. For THC, the majority of patients (62.6%) purchased a steady amount but at different levels: consistently low (4.1 mg) or moderate (7.4 mg). Three groups, representing 22.0% together, exhibited doses that either fluctuate or constantly increase over time (5-20 mg). A final group of patients (15.8%) exhibited constant decrease in dose from 11 to 5 mg. For CBD, the data show similar trajectories, but at the generally higher values (4-16 mg). Patients with chronic pain, neuropathy, and cancer were overrepresented in groups where higher doses of THC were purchased over time. Patients with epilepsy had a higher representation in groups with higher doses of CBD across time.</p><p><strong>Implications: </strong>Results suggest heterogeneous dosing patterns and trajectories in the use of medical cannabis by patients with different medical conditions.</p>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics, Safety, Tolerability, and Exploratory Efficacy of Upadacitinib in Children with Severe Atopic Dermatitis","authors":"Yuli Qian PhD ,&nbsp;Eliza M. Raymundo MD ,&nbsp;Shuai Hao PhD ,&nbsp;Kristina Unnebrink PhD ,&nbsp;Gweneth F. Levy MD ,&nbsp;Henrique D. Teixeira PhD ,&nbsp;Alvina D. Chu MD ,&nbsp;Zachary A. Zinn MD ,&nbsp;Amy S. Paller MD ,&nbsp;Wei Liu PhD ,&nbsp;Mohamed-Eslam F. Mohamed RPh, PhD, FCP","doi":"10.1016/j.clinthera.2024.07.003","DOIUrl":"10.1016/j.clinthera.2024.07.003","url":null,"abstract":"<div><h3>Purpose</h3><div>This study aims to characterize the pharmacokinetics, safety, tolerability, and exploratory efficacy of upadacitinib, an oral Janus kinase inhibitor approved for treating moderate to severe atopic dermatitis (AD) in adults and adolescents, in children with severe AD.</div></div><div><h3>Methods</h3><div>In an open-label, multiple-dose, Phase 1 study, pediatric patients with severe AD from two age groups (2 to &lt;6 years and 6 to &lt;12 years) received bodyweight-based dosing regimens of upadacitinib using either twice-daily immediate-release (IR) oral solution or once-daily extended-release (ER) tablets. A pharmacokinetic assessment was conducted on Day 7 of the study, which was followed by a long-term safety and exploratory efficacy evaluation for up to 108 weeks. The results reported here are based on an interim analysis when the study had completed enrollment and pharmacokinetic assessment.</div></div><div><h3>Findings</h3><div>A total of 35 patients were enrolled and received upadacitinib. The maximum upadacitinib plasma concentration was attained within a median time of 0.5 to 2 hours and 2 to 2.5 hours for the IR oral solution and ER tablet formulations, respectively. Upadacitinib functional half-life was generally shorter with IR oral solution relative to ER tablets. Upadacitinib apparent oral clearance decreased with decreasing body weight in the pediatric patients enrolled in this study. Upadacitinib was generally safe and well tolerated. The most common (≥3 patients) adverse events were upper respiratory tract infection, COVID-19 infection, headache, abdominal discomfort, vomiting, asthma, and cough. No new safety risks were identified compared to the known safety profile for upadacitinib in adults and adolescents. In the 30 patients with available exploratory efficacy data at Week 12, 36.7% achieved validated Investigator's Global Assessment scale for AD score of 0 or 1 (Validated Investigator Global Assessment for AD 0/1), and 70.0% had Eczema Area and Severity Index (EASI) improvement of at least 75% (EASI 75).</div></div><div><h3>Implications</h3><div>The characterized pharmacokinetic profiles in this study, together with the observed safety and exploratory efficacy results, support further investigation of the current upadacitinib dosing regimen in future confirmatory Phase 3 clinical trials in children with AD.</div><div>Clinical Trial Number: NCT03646604, registered 2018-08-23</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 10","pages":"Pages 733-741"},"PeriodicalIF":3.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}