Clinical therapeutics最新文献

{"title":"Aspirin and Ticagrelor Versus Aspirin and Clopidogrel or Prasugrel and the Effect on Staphylococcal-associated Infections: A Real-world Study","authors":"Hani Essa MD ,&nbsp;Wern Yew Ding PhD ,&nbsp;Faraz Rana MD ,&nbsp;Sizheng Steven Zhao PhD ,&nbsp;Matthew Anson MBBS ,&nbsp;Philip Austin MRes ,&nbsp;Gema Hernández ,&nbsp;Pankaj Lal MD ,&nbsp;Gregory Y.H. Lip MD ,&nbsp;Uazman Alam PhD","doi":"10.1016/j.clinthera.2024.07.001","DOIUrl":"10.1016/j.clinthera.2024.07.001","url":null,"abstract":"<div><h3>Purpose</h3><p>Antiplatelet therapy is used for the primary and secondary prevention of thrombotic diseases such as acute coronary syndrome (ACS). These patients are more vulnerable to infections, as such, strategies are required to mitigate these risks.</p></div><div><h3>Methods</h3><p>We conducted a retrospective cohort study using TriNetX, a global federated health research network that includes both inpatient and outpatient electronic medical records from health care organizations worldwide. Patients ≥18 years old, after ACS, who were placed on aspirin and ticagrelor were compared with patients placed on aspirin and clopidogrel or prasugrel. Patients were identified using International Statistical Classification of Diseases and Related Health Problems terminology codes. After propensity score matching (1:1), a total of 239,358 patients were identified in each cohort. The primary outcomes of interest investigated were rates of (1) acute and subacute infective endocarditis, (2) sepsis of unknown origin, (3) staphylococcus arthritis, (4) cellulitis and acute lymphangitis, (5) <em>Staphylococcus aureus</em> bacteremia, and (6) staphylococcal pneumonia after initiation of treatment. Outcomes were analyzed at 1, 3, and 5 years.</p></div><div><h3>Findings</h3><p>At 5 years, a combination of aspirin and ticagrelor, compared with a combination of aspirin and clopidogrel or prasugrel, was associated with significantly reduced rates of (1) acute and subacute endocarditis (hazard ratio [HR] plus 95% CI) (HR = 0.85; 0.77–0.945; <em>P =</em> 0.030), (2) sepsis of unknown origin (HR = 0.89; 95% CI, 0.86–0.91; <em>P</em> &lt; 0.0001), (3) cellulitis and acute lymphangitis (HR = 0.89; 95% CI, 0.87–0.92; <em>P &lt;</em> 0.0001, and (4) <em>Staphylococcus aureus</em> bacteremia (HR = 0.72; 95% CI, 0.61–0.85; <em>P =</em> 0.0007). However, a combination of aspirin and clopidogrel was associated with a marinally lower risk of staphylococcal pneumonia (HR = 1.04; 95% CI, 1.01–1.062; <em>P &lt;</em> 0.0001).</p></div><div><h3>Implications</h3><p>A combination of aspirin and ticagrelor is associated with a lower rate of a variety of bacterial infections. This combination warrants further investigation in <em>in-vitro</em> studies to tease out mechanisms and through clinical randomized trials in groups who have ACS and are at high infection risk.</p></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 9","pages":"Pages 689-695"},"PeriodicalIF":3.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995475","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 of Azvudine for High-risk Outpatients with Mild-to-moderate Coronavirus Disease 2019 in China","authors":"Hui Yang MD ,&nbsp;Zhaojian Wang MPharm ,&nbsp;Chunping Wang MS ,&nbsp;Ying Zhang MPharm ,&nbsp;Sheng Han PhD ,&nbsp;Zhuoling An PhD","doi":"10.1016/j.clinthera.2024.07.009","DOIUrl":"10.1016/j.clinthera.2024.07.009","url":null,"abstract":"<div><h3>Purpose</h3><p>This study aimed to evaluate the cost-effectiveness of Azvudine for the treatment of mild-to-moderate coronavirus disease 2019 in high-risk outpatients using real-world data and relevant references.</p></div><div><h3>Methods</h3><p>In the decision-tree model, 2 cohorts were organized in a single center to compare the cost-effectiveness between the Azvudine plus symptomatic treatment group and the symptomatic treatment group. We calculated the cost and mortality rate for both groups. The incremental cost-effectiveness ratio was used to illustrate the cost-effectiveness. To assess the uncertainty of the model parameters, we conducted 1-way and probabilistic sensitivity analyses.</p></div><div><h3>Findings</h3><p>In total, there were 804 outpatients included in the model. Among these, 317 patients received Azvudine plus symptomatic treatment, whereas the remaining 487 participants were treated with symptomatic treatment alone. The costs in the Azvudine and control groups were 1055.48 yuan and 2466.97 yuan and the survival rates were 100.00% and 98.70%, respectively. After calculation, the incremental cost-effectiveness ratio was determined to be −108,817.48 yuan per person. In the section of 1-way and probabilistic sensitivity analyses, Azvudine was still proven to be cost-effective.</p></div><div><h3>Implications</h3><p>Our results support the usage of Azvudine for the treatment of high-risk outpatients with mild-to-moderate coronavirus disease 2019 from economic perspective.</p></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 9","pages":"Pages e1-e5"},"PeriodicalIF":3.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999557","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 COMT-inhibitors as Adjuvant Treatments to Levodopa in Patients with Advanced Parkinson's Disease","authors":"Nayoung Kwak MS ,&nbsp;Myung-Jun Lee MD ,&nbsp;Hye-Young Kang PhD ,&nbsp;Hankil Lee PhD","doi":"10.1016/j.clinthera.2024.06.016","DOIUrl":"10.1016/j.clinthera.2024.06.016","url":null,"abstract":"<div><h3>Purpose</h3><p>We aimed to elicit scientific evidence on the cost-effectiveness of two catechol-O-methyltransferase inhibitors (COMT-i) versus no COMT-i in patients with advanced Parkinson's disease.</p></div><div><h3>Methods</h3><p>A mixed model of the decision tree and a Markov model with three health states by OFF-time level (&lt;25%, ≥25%, and death) was constructed to compare opicapone (OPC), entacapone (ENT), and no COMT-i over a lifetime. A hypothetical cohort of 10,000 patients was created and simulated based on the characteristics of the BIPARK trial subjects.</p></div><div><h3>Findings</h3><p>Two COMT-i (OPC and ENT) were identified as a cost-effective option compared to no COMT-i. Probabilistic sensitivity analysis showed that over 90% of the simulations proved the robust cost-effectiveness of COMT-i. When the time horizon as the most influential factor decreases to a 5- and 10-year period, COMT-i can be a cost-saving option. Although ENT may be the preferred option over OPC economically because of its lower price, OPC can be acceptable if the drug price is reduced by 17%.</p></div><div><h3>Implications</h3><p>Add-on treatment with COMT-i in patients with PD receiving levodopa/carbidopa appears to be cost-saving compared with not using COMT-i. In the future, it is necessary to evaluate the economic evaluation of COMT-i based on long-term real-world evidence.</p></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 9","pages":"Pages 670-676"},"PeriodicalIF":3.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874372","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":"HARMONIZE Asia: A Phase III Randomized Study to Investigate the Efficacy and Safety of Sodium Zirconium Cyclosilicate in Patients with Hyperkalemia in China","authors":"Xinling Liang MD, PhD ,&nbsp;Wanhong Lu MD, PhD ,&nbsp;Xueqing Yu MD, PhD ,&nbsp;Hong Cheng MD ,&nbsp;Qiang He MD ,&nbsp;Qingfeng Peng MD ,&nbsp;Zhaohui Ni MD, PhD ,&nbsp;Gang Long MD, PhD ,&nbsp;Lihua Wang MD, PhD ,&nbsp;Wei Chen MD, PhD ,&nbsp;Rong Li MD ,&nbsp;June Zhao MD, PhD ,&nbsp;Yong Zhang PhD ,&nbsp;Vera Lisovskaja PhD ,&nbsp;Zhiji Tang MSc, PhD","doi":"10.1016/j.clinthera.2024.07.004","DOIUrl":"10.1016/j.clinthera.2024.07.004","url":null,"abstract":"<div><h3>Purpose</h3><p>Sodium zirconium cyclosilicate (SZC) is an oral potassium (K⁺)-lowering therapy for adults with hyperkalemia. HARMONIZE Asia (ClinicalTrials.gov identifier: NCT03528681) evaluated the efficacy and safety of SZC in Chinese patients with hyperkalemia.</p></div><div><h3>Methods</h3><p>This Phase III, randomized, double-blind, placebo-controlled study recruited patients with serum K⁺ (sK⁺) ≥5.1 mmol/L at 35 sites in China. Patients received SZC 10 g three times daily (TID) for 24 or 48 hours during an open-label initial phase (OLP). Those patients achieving normokalemia (sK⁺ 3.5–5.0 mmol/L inclusive) entered a 28-day randomized (2:2:1) treatment phase (RTP) and received SZC 5 g, SZC 10 g, or placebo once daily. The primary endpoint was mean sK⁺ during RTP Days 8 to 29. Secondary endpoints included mean change in sK⁺ during the OLP, the proportion of patients who achieved normokalemia at the end of the OLP, the proportion that maintained normokalemia during the RTP, and time to recurrence of hyperkalemia.</p></div><div><h3>Findings</h3><p>In total, 270 patients received SZC 10 g TID during the OLP; 256 (94.8%) completed the OLP. During the OLP, mean sK⁺ decreased by 1.1 mmol/L from baseline (5.9 mmol/L; <em>P</em> &lt; 0.001) and 87.4% of patients achieved normokalemia. During the RTP, SZC 5 g and 10 g reduced mean sK⁺ versus placebo in a dose-dependent manner (each <em>P</em> &lt; 0.001); least-squares means (95% confidence interval [CI]) sK⁺ were 4.9 mmol/L (4.7, 5.0), 4.4 mmol/L (4.3, 4.6), and 5.2 mmol/L (5.1, 5.4) for SZC 5 g, 10 g, and placebo, respectively. At RTP end, the proportions of patients who maintained normokalemia were 58.8% (SZC 5 g; odds ratio vs placebo, 2.5 [95% CI: 1.1, 6.1; <em>P</em> = 0.035]), 76.5% (SZC 10 g; odds ratio vs placebo, 6.3 [95% CI: 2.6, 15.3; <em>P</em> &lt; 0.001]), and 36.8% for placebo. Risk of recurrent hyperkalemia was reduced by 61.0% and 84.0% with SZC 5 g and SZC 10 g, respectively, versus placebo (each <em>P</em> &lt; 0.001). During the RTP, the incidence of adverse events was numerically higher with SZC 5 g (50.0% of patients) and 10 g (44.0%) versus placebo (36.0%); driven primarily by peripheral edema and constipation.</p></div><div><h3>Implications</h3><p>Both SZC doses demonstrated clinically relevant and statistically significant, dose-dependent efficacy in managing sK⁺ levels in Chinese patients with hyperkalemia, compared with placebo. SZC tolerability was broadly aligned with the known safety profile of SZC.</p></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 9","pages":"Pages 702-710"},"PeriodicalIF":3.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901192","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":"Pancreatitis and Pancreatic Cancer Risk Among Patients With Type 2 Diabetes Receiving Dipeptidyl Peptidase 4 Inhibitors: An Updated Meta-Analysis of Randomized Controlled Trials","authors":"Adili Tuersun MS ,&nbsp;Guanxin Hou BS ,&nbsp;Gang Cheng PhD","doi":"10.1016/j.clinthera.2024.06.015","DOIUrl":"10.1016/j.clinthera.2024.06.015","url":null,"abstract":"<div><h3>Purpose</h3><p>This meta-analysis sought to assess the relationship between dipeptidyl peptidase-4 inhibitors (DPP-4) and the risk of pancreatitis and pancreatic cancer by synthesizing data from randomized, controlled trials, in light of the conflicting findings from observational studies and previous meta-analyses.</p></div><div><h3>Methods</h3><p>Cochrane, Embase, ClinicalTrials.gov, and PubMed databases that compared the use of DPP-4 inhibitors and that reported pancreatitis and pancreatic cancer events in patients with diabetes mellitus Type 2 (T2DM) were searched using specific terms. Studies were included if they satisfied the following inclusion criteria: They were randomized trials comparing DPP-4 inhibitors use in patients with T2DM; The study's duration was longer than 24 weeks; And they reported pancreatitis and pancreatic cancer events. Stata 15 MP was used to analyze the data, and odds ratios (OR) with 95% confidence intervals (CI) were used to represent the results.</p></div><div><h3>Findings</h3><p>A total of 81,737 participants with T2DM were included in the analysis. The results showed that during a mean follow-up period of 24 to 520 weeks, The use of DPP-4 inhibitors was not associated with an increased risk of pancreatitis (Peto-OR 0.97; 95% CI: 0.74, 1.27) or pancreatic cancer (Peto-OR = 0.88; 95% CI: 0.59, 1.30).</p></div><div><h3>Implications</h3><p>Current evidence fails to validate a significant correlation between DPP-4 therapy and pancreatitis or pancreatic cancer. However, subgroup analyses showed that sitagliptin was associated with a significant reduction in pancreatitis risk compared to the control group; furthermore, when comparing different types of control medications, a significant decrease in pancreatic cancer risk was observed among DPP-4 users compared to GLP-1 users.</p></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 8","pages":"Pages 650-656"},"PeriodicalIF":3.2,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859289","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 Mesotherapy in Post-COVID Pain Syndrome: Retrospective Cohort Study of 96 Patients","authors":"","doi":"10.1016/j.clinthera.2024.05.004","DOIUrl":"10.1016/j.clinthera.2024.05.004","url":null,"abstract":"<div><h3>Purpose</h3><p>Musculoskeletal pain may occur after becoming infected with SARS-Cov2. This study was designed to evaluate the efficacy of mesotherapy in treating chronic pain following COVID-19 infection.</p></div><div><h3>Methods</h3><p><span><span>A retrospective review was conducted of the records of 96 patients with post-COVID pain syndrome. Those who were eligible for oral therapy or mesotherapy, included in the study. Patients receiving oral treatment with </span>diclofenac potassium, </span>thiocolchicoside<span><span> and cyanocobalamin<span> were included in one group (n = 46), and patients receiving intradermal mesotherapy with 2% lidocaine + cyanocobalamin were included in another group (n = 50). The results of the Visual Analogue Scale (VAS) and the Leeds Assessment of Neuropathic </span></span>Symptoms and Signs (LANSS) were individually assessed before and one week after the treatment.</span></p></div><div><h3>Findings</h3><p>The participants were 40.2 ± 11.1 years old on average. Of the participants, 35.4% (n = 34) were male and 64.6% (n = 62) were female. Before treatment, there was no statistically significant difference between the patients in terms of VAS and LANSS scores. Following the treatment, a notable positive response was observed in both groups. Nevertheless, when compared to the oral treatment group, the mesotherapy group exhibited a more pronounced enhancement in VAS and LANSS scores (<em>P</em> &lt; 0.001, <em>P</em> &lt; 0.001, respectively).</p></div><div><h3>Implications</h3><p>While both mesotherapy and oral therapy offer benefits in reducing pain and alleviating neuropathic symptoms in post-COVID pain syndrome, mesotherapy stands out as an especially effective and well-tolerated treatment method, surpassing the efficacy of the oral alternative.</p></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 8","pages":"Pages e1-e5"},"PeriodicalIF":3.2,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141442262","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":"A Phase I Dose-Escalation Study of The Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Polyethylene Glycol-Erythropoietin (PEG-EPO) in Healthy Subjects","authors":"Chaoying Hu ,&nbsp;Wanling Sun ,&nbsp;Yuanyuan Wu ,&nbsp;Junlong Huang ,&nbsp;Xiangrong Zhang ,&nbsp;Lan Zhang","doi":"10.1016/j.clinthera.2024.06.018","DOIUrl":"10.1016/j.clinthera.2024.06.018","url":null,"abstract":"<div><h3>Purpose</h3><p>This first-in-human trial aimed to investigate the pharmacokinetics and pharmacodynamics characteristics and safety and tolerability of single ascending doses of subcutaneous polyethylene glycol-erythropoietin (PEG-EPO) in healthy subjects.</p></div><div><h3>Methods</h3><p>In this phase I, randomized, double-blind, placebo-controlled, dose-escalating trial, subjects were sequentially enrolled into 7 cohorts with 12 subjects in each cohort and randomized in a 5:1 ratio to receive a single dose of 0.2, 0.4, 0.8, 1.6, 2.4, 3.6, or 4.8 µg/kg PEG-EPO or matching placebo. Safety and tolerability including dose-limiting toxicities (DLTs) were assessed. Pharmacokinetics parameters, including C_max, AUC_0-inf, <em>T</em>_max, and <em>t</em>_1/2, and pharmacodynamics parameters, including reticulocyte count and hemoglobin content, were evaluated.</p></div><div><h3>Findings</h3><p>Eighty-four subjects (median age 30.4 years and 77.4% male) were enrolled. No subjects developed DLTs. Any grade treatment-related adverse events occurred in 66.7% of the subjects, but most (92.9%) were mild. No serious adverse events and no death occurred. Forty percent of the subjects receiving PEG-EPO had iron decreased, 27.1% reported ferritin decreased, 25.7% showed unsaturated iron binding capacity increased, and 17.1% had neutrophil count decreased. <em>C</em>_max exhibited a dose-disproportionate rise from a geometric mean of 525 pg/mL with 0.2 µg/kg PEG-EPO to 23196 pg/mL with 4.8 µg/kg PEG-EPO. The mean t_1/2 ranged between 82.4 ± 21.3 h with 0.4 µg/kg PEG-EPO and 160.6 ± 65.7 h with 1.6 µg/kg PEG-EPO. AUC_0-inf displayed a largely dose-proportional rise from 226264.5 pg*h/mL with 0.2 µg/kg PEG-EPO to 5206434.0 pg*h/mL with 4.8 µg/kg PEG-EPO. The absolute reticulocyte count increased with escalating doses of PEG-EPO, with the mean maximal change from baseline between 3.2 ± 1.5*10^10/L (Q1,Q3 1.8-3.6*10^10/L) with PEG-EPO 0.2 µg/kg and 9.3 ± 4.0*10^10/L (Q1,Q3 6.2-13.5*10^10/L) with 3.6 µg/kg PEG-EPO. The mean maximal change from baseline in the mean hemoglobin content ranged between 5.9 ± 4.4 g/L (Q1,Q3 3.5,7.0) with 0.2 µg/kg PEG-EPO and 15.4 ± 8.7 g/L (Q1,Q3 10.5,20.0) with 2.4 µg/kg PEG-EPO.</p></div><div><h3>Implications</h3><p>This trial demonstrated that PEG-EPO was safe and tolerable in healthy subjects. The subcutaneous route of administration allows outpatient treatment and the pharmacokinetics characteristics of PEG-EPO support less frequent dosing regimens and effective treatment for chronic kidney disease patients with anemia.</p></div><div><h3>Trial registration</h3><p>clinicaltrials.gov identifier: NCT03657238.</p></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 8","pages":"Pages 636-643"},"PeriodicalIF":3.2,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0149291824001930/pdfft?md5=c371f70c3c8154cc0edf78c2f1a3d742&pid=1-s2.0-S0149291824001930-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141906137","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":"Physiologically Based Pharmacokinetic Model for Predicting Omadacycline Pharmacokinetics and Pharmacodynamics in Healthy and Hepatic Impairment Populations","authors":"Ailin Zhang MS ,&nbsp;Yuxuan Sun MS ,&nbsp;Meiling Zuo MS ,&nbsp;Huiyu Wei ,&nbsp;Jingtao Chen ,&nbsp;Mingfeng Zhao MD ,&nbsp;Wenjie Yang MM ,&nbsp;Liqin Zhu PhD","doi":"10.1016/j.clinthera.2024.06.014","DOIUrl":"10.1016/j.clinthera.2024.06.014","url":null,"abstract":"<div><h3>Purpose</h3><p>Omadacycline is a new broad-spectrum aminomethylcycline antibiotic. However, there have been limited pharmacokinetic and pharmacodynamic (PK/PD) studies of omadacycline in patients with hepatic impairment. The aim of this study was to explore the PK/PD of omadacycline intravenous administration in healthy and hepatically impaired populations.</p></div><div><h3>Methods</h3><p>A physiologically based pharmacokinetic (PBPK) model of omadacycline was developed and validated based on published demographic data and the physiochemical properties of omadacycline. The PK processes in healthy adults were simulated and then extrapolated to a hepatically impaired population. Monte Carlo simulations were performed for PD evaluation by calculating the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of the approved dosages.</p></div><div><h3>Findings</h3><p>In the hepatically impaired population, there was no significant difference in the maximum concentration (C_max) compared with the healthy population, while the area under the plasma concentration-time curve from the first data point extrapolated to infinity (AUC_inf) showed a slight increase. Monte Carlo simulations indicated that the dosage of 200 mg once daily or 100 mg twice daily intravenously (loading dose) and 100 mg once daily intravenously (maintenance dose) could cover the common pathogens of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) : <em>Streptococcus pneumoniae, Haemophilus influenzae</em>, and <em>Staphylococcus aureus</em>.</p></div><div><h3>Implications</h3><p>Hepatic impairment exerts little impact on the PK properties of omadacycline, and no dosage adjustments are necessary for patients with mild and moderate hepatic impairment. Current dosing regimens are predicted to produce satisfactory therapeutic effects against non–drug-resistant strains of <em>Staphylococcus aureus, Streptococcus pneumoniae</em>, and <em>Haemophilus influenzae</em> but may not produce the desired AUC/MIC ratios in patients with <em>Escherichia coli</em> or <em>Klebsiella pneumoniae</em>.</p></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 8","pages":"Pages 629-635"},"PeriodicalIF":3.2,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787520","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":"Artificial Intelligence, Drug Development and Frameworks: An Opportunity to Enhance Understanding","authors":"Paul Beninger MD, MBA","doi":"10.1016/j.clinthera.2024.07.005","DOIUrl":"10.1016/j.clinthera.2024.07.005","url":null,"abstract":"","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 8","pages":"Pages 595-596"},"PeriodicalIF":3.2,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897008","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":"Dosing Strategy of Ramosetron to Prevent Postoperative Nausea and Vomiting and Development of Prediction Models Using Data Obtained From Randomized Controlled Trials: A Comparative Study","authors":"","doi":"10.1016/j.clinthera.2024.05.003","DOIUrl":"10.1016/j.clinthera.2024.05.003","url":null,"abstract":"<div><h3>Purpose</h3><p>The study aimed to compare the postoperative nausea and vomiting (PONV) preventive effect of repeated administration of ramosetron with the standard treatment group and compare models to predict the incidence of PONV using machine-learning techniques.</p></div><div><h3>Methods</h3><p>A total of 261 patients scheduled for breast surgery were analyzed to evaluate the effectiveness of repeated intravenous administration of ramosetron. All patients were administered 0.3 mg ramosetron just before the end of surgery. For the repeated dose of ramosetron group, an additional dose of 0.3 mg was administered at 4, 22, and 46 hours after the end of the surgery. Postoperative nausea, vomiting, and retching were evaluated using the Rhodes Index of Nausea, Vomiting, and Retching at 6, 24, and 48 hours postoperatively. Previously published randomized controlled data were combined with the data of this study to create a new dataset of 1390 patients, and machine-learning–based PONV prediction models (classification tree, random forest, extreme gradient boosting, and neural network) was constructed and compared with the Apfel model.</p></div><div><h3>Findings</h3><p>Fifty patients (38.5%) and 60 patients (45.8%) reported nausea, vomiting, or retching 48 hours postoperatively in the standard and repeated-dose groups, respectively (<em>P</em> = 0.317, χ² test). Median sensitivity, specificity, and accuracy of the Apfel model analyzed using the training set were 0.815, 0.344, and 0.495, respectively.</p></div><div><h3>Implications</h3><p>The repeated administration of ramosetron did not reduce the incidence of PONV. The Apfel model had high sensitivity, however, its specificity and accuracy were lower than that in machine-learning–based models.</p></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 8","pages":"Pages 604-611"},"PeriodicalIF":3.2,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0149291824001103/pdfft?md5=b90fe5cbe43e9777f73668b323ff3911&pid=1-s2.0-S0149291824001103-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426544","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}