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Economic Evaluation of Rotavirus Vaccination in Children Aged Under Five Years in South Africa. 南非五岁以下儿童接种轮状病毒疫苗的经济评估。
IF 3.2 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-11-01 Epub Date: 2023-10-13 DOI: 10.1007/s40261-023-01312-4
Ahmed Mohy, Nicola Page, Welekazi Boyce, Jorge A Gomez

Background and objective: Evidence on the economic value of rotavirus vaccines in middle-income countries is limited. We aimed to model the implementation of three vaccines (human rotavirus, live, attenuated, oral vaccine [HRV, 2 doses]; rotavirus vaccine, live, oral, pentavalent [HBRV, 3 doses] and rotavirus vaccine, live attenuated oral, freeze-dried [BRV-PV, 3 doses] presented in 1-dose and 2-dose vials) into the South African National Immunisation Programme.

Methods: Cost and cost-effectiveness analyses were conducted to compare three rotavirus vaccines using a static, deterministic, population model in children aged <5 years in South Africa from country payer and societal perspectives. Deterministic and probabilistic sensitivity analyses were conducted to assess the impact of uncertainty in model inputs.

Results: The human rotavirus, live, attenuated, oral vaccine (HRV) was associated with cost savings versus HBRV from both perspectives, and versus BRV-PV 1-dose vial from the societal perspective. In the cost-effectiveness analysis, HRV was estimated to avoid 1,107 home care rotavirus gastroenteritis (RVGE) events, 247 medical visits, 35 hospitalisations, and 4 RVGE-related deaths versus HBRV and BRV-PV. This translated to 73 quality-adjusted life years gained. HRV was associated with lower costs versus HBRV from both payer (-$3.9M) and societal (-$11.5M) perspectives and versus BRV-PV 1-dose vial from the societal perspective (-$3.8M), dominating those options. HRV was associated with higher costs versus BRV-PV 1-dose vial from the payer perspective and versus BRV-PV 2‑dose vial from both payer and societal perspectives (ICERs: $51,834, $121,171, and $16,717, respectively), exceeding the assumed cost-effectiveness threshold of 0.5 GDP per capita.

Conclusion: Vaccination with a 2-dose schedule of HRV may lead to better health outcomes for children in South Africa compared with the 3-dose schedule rotavirus vaccines.

背景和目的:关于轮状病毒疫苗在中等收入国家的经济价值的证据有限。我们旨在对南非国家免疫计划中三种疫苗(人轮状病毒活疫苗、减毒口服疫苗[HRV,2剂];轮状病毒疫苗、活疫苗、口服五价疫苗[HBRRV,3剂]和轮状病毒减毒口服活疫苗、冻干疫苗[BRV-PV,3剂)的实施进行建模。方法:成本和成本效益分析使用静态、确定性的儿童群体模型对三种轮状病毒疫苗进行了比较。结果:从两个角度来看,人类轮状病毒减毒活口服疫苗(HRV)与HBRV相比,以及从社会角度来看,与BRV-PV单剂量小瓶相比,都与成本节约有关。在成本效益分析中,与HBRV和BRV-PV相比,HRV估计可避免1107例家庭护理轮状病毒肠胃炎(RVGE)事件、247次就诊、35次住院和4例RVGE相关死亡。这意味着增加了73年的质量调整寿命。从付款人(-390万美元)和社会(-1150万美元)的角度来看,HRV与较低的HBRV成本相关,从社会角度来看,与BRV-PV 1剂量小瓶(-38万美元)相比,HRV占主导地位。从付款人的角度来看,HRV与BRV-PV 1剂量小瓶和从付款人和社会的角度来看BRV-PV 2剂量小瓶相比,成本更高(ICERs:分别为51834美元、121171美元和16717美元),超过了人均GDP 0.5的假设成本效益阈值。结论:与3剂轮状病毒疫苗相比,接种2剂计划的HRV疫苗可能会为南非儿童带来更好的健康结果。
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引用次数: 0
Efficacy and Safety of Activated Prothrombin Complex Concentrate for Reversal of the Anticoagulant Effect of Apixaban and Rivaroxaban in Patients with Major Bleeding. 活化凝血酶原复合物浓缩物逆转阿哌沙班和利伐沙班对大出血患者的抗凝作用的有效性和安全性。
IF 3.2 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-11-01 Epub Date: 2023-10-26 DOI: 10.1007/s40261-023-01316-0
Marwan Sheikh-Taha, Holly L Clark, R Monroe Crawley

Background: The use of activated prothrombin complex concentrate (aPCC) to treat direct oral anticoagulant (DOAC)-associated bleeding is off-label and clinical experience is limited.

Objectives: We aimed to assess the efficacy and safety of aPCC in reversing the anticoagulant effect of apixaban and rivaroxaban in patients presenting with major bleeding.

Methods: A retrospective cohort study of adult non-randomized patients was conducted at a tertiary referral medical center in the United States (US) to investigate the use of aPCC for the reversal of the anticoagulant effect of apixaban and rivaroxaban in patients presenting with major bleeding. The primary outcome was achieving clinical hemostasis according to prespecified criteria. Safety outcomes included the occurrence of thrombotic events during hospitalization.

Results: A total of 217 patients were included in the study. Intracranial hemorrhage (ICH) was the most common site of bleeding (n = 100, 46.1%), followed by gastrointestinal bleed (n = 87, 40.1%). Clinical hemostasis was achieved in 170 patients (78.3%), and the risk of not achieving hemostasis with ICH-related bleeding was significantly higher than that of non-ICH-related bleeding (2.5, 95% confidence interval [CI] 1.44-4.34; p < 0.001). Eight patients not achieving hemostasis died during hospitalization, all of whom were suffering from ICH, and mortality associated with non-ICH-related bleeding was significantly lower compared with ICH-related bleeding (0.91, 95% CI 0.86-0.97; p < 0.001). Thromboembolic events during hospitalization occurred in one patient (0.5%).

Conclusions: The use of aPCC for the management of apixaban- or rivaroxaban-related major bleeding is effective in most cases and is associated with a low risk of thromboembolism.

背景:使用活化凝血酶原复合物浓缩物(aPCC)治疗直接口服抗凝剂(DOAC)相关出血是不规范的,临床经验有限。目的:我们旨在评估aPCC在逆转阿哌沙班和利伐沙班对大出血患者的抗凝作用方面的有效性和安全性。方法:在美国三级转诊医疗中心对成年非随机患者进行回顾性队列研究,以研究aPCC在逆转阿哌沙班和利伐沙班对大出血患者的抗凝作用方面的作用。主要结果是根据预先指定的标准实现临床止血。安全性结果包括住院期间血栓事件的发生。结果:共有217名患者被纳入研究。颅内出血(ICH)是最常见的出血部位(n = 100,46.1%),然后是胃肠道出血(n = 87,40.1%)。170名患者(78.3%)实现了临床止血,与非ICH相关的出血相比,ICH相关出血无法止血的风险显著较高(2.5,95%置信区间[CI]1.44-4.34;p 结论:在大多数情况下,使用aPCC治疗阿哌沙班或利伐沙班相关的大出血是有效的,并且与血栓栓塞的低风险相关。
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引用次数: 0
The Safety and Efficacy of Quadruple Ultra-Low-Dose Combination (Quadpill) for Hypertension Treatment: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. 四倍超低剂量联合用药(Quadpill)治疗高血压的安全性和有效性:随机对照试验的系统评价和荟萃分析。
IF 3.2 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-11-01 Epub Date: 2023-10-30 DOI: 10.1007/s40261-023-01313-3
Mohamed Abuelazm, Shafaqat Ali, Othman Saleh, Amr Badr, Obieda Altobaishat, Majd M AlBarakat, Aya Aboutaleb, Abdelmonem Siddiq, Basel Abdelazeem

Background and objective: Quadpill, a single pill containing a quadruple combination of quarter doses of four antihypertensive agents, has been investigated for hypertension treatment. This meta-analysis aims to evaluate the safety and efficacy of quadpill for hypertension management.

Methods: We conducted a systematic review and meta-analysis synthesizing randomized controlled trials evaluating quadpill versus monotherapy or placebo in patients with hypertension, which were retrieved by systematically searching PubMed, EMBASE, Web of Science, SCOPUS, and Cochrane through 17 February, 2023. Continuous and dichotomous outcomes were pooled using mean difference (MD) and risk ratio (RR) along with confidence interval (CI), using Revman Version 5.4 software. Our protocol has been published in PROSPERO with ID: CRD42023406527.

Results: Four randomized controlled trials with a total of 779 patients were included in our analysis. Quadpill was effective in controlling systolic blood pressure in the short term [4-6 weeks] (RR: - 13.00 with 95% CI [- 17.22, - 8.78], p = 0.00001) and in the long term [12 weeks] (RR: - 6.18 with 95% CI [- 9.35, - 3.01], p = 0.0001). Quadpill was also effective in controlling automated diastolic blood pressure in the short term [4-6 weeks] (MD: - 8.15 with 95% CI [- 9.42, - 6.89], p = 0.00001) and in the long term [12 weeks] (MD: - 6.35 with 95% CI [- 10.37, - 2.33], p = 0.002). Moreover, patients in the quadpill group significantly achieved target blood pressure <140/90 (RR: 1.77 with 95% CI [1.26, 2.51], p = 0.001) compared with the control group.

Conclusions: The quadruple ultra-low-dose combination of antihypertensive drugs (quadpill) was effective and safe for hypertension treatment. However, further large-scale, multicenter, randomized controlled trials are still warranted before endorsement in clinical practice.

背景和目的:Quadpill是一种含有四分之一剂量四种降压药的单一药丸,已被研究用于治疗高血压。本荟萃分析旨在评估四元片治疗高血压的安全性和有效性。方法:我们进行了一项系统综述和荟萃分析,综合了随机对照试验,评估了四元药丸与单药治疗或安慰剂治疗高血压患者的疗效,这些试验通过系统搜索PubMed、EMBASE、Web of Science、SCOPUS和Cochrane检索到,截至2023年2月17日。使用Revman 5.4版软件,使用平均差(MD)、风险比(RR)和置信区间(CI)合并连续和二分结果。我们的方案已发表在PROSPERO上,ID:CRD42023406527。结果:我们的分析包括四项随机对照试验,共779名患者。Quadpill在短期[4-6周](RR:-13.00,95%CI[-17.22,-8.78],p=0.0001)和长期[12周](RR:-6.18,95%CI[-9.35,-3.01],p=0.0001,p=0.0001)和长期[12周](MD:-6.35,95%CI[-10.37,-2.33],p=0.002)。此外,四元片组患者显著达到了目标血压。结论:四元片超低剂量联合降压药(四元片)治疗高血压是有效和安全的。然而,在临床实践中批准之前,仍有必要进行进一步的大规模、多中心、随机对照试验。
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引用次数: 0
Cost-Effectiveness Analysis of Atezolizumab versus Platinum-Based Chemotherapy as First-Line Treatment for Patients with Unresectable Advanced Non-small Cell Lung Cancer with PD-L1 Expression Status in Japan. 在日本,阿替佐利珠单抗与铂类化疗作为PD-L1表达状态的不可切除晚期非小细胞肺癌癌症患者的一线治疗的成本-效果分析。
IF 3.2 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-11-01 Epub Date: 2023-10-27 DOI: 10.1007/s40261-023-01311-5
Yugo Chisaki, Hajime Nakano, Juna Minamide, Yoshitaka Yano

Background and objectives: Atezolizumab has demonstrated safety and efficacy in patients with metastatic non-small cell lung cancer (NSCLC) in the IMpower110 trial. The aim of this study was to evaluate the cost-effectiveness of atezolizumab as the first-line treatment for patients with unresectable advanced NSCLC, including programmed cell death ligand-1 (PD-L1)-positive probability testing, from the perspective of healthcare costs in Japan.

Methods: A cost-effectiveness analysis model for atezolizumab, including PD-L1-positive probability testing, was used to construct a partitioned survival model with three health states. To assess the robustness, a probabilistic sensitivity analysis (PSA) was conducted. The acceptable probability was defined as the probability of willingness-to-pay (WTP) over the incremental cost-effectiveness ratio (ICER). Multiple repetitions at WTP thresholds were calculated by continuously reducing the atezolizumab price.

Results: The ICER per quality-adjusted life year (QALY) for atezolizumab therapy only for patients with high PD-L1 expression compared to platinum-based chemotherapy for all patients was 31,975,792 yen per QALY. This is higher than the WTP threshold of 15,000,000 yen. If the cost of atezolizumab were reduced to 54% of the original cost (563,917 yen), the strategy of using atezolizumab for patients with high PD-L1 could become more cost-effective.

Conclusions: The results indicated that atezolizumab was not cost-effective compared to platinum-based chemotherapy as a first-line treatment for patients with unresectable advanced NSCLC. However, we suggest that the price of atezolizumab should be reduced to 54% of the original cost to meet the WTP threshold of 15,000,000 yen per QALY.

背景和目的:在IMpower110试验中,阿替佐利单抗已证明对转移性癌症(NSCLC)患者的安全性和有效性。本研究的目的是从日本医疗成本的角度评估atezolizumab作为不可切除的晚期NSCLC患者的一线治疗的成本效益,包括程序性细胞死亡配体-1(PD-L1)阳性概率测试。方法:atezolizmab的成本效益分析模型,包括PD-L1阳性概率测试,用于构建具有三种健康状态的分区生存模型。为了评估稳健性,进行了概率敏感性分析(PSA)。可接受概率被定义为支付意愿(WTP)超过增量成本效益比(ICER)的概率。通过持续降低atezolizumab的价格来计算WTP阈值的多次重复。结果:与所有患者的铂类化疗相比,仅针对PD-L1高表达患者的atezolizimab治疗的每质量调整生命年(QALY)的ICER为31975792日元/QALY。这高于1500万日元的WTP阈值。如果atezolizumab的成本降低到原始成本的54%(563917日元),那么针对高PD-L1患者使用atezolizmab的策略可能会变得更具成本效益。结论:结果表明,与铂类化疗相比,atezolizimab作为不可切除的晚期NSCLC患者的一线治疗方法并不具有成本效益。然而,我们建议atezolizumab的价格应降至原始成本的54%,以达到每QALY 15000000日元的WTP阈值。
{"title":"Cost-Effectiveness Analysis of Atezolizumab versus Platinum-Based Chemotherapy as First-Line Treatment for Patients with Unresectable Advanced Non-small Cell Lung Cancer with PD-L1 Expression Status in Japan.","authors":"Yugo Chisaki, Hajime Nakano, Juna Minamide, Yoshitaka Yano","doi":"10.1007/s40261-023-01311-5","DOIUrl":"10.1007/s40261-023-01311-5","url":null,"abstract":"<p><strong>Background and objectives: </strong>Atezolizumab has demonstrated safety and efficacy in patients with metastatic non-small cell lung cancer (NSCLC) in the IMpower110 trial. The aim of this study was to evaluate the cost-effectiveness of atezolizumab as the first-line treatment for patients with unresectable advanced NSCLC, including programmed cell death ligand-1 (PD-L1)-positive probability testing, from the perspective of healthcare costs in Japan.</p><p><strong>Methods: </strong>A cost-effectiveness analysis model for atezolizumab, including PD-L1-positive probability testing, was used to construct a partitioned survival model with three health states. To assess the robustness, a probabilistic sensitivity analysis (PSA) was conducted. The acceptable probability was defined as the probability of willingness-to-pay (WTP) over the incremental cost-effectiveness ratio (ICER). Multiple repetitions at WTP thresholds were calculated by continuously reducing the atezolizumab price.</p><p><strong>Results: </strong>The ICER per quality-adjusted life year (QALY) for atezolizumab therapy only for patients with high PD-L1 expression compared to platinum-based chemotherapy for all patients was 31,975,792 yen per QALY. This is higher than the WTP threshold of 15,000,000 yen. If the cost of atezolizumab were reduced to 54% of the original cost (563,917 yen), the strategy of using atezolizumab for patients with high PD-L1 could become more cost-effective.</p><p><strong>Conclusions: </strong>The results indicated that atezolizumab was not cost-effective compared to platinum-based chemotherapy as a first-line treatment for patients with unresectable advanced NSCLC. However, we suggest that the price of atezolizumab should be reduced to 54% of the original cost to meet the WTP threshold of 15,000,000 yen per QALY.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"839-850"},"PeriodicalIF":3.2,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"61561369","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}
引用次数: 0
Pharmacokinetics and Safety of Eptinezumab in Healthy Chinese Participants: A Randomized Clinical Trial. Eptinezumab在健康中国参与者中的药代动力学和安全性:一项随机临床试验。
IF 3.2 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-11-01 Epub Date: 2023-11-02 DOI: 10.1007/s40261-023-01315-1
Xue-Ning Li, Hong-Rong Xu, Ellen Cui, Kamilla Buchberg Petersen, Janka Ryding, Anders Ettrup, Jette Buch Østergaard, Frank Larsen

Background and objective: Most evidence suggests that the pharmacokinetics of monoclonal antibodies (mAbs) are not meaningfully altered by patient characteristics, including racial/ethnic differences. Nevertheless, the pharmacokinetic profile of eptinezumab has not been evaluated in a Chinese population. This study was designed to confirm the hypothesis that the pharmacokinetic profile of the anti-calcitonin gene-related peptide mAb, eptinezumab, is similar in healthy Chinese individuals to that of healthy non-Asian individuals and non-Asian patients with migraine.

Methods: Over a study period of 12 weeks, healthy adult Chinese participants (N = 20) were randomized (1:1) to receive a single intravenous dose of eptinezumab 100 mg (n = 10) or 300 mg (n = 10) in a prospective, single-site, open-label parallel-group trial. Blood samples for the evaluation of plasma eptinezumab concentrations were obtained over 84 days, and standard pharmacokinetic parameters were derived.

Results: Mean maximum plasma concentrations (Cmax) of eptinezumab occurred 1.0-1.5 h post start of infusion, were similar between the 100 mg and 300 mg dose groups, and slowly declined in a biphasic manner. Cmax and area under the drug concentration-time curve (AUC) increased in a dose-proportional manner. Volume of distribution and clearance were similar between the 100 mg and 300 mg dose groups, and half-life was 22.5-28.1 days. Eptinezumab was generally well tolerated with no new safety signals identified. Only one participant, randomized to the 100 mg dose group, was positive for eptinezumab anti-drug antibodies, but negative for neutralizing antibodies, with no impact on pharmacokinetics.

Conclusion: The pharmacokinetic profile of eptinezumab in healthy Chinese individuals was generally similar to that reported for non-Asian populations with migraine, and eptinezumab was generally well tolerated. Evaluation of immunogenicity showed no evidence of an impact of anti-drug antibodies or neutralizing antibodies on safety profiles. This supports the globally approved doses of 100 mg and 300 mg as being appropriate for Chinese patients with episodic migraine or chronic migraine.

背景和目的:大多数证据表明,单克隆抗体(mAbs)的药代动力学不会因患者特征(包括种族/民族差异)而发生有意义的改变。然而,依替尼单抗的药代动力学特征尚未在中国人群中进行评估。本研究旨在证实抗降钙素基因相关肽mAb(依替尼单抗)在健康中国人中的药代动力学特征与健康非亚洲人和非亚洲人偏头痛患者相似的假设。方法:在为期12周的研究期间,在一项前瞻性、单点、开放标签平行组试验中,健康的中国成年参与者(N=20)被随机(1:1)接受单次静脉注射剂量的依替尼单抗100 mg(N=10)或300 mg(N=10)。在84天内获得用于评估血浆依替尼单抗浓度的血样,并得出标准药代动力学参数。结果:依替尼单抗的平均最大血浆浓度(Cmax)发生在输注开始后1.0-1.5小时,在100 mg和300 mg剂量组之间相似,并以双相方式缓慢下降。Cmax和药物浓度-时间曲线下面积(AUC)以剂量成比例的方式增加。100 mg和300 mg剂量组之间的分布体积和清除率相似,半衰期为22.5-28.1天。Eptinezumab通常耐受性良好,没有发现新的安全信号。只有一名被随机分配到100 mg剂量组的参与者对依替尼单抗抗药物抗体呈阳性,但对中和抗体呈阴性,对药代动力学没有影响。结论:依替尼单抗在健康中国人中的药代动力学特征与非亚洲偏头痛患者的药代学特征大体相似,且依替尼珠单抗总体耐受性良好。免疫原性评估显示,没有证据表明抗药物抗体或中和抗体对安全性有影响。这支持了全球批准的100 mg和300 mg剂量适用于发作性偏头痛或慢性偏头痛的中国患者。
{"title":"Pharmacokinetics and Safety of Eptinezumab in Healthy Chinese Participants: A Randomized Clinical Trial.","authors":"Xue-Ning Li, Hong-Rong Xu, Ellen Cui, Kamilla Buchberg Petersen, Janka Ryding, Anders Ettrup, Jette Buch Østergaard, Frank Larsen","doi":"10.1007/s40261-023-01315-1","DOIUrl":"10.1007/s40261-023-01315-1","url":null,"abstract":"<p><strong>Background and objective: </strong>Most evidence suggests that the pharmacokinetics of monoclonal antibodies (mAbs) are not meaningfully altered by patient characteristics, including racial/ethnic differences. Nevertheless, the pharmacokinetic profile of eptinezumab has not been evaluated in a Chinese population. This study was designed to confirm the hypothesis that the pharmacokinetic profile of the anti-calcitonin gene-related peptide mAb, eptinezumab, is similar in healthy Chinese individuals to that of healthy non-Asian individuals and non-Asian patients with migraine.</p><p><strong>Methods: </strong>Over a study period of 12 weeks, healthy adult Chinese participants (N = 20) were randomized (1:1) to receive a single intravenous dose of eptinezumab 100 mg (n = 10) or 300 mg (n = 10) in a prospective, single-site, open-label parallel-group trial. Blood samples for the evaluation of plasma eptinezumab concentrations were obtained over 84 days, and standard pharmacokinetic parameters were derived.</p><p><strong>Results: </strong>Mean maximum plasma concentrations (C<sub>max</sub>) of eptinezumab occurred 1.0-1.5 h post start of infusion, were similar between the 100 mg and 300 mg dose groups, and slowly declined in a biphasic manner. C<sub>max</sub> and area under the drug concentration-time curve (AUC) increased in a dose-proportional manner. Volume of distribution and clearance were similar between the 100 mg and 300 mg dose groups, and half-life was 22.5-28.1 days. Eptinezumab was generally well tolerated with no new safety signals identified. Only one participant, randomized to the 100 mg dose group, was positive for eptinezumab anti-drug antibodies, but negative for neutralizing antibodies, with no impact on pharmacokinetics.</p><p><strong>Conclusion: </strong>The pharmacokinetic profile of eptinezumab in healthy Chinese individuals was generally similar to that reported for non-Asian populations with migraine, and eptinezumab was generally well tolerated. Evaluation of immunogenicity showed no evidence of an impact of anti-drug antibodies or neutralizing antibodies on safety profiles. This supports the globally approved doses of 100 mg and 300 mg as being appropriate for Chinese patients with episodic migraine or chronic migraine.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"873-881"},"PeriodicalIF":3.2,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10632206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71421307","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}
引用次数: 0
Effect of Daridorexant on the Pharmacokinetics of P-Glycoprotein Substrate Dabigatran Etexilate and Breast Cancer Resistance Protein Substrate Rosuvastatin in Healthy Subjects. Daridorexant对健康受试者P-糖蛋白底物Dabigatran Etexilate和乳腺癌症耐药蛋白底物Rosuvastin药代动力学的影响。
IF 3.2 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-11-01 Epub Date: 2023-10-19 DOI: 10.1007/s40261-023-01310-6
Marion Anliker-Ort, Jasper Dingemanse, Luboš Janů, Priska Kaufmann

Background and objective: The dual orexin receptor antagonist daridorexant was approved in 2022 for the treatment of insomnia at doses up to 50 mg once per night. This study aimed at investigating the effect of daridorexant 50 mg at steady state on the pharmacokinetics of dabigatran, the active moiety of dabigatran etexilate, and rosuvastatin, sensitive substrates of P-glycoprotein and breast cancer resistance protein, respectively.

Methods: This single-center, open-label, fixed-sequence study enrolled 24 healthy male subjects who were dosed orally with dabigatran etexilate 75 mg on days 1 (Treatment A1) and 9 (Treatment C1) as well as rosuvastatin 10 mg on days 3 (Treatment A2) and 11 (Treatment C2). On days 7-14, daridorexant (50 mg once daily) was administered. Blood samples for the pharmacokinetics of both substrates and the pharmacodynamics of dabigatran, i.e., two coagulation tests, were collected and safety assessments performed. Noncompartmental pharmacokinetic parameters and pharmacodynamic variables were evaluated with geometric mean ratios and 90% confidence intervals of Treatment C1/C2 versus A1/A2.

Results: Geometric mean ratios (90% confidence interval) of dabigatran maximum plasma concentration and area under the plasma concentration-time curve were 1.3 (1.0-1.7) and 1.4 (1.1-1.9), respectively, whereas the time to maximum plasma concentration and terminal half-life were comparable between treatments. Pharmacodynamic variables showed a similar pattern as dabigatran pharmacokinetics in both treatments. Rosuvastatin pharmacokinetics were unchanged upon concomitant daridorexant administration. All treatments were well tolerated.

Conclusions: A mild inhibition of P-glycoprotein was observed after administration of daridorexant (50 mg once daily) at steady state, whereas breast cancer resistance protein was not affected.

Clinical trial registration: NCT05480475; date of registration: 29 July, 2022.

背景和目的:双食欲素受体拮抗剂daridorexant于2022年被批准用于治疗失眠,剂量高达50 mg,每晚一次。本研究旨在研究daridorexant 50mg在稳定状态下分别对P-糖蛋白和乳腺癌症耐药性蛋白敏感底物达比加群酯的活性部分达比加群组和瑞舒伐他汀的药代动力学的影响。方法:这项单中心、开放标签、固定序列研究纳入了24名健康男性受试者,他们在第1天(治疗A1)和第9天(治疗C1)口服达比加群酯75mg,在第3天(治疗A2)和第11天(治疗C2)口服瑞舒伐他汀10mg。在第7-14天,给予daridorexant(50mg,每日一次)。采集两种底物的药代动力学和达比加群的药效学血样,即两次凝血试验,并进行安全性评估。用C1/C2与A1/A2治疗的几何平均比值和90%置信区间评估非室药代动力学参数和药效学变量。结果:达比加群最大血浆浓度和血浆浓度-时间曲线下面积的几何平均比(90%置信区间)分别为1.3(1.0-1.7)和1.4(1.1-1.9),而达到最大血浆浓度的时间和终末半衰期在治疗之间是可比较的。药效学变量在两种治疗中显示出与达比加群药代动力学相似的模式。瑞舒伐他汀的药代动力学在同时给药daridorexant后没有变化。所有治疗都具有良好的耐受性。结论:在稳定状态下给予daridorexant(50mg,每日一次)后,观察到P-糖蛋白的轻度抑制,而乳腺癌症耐药性蛋白不受影响。临床试验注册号:NCT05480475;注册日期:2022年7月29日。
{"title":"Effect of Daridorexant on the Pharmacokinetics of P-Glycoprotein Substrate Dabigatran Etexilate and Breast Cancer Resistance Protein Substrate Rosuvastatin in Healthy Subjects.","authors":"Marion Anliker-Ort, Jasper Dingemanse, Luboš Janů, Priska Kaufmann","doi":"10.1007/s40261-023-01310-6","DOIUrl":"10.1007/s40261-023-01310-6","url":null,"abstract":"<p><strong>Background and objective: </strong>The dual orexin receptor antagonist daridorexant was approved in 2022 for the treatment of insomnia at doses up to 50 mg once per night. This study aimed at investigating the effect of daridorexant 50 mg at steady state on the pharmacokinetics of dabigatran, the active moiety of dabigatran etexilate, and rosuvastatin, sensitive substrates of P-glycoprotein and breast cancer resistance protein, respectively.</p><p><strong>Methods: </strong>This single-center, open-label, fixed-sequence study enrolled 24 healthy male subjects who were dosed orally with dabigatran etexilate 75 mg on days 1 (Treatment A1) and 9 (Treatment C1) as well as rosuvastatin 10 mg on days 3 (Treatment A2) and 11 (Treatment C2). On days 7-14, daridorexant (50 mg once daily) was administered. Blood samples for the pharmacokinetics of both substrates and the pharmacodynamics of dabigatran, i.e., two coagulation tests, were collected and safety assessments performed. Noncompartmental pharmacokinetic parameters and pharmacodynamic variables were evaluated with geometric mean ratios and 90% confidence intervals of Treatment C1/C2 versus A1/A2.</p><p><strong>Results: </strong>Geometric mean ratios (90% confidence interval) of dabigatran maximum plasma concentration and area under the plasma concentration-time curve were 1.3 (1.0-1.7) and 1.4 (1.1-1.9), respectively, whereas the time to maximum plasma concentration and terminal half-life were comparable between treatments. Pharmacodynamic variables showed a similar pattern as dabigatran pharmacokinetics in both treatments. Rosuvastatin pharmacokinetics were unchanged upon concomitant daridorexant administration. All treatments were well tolerated.</p><p><strong>Conclusions: </strong>A mild inhibition of P-glycoprotein was observed after administration of daridorexant (50 mg once daily) at steady state, whereas breast cancer resistance protein was not affected.</p><p><strong>Clinical trial registration: </strong>NCT05480475; date of registration: 29 July, 2022.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"827-837"},"PeriodicalIF":3.2,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49674989","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}
引用次数: 0
Use of Acitretin Among Girls and Women of Childbearing Age and Occurrence of Acitretin-Exposed Pregnancies in Germany. 德国育龄女孩和妇女使用阿曲素与阿曲素暴露妊娠的发生率。
IF 3.2 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-11-01 Epub Date: 2023-10-31 DOI: 10.1007/s40261-023-01314-2
Jonas Reinold, Bianca Kollhorst, Hellen L Temme, Nadine Wentzell, Ulrike Haug

Background and objective: Acitretin has long-lasting teratogenic properties. Therefore, pregnancies must be avoided during and within 3 years after acitretin treatment. We aimed to describe (i) acitretin use in women of childbearing age in Germany, (ii) the occurrence of acitretin-exposed pregnancies, and (iii) malformations among children exposed in utero.

Methods: Using 2004-2019 data from the German Pharmacoepidemiological Research Database (GePaRD-claims data from ~ 20% of the German population), we determined annual age-standardized prevalence of acitretin use among girls and women aged 13-49 years. In longitudinal analyses, we estimated the number of exposed pregnancies by assessing whether the exposure window assigned to the last dispensation before pregnancy (days covered by dispensation plus 3 years) overlapped the onset of pregnancy or whether there was a dispensation in the first eight weeks of pregnancy. Data of live-born children with in utero exposure to acitretin were reviewed to assess the presence of congenital malformations.

Results: The age-standardized prevalence of acitretin use per 1000 girls and women was 0.04 in 2019. We identified 35 acitretin-exposed pregnancies; 94.3% of these pregnancies were classified as exposed because they occurred within 3 years after stopping acitretin treatment. Among 18 live-born children linked to their mother, four children (22.2%) had congenital malformations (three children with a major malformation).

Conclusions: We observed 35 acitretin-exposed pregnancies mainly because treatment ended too late before pregnancy. Approximately one in five children born from these pregnancies had malformations, highlighting the importance of drawing more attention to the long-lasting teratogenicity of this drug.

背景和目的:阿曲汀具有长期的致畸特性。因此,在阿曲汀治疗期间和治疗后3年内必须避免怀孕。我们的目的是描述(i)德国育龄妇女使用阿曲汀,(ii)暴露于阿曲汀的妊娠发生率,以及(iii)暴露于子宫内的儿童畸形。方法:使用德国药物流行病学研究数据库2004-2019年的数据(GePaRD声称数据来自~ 20%的德国人口),我们确定了13-49岁女孩和妇女使用阿曲汀的年度年龄标准化流行率。在纵向分析中,我们通过评估妊娠前最后一次给药的暴露窗口(给药天数加3年)是否与妊娠期重叠,或者在妊娠的前八周是否有给药,来估计暴露妊娠的数量。回顾了子宫内接触阿曲汀的活产儿童的数据,以评估先天畸形的存在。结果:2019年,每1000名女孩和妇女使用阿曲汀的年龄标准化患病率为0.04。我们确定了35例暴露于阿曲汀的妊娠;94.3%的妊娠被归类为暴露妊娠,因为它们发生在停止阿曲汀治疗后的3年内。在与母亲有联系的18名活产儿童中,有4名儿童(22.2%)患有先天性畸形(3名儿童患有严重畸形)。结论:我们观察到35例接触阿曲汀的妊娠,主要是因为治疗在妊娠前结束得太晚。大约五分之一的这些妊娠期出生的儿童患有畸形,这突出了引起人们更多关注这种药物长期致畸性的重要性。
{"title":"Use of Acitretin Among Girls and Women of Childbearing Age and Occurrence of Acitretin-Exposed Pregnancies in Germany.","authors":"Jonas Reinold, Bianca Kollhorst, Hellen L Temme, Nadine Wentzell, Ulrike Haug","doi":"10.1007/s40261-023-01314-2","DOIUrl":"10.1007/s40261-023-01314-2","url":null,"abstract":"<p><strong>Background and objective: </strong>Acitretin has long-lasting teratogenic properties. Therefore, pregnancies must be avoided during and within 3 years after acitretin treatment. We aimed to describe (i) acitretin use in women of childbearing age in Germany, (ii) the occurrence of acitretin-exposed pregnancies, and (iii) malformations among children exposed in utero.</p><p><strong>Methods: </strong>Using 2004-2019 data from the German Pharmacoepidemiological Research Database (GePaRD-claims data from ~ 20% of the German population), we determined annual age-standardized prevalence of acitretin use among girls and women aged 13-49 years. In longitudinal analyses, we estimated the number of exposed pregnancies by assessing whether the exposure window assigned to the last dispensation before pregnancy (days covered by dispensation plus 3 years) overlapped the onset of pregnancy or whether there was a dispensation in the first eight weeks of pregnancy. Data of live-born children with in utero exposure to acitretin were reviewed to assess the presence of congenital malformations.</p><p><strong>Results: </strong>The age-standardized prevalence of acitretin use per 1000 girls and women was 0.04 in 2019. We identified 35 acitretin-exposed pregnancies; 94.3% of these pregnancies were classified as exposed because they occurred within 3 years after stopping acitretin treatment. Among 18 live-born children linked to their mother, four children (22.2%) had congenital malformations (three children with a major malformation).</p><p><strong>Conclusions: </strong>We observed 35 acitretin-exposed pregnancies mainly because treatment ended too late before pregnancy. Approximately one in five children born from these pregnancies had malformations, highlighting the importance of drawing more attention to the long-lasting teratogenicity of this drug.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"865-872"},"PeriodicalIF":3.2,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10632260/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71421308","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}
引用次数: 0
Safety of Interleukin Inhibitors in Patients with Plaque Psoriasis and Neoplasm: A Retrospective Study from Two Referral Centers. 白细胞介素抑制剂在斑块型银屑病和肿瘤患者中的安全性:来自两个转诊中心的回顾性研究。
IF 3.2 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-10-01 Epub Date: 2023-09-16 DOI: 10.1007/s40261-023-01306-2
Luigi Gargiulo, Luciano Ibba, Mario Valenti, Diego Orsini, Antonio Cristaudo, Pasquale Frascione, Antonio Costanzo, Alessandra Narcisi
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引用次数: 0
Acthar® Gel Treatment for Patients with Autoimmune and Inflammatory Diseases: An Historical Perspective and Characterization of Clinical Evidence. Acthar®凝胶治疗自身免疫性和炎症性疾病患者:历史视角和临床证据特征。
IF 3.2 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-10-01 Epub Date: 2023-10-04 DOI: 10.1007/s40261-023-01303-5
Jeffrey Kaplan, Anca Askanase, David Chu, Abdul Abdellatif, Dhiman Basu, Mehdi Mirsaeidi

Acthar® Gel (repository corticotropin injection) is a naturally sourced complex mixture of adrenocorticotropic hormone analogs and other pituitary peptides that is believed to have both steroidogenic and nonsteroidogenic immunomodulatory effects via activation of melanocortin receptors in various cells throughout the body. Since 1952, Acthar has been approved by the US Food and Drug Administration to treat a variety of autoimmune and inflammatory diseases. Since 2014, Mallinckrodt Pharmaceuticals has conducted a large number of preclinical, clinical, and real-world-evidence studies of Acthar for the treatment of rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis and polymyositis, multiple sclerosis relapse, ophthalmic disorders, sarcoidosis, and nephrotic syndrome. To date, Acthar has been the subject of more than 500 publications, many of which demonstrate the safety and efficacy of Acthar in patients with inflammatory diseases for whom standard treatments were ineffective or intolerable. Here, we review the history of Acthar and the findings of studies that have investigated the mechanism of action, safety, efficacy, and real-world effectiveness of Acthar for the treatment of inflammatory diseases.

Acthar®凝胶(储存库促肾上腺皮质素注射液)是一种天然来源的促肾上腺皮质激素类似物和其他垂体肽的复杂混合物,据信通过激活全身各种细胞中的黑素皮质素受体,具有甾体和非甾体免疫调节作用。自1952年以来,Acthar已被美国食品药品监督管理局批准用于治疗各种自身免疫性和炎症性疾病。自2014年以来,Mallinckrodt Pharmaceuticals对Acthar治疗类风湿性关节炎、系统性红斑狼疮、皮肌炎和多发性肌炎、多发性硬化症复发、眼科疾病、结节病和肾病综合征进行了大量临床前、临床和现实世界的证据研究。迄今为止,Acthar已成为500多篇出版物的主题,其中许多出版物证明了Acthar对标准治疗无效或无法忍受的炎症性疾病患者的安全性和有效性。在这里,我们回顾了Acthar的历史,以及研究Acthar治疗炎症性疾病的作用机制、安全性、疗效和现实有效性的研究结果。
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引用次数: 0
A Phase 1 Study of Ensitrelvir Fumaric Acid Tablets Evaluating the Safety, Pharmacokinetics and Food Effect in Healthy Adult Populations. 恩西韦-富马酸片的1期研究,评估健康成年人群的安全性、药代动力学和食物效果。
IF 2.9 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-10-01 Epub Date: 2023-10-05 DOI: 10.1007/s40261-023-01309-z
Ryosuke Shimizu, Takuhiro Sonoyama, Takahiro Fukuhara, Aya Kuwata, Yumiko Matsuo, Ryuji Kubota
<p><strong>Background: </strong>A reported clinical pharmacokinetics and safety study of suspension formulation of ensitrelvir, a therapeutic agent used in severe acute respiratory syndrome coronavirus 2 infection, demonstrated favorable pharmacokinetics and was well tolerated in healthy male Japanese and White participants. Understanding the safety and pharmacokinetic features of ensitrelvir (using the formulation approved for clinical use) in various populations, and the effect of food, is crucial for optimal clinical use.</p><p><strong>Objectives: </strong>The objectives of this study were to (1) assess the safety, tolerability, and pharmacokinetics of ensitrelvir following multiple-dose administration of ensitrelvir tablets in populations with different races, ages, and sex; and (2) assess the effect of food on the pharmacokinetics of ensitrelvir tablets in the fasted or fed state.</p><p><strong>Methods: </strong>A phase 1, multicenter, double-blinded, randomized, placebo-controlled study was conducted to evaluate the safety and pharmacokinetics of once-daily ensitrelvir tablets at loading/maintenance doses of 375/125 mg or 750/250 mg for 5 days in healthy Japanese females, Japanese elderly (only 375/125 mg), and White male and female participants. An open-label, two-group, two-period crossover study was also conducted to estimate the effect of food on the pharmacokinetics of ensitrelvir at single dose of 375 mg. The nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded in safety assessments in both studies.</p><p><strong>Results: </strong>The maximum plasma concentration (C<sub>max</sub>) and area under the plasma concentration-time curve (AUC) were similar within these populations. The geometric mean half-life of ensitrelvir following multiple-dose administration was 48.7-58.9 h across all cohorts. The C<sub>max</sub> and AUC increased in a dose-proportional manner in Japanese female participants, and increased in a less than dose-proportional manner in White participants. Furthermore, there was no clear relationship between the dose and geometric mean half-life of ensitrelvir. The plasma concentration at 24 h (C<sub>24</sub>) after an initial dose of 375/125 mg exceeded the target plasma concentration (6.09 µg/mL) in all populations. Regarding the effect of food on the pharmacokinetics of ensitrelvir, although time to C<sub>max</sub> in the fed state was delayed, there was no clinically meaningful difference in the exposure levels (C<sub>max</sub> and AUC) of ensitrelvir between the fasted and fed states. Most treatment-emergent adverse events were mild in nature and had resolved.</p><p><strong>Conclusion: </strong>Ensitrelvir (375/125 mg and 750/250 mg tablet formulation) was well tolerated, without any major safety concerns. The pharmacokinetics of ensitrelvir between all populations in the study were similar and C<sub>24</sub> exceeded the target plasma concentration at 375/125 mg. These result
背景:据报道,一项用于严重急性呼吸系统综合征冠状病毒2型感染的治疗剂ensitrelvir混悬制剂的临床药代动力学和安全性研究表明,该制剂具有良好的药代动力学,在健康的日本男性和白人参与者中耐受性良好。了解ensitrelvir(使用批准用于临床的制剂)在不同人群中的安全性和药代动力学特征,以及食物的效果,对于优化临床使用至关重要。目的:本研究的目的是:(1)评估在不同种族、年龄和性别的人群中多剂量给药艾司韦片后艾司韦的安全性、耐受性和药代动力学;以及(2)评估食物对禁食或喂食状态下的恩司他韦片的药代动力学的影响。方法:进行了一项1期、多中心、双盲、随机、安慰剂对照研究,以评估在健康日本女性、日本老年人(仅375/125 mg)和白人男性和女性参与者中,每天一次、375/125毫克或750/250毫克负荷/维持剂量的阿司韦片剂持续5天的安全性和药代动力学。还进行了一项开放标签、两组、两个周期的交叉研究,以评估食物对单剂量375 mg的恩曲韦药代动力学的影响。在两项研究的安全性评估中评估并记录了治疗突发不良事件的性质、频率和严重程度。结果:在这些人群中,最大血浆浓度(Cmax)和血浆浓度-时间曲线下面积(AUC)相似。在所有队列中,多剂量给药后恩司曲韦的几何平均半衰期为48.7-58.9小时。日本女性受试者的Cmax和AUC以剂量成比例的方式增加,而白人受试者则以低于剂量成比例方式增加。此外,恩西曲韦的剂量和几何平均半衰期之间没有明确的关系。在所有人群中,初始剂量375/125 mg后24小时(C24)的血浆浓度均超过目标血浆浓度(6.09µg/mL)。关于食物对恩曲韦药代动力学的影响,尽管喂食状态下达到Cmax的时间延迟,但禁食状态和喂食状态下恩曲韦的暴露水平(Cmax和AUC)没有临床意义的差异。大多数治疗引发的不良事件性质轻微,已得到解决。结论:恩西韦(375/125 mg和750/250 mg片剂制剂)耐受性良好,没有任何重大安全问题。在研究中,所有人群之间的恩曲韦药代动力学相似,C24在375/125 mg时超过了目标血浆浓度。这些结果表明,恩曲韦可以有效给药,无需根据年龄、性别和种族进行剂量调整,无需食物限制。临床试验注册:日本临床试验注册标识符:jRCT203110202,于2021年7月16日注册。
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引用次数: 0
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Clinical Drug Investigation
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