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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 Medicine 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。
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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 Medicine 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。
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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 Medicine 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。
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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 Medicine 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 Medicine 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
Effectiveness of Dupilumab for Chronic Prurigo in Chinese Patients: A Real-World Case Series Study. Dupilumab治疗中国患者慢性Prurigo的疗效:一项真实世界的病例系列研究。
IF 3.2 3区 医学 Q2 Medicine Pub Date : 2023-10-01 Epub Date: 2023-09-17 DOI: 10.1007/s40261-023-01307-1
Lu Wei, Mengting Yin, Xu Yang, Jiaying Chen, Ruimiao Wu, Heng Yang, Xia Dou

Background: Treatment of chronic prurigo (CPG) is challenging. As an antagonist of IL-4R, dupilumab has shown effectiveness in treating CPG in several clinical studies. Recently, the US Food and Drug Administration (FDA) approved dupilumab for the treatment of prurigo nodularis (PN).

Objectives: The purpose of this study was to examine the efficacy of dupilumab in Chinese patients with CPG, and to analyze the difference in response between subtypes of CPG.

Methods: This retrospective study included 18 patients with CPG who were treated with dupilumab for at least 16 weeks from March 2022 to October 2022. Disease severity and patient self-assessment questionnaires were assessed at baseline and each visit, including the peak Pruritus Visual Analogue Scale (PP-VAS), Prurigo Activity and Severity Score (PAS), Investigator Global Assessment (IGA), Dermatology Life Quality Index (DLQI), Hospital Anxiety and Depression Scale (HADS) and Itchy-specific Quality of Life questionnaire (ItchyQoL).

Results: After 2 weeks of dupilumab treatment, pruritus scores were significantly reduced as measured by PP-VAS scores. Prurigo Activity and Severity scores decreased significantly at Week 2, whereas IGA improved significantly at Week 8. The DLQI, HADS, and ItchyQoL scores at Week 16 also showed significant improvement from baseline. Patients in all subtypes showed improvement in pruritus and lesion severity.

Conclusions: Dupilumab was effective in improving pruritus and lesions in patients with various subtypes of CPG.

背景:慢性瘙痒症(CPG)的治疗具有挑战性。作为IL-4R的拮抗剂,dupilumab在几项临床研究中显示出治疗CPG的有效性。最近,美国食品药品监督管理局(FDA)批准了杜匹单抗治疗结节性瘙痒症(PN)。目的:本研究旨在检验杜匹单抗对中国CPG患者的疗效,并分析CPG亚型之间的反应差异。方法:这项回顾性研究包括18名CPG患者,他们在2022年3月至2022年10月期间接受了至少16周的dupilumab治疗。在基线和每次就诊时评估疾病严重程度和患者自我评估问卷,包括瘙痒视觉模拟量表峰值(PP-VAS)、瘙痒活动和严重程度评分(PAS)、研究者全球评估(IGA)、皮肤病学生活质量指数(DLQI),医院焦虑抑郁量表(HADS)和瘙痒特异性生活质量问卷(ItchyQoL)。结果:dupilumab治疗2周后,通过PP-VAS评分测量,瘙痒评分显著降低。Prurigo活动和严重程度评分在第2周显著下降,而IGA在第8周显著改善。第16周的DLQI、HADS和ItchyQoL评分也比基线有显著改善。所有亚型患者的瘙痒和病变严重程度均有改善。结论:Dupilumab可有效改善不同亚型CPG患者的瘙痒和病变。
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引用次数: 0
Effectiveness and Safety of Remdesivir in Treating Hospitalised Patients with COVID-19: A Propensity Score Analysis of Real-Life Data from a Monocentric Observational Study in Times of Health Emergency. Remdesivir治疗新冠肺炎住院患者的有效性和安全性:一项卫生紧急时期单中心观察研究的现实生活数据倾向评分分析。
IF 3.2 3区 医学 Q2 Medicine Pub Date : 2023-10-01 Epub Date: 2023-09-22 DOI: 10.1007/s40261-023-01304-4
Nicola Ughi, Davide Paolo Bernasconi, Francesca Del Gaudio, Armanda Dicuonzo, Alessandro Maloberti, Cristina Giannattasio, Paolo Tarsia, Giovanna Travi, Francesco Scaglione, Fabrizio Colombo, Michaela Bertuzzi, Antonella Adinolfi, Maria Grazia Valsecchi, Claudio Rossetti, Oscar Massimiliano Epis

Background and objectives: Remdesivir is an antiviral agent, which was shown to be safe and effective in treating early COVID-19, but its favourable impact in hospitalised patients with non-critical disease is still under investigation. The present study aimed to assess the effectiveness and safety of remdesivir as a treatment for hospitalised patients with COVID-19 by a propensity score analysis of observational data.

Methods: In this monocentric retrospective cohort study, the effectiveness and safety of a 5-day course of remdesivir (200 mg intravenously at Day 1, then 100 mg from Days 2-5) in association with the standard of care were assessed in comparison with the standard of care only. The primary endpoint was the proportion of recovery on Day 14.

Results: Of 3662 eligible inpatients who tested positive for the severe acute respiratory syndrome coronavirus 2 genome by nasopharyngeal swab at admission, 861 (24%) non-critical patients were included in a propensity score analysis and 281 (33%) were exposed to remdesivir. In total, 242/281 (86.1%) and 435/580 (75.0%) patients recovered in exposed and non-exposed, respectively, with a relative improvement of 11.1% (95% CI + 5.8 to 16.5%; unadjusted odds ratio: 2.07, 95% CI 1.40-3.05, p = 0.0001; after adjustment by propensity score weighting, odds ratio: 1.92, 95% CI 1.30-2.83, p = 0.001). In treated patients, 1 (0.03%) anaphylactic reaction and 1 (0.03%) acute reaction during drug injection were reported, and 24 (8.5%) patients stopped the treatment due to adverse reactions. No significant differences were found with respect to the secondary efficacy endpoints (in-hospital all-cause death, need for intensive care treatments, clinical improvement score at Day 28) and safety endpoints (any and serious adverse reactions).

Conclusion: A 5-day course of remdesivir in association with the standard of care effectively promoted recovery from COVID-19 among non-critical in-hospital patients and had an acceptable safety profile.

背景和目的:Remdesivir是一种抗病毒药物,在治疗早期新冠肺炎方面被证明是安全有效的,但其对非危重症住院患者的有利影响仍在调查中。本研究旨在通过观察数据的倾向评分分析,评估瑞德西韦治疗新冠肺炎住院患者的有效性和安全性。方法:在这项单中心回顾性队列研究中,与仅护理标准相比,评估了与护理标准相关的5天疗程瑞德西韦(第1天静脉注射200 mg,第2-5天静脉注射100 mg)的有效性和安全性。主要终点是第14天的康复比例。结果:在入院时鼻咽拭子检测出严重急性呼吸综合征冠状病毒2基因组呈阳性的3662名符合条件的住院患者中,861名(24%)非危重患者被纳入倾向评分分析,281名(33%)患者暴露于瑞德西韦。总的来说,242/281(86.1%)和435/580(75.0%)患者在暴露和非暴露中分别康复,相对改善11.1%(95%CI+5.8-16.5%;未经调整的比值比:2.07,95%CI1.40-3.05,p=0.0001;通过倾向评分加权调整后,比值比:1.92,95%CI1.30-2.83,p=0.001),报告了1例(0.03%)药物注射过程中的过敏反应和1例(0.03%)急性反应,24例(8.5%)患者因不良反应停止治疗。次要疗效终点(住院全因死亡、需要重症监护治疗、第28天的临床改善分数)和安全性终点(任何和严重不良反应)没有发现显著差异住院患者,具有可接受的安全性。
{"title":"Effectiveness and Safety of Remdesivir in Treating Hospitalised Patients with COVID-19: A Propensity Score Analysis of Real-Life Data from a Monocentric Observational Study in Times of Health Emergency.","authors":"Nicola Ughi,&nbsp;Davide Paolo Bernasconi,&nbsp;Francesca Del Gaudio,&nbsp;Armanda Dicuonzo,&nbsp;Alessandro Maloberti,&nbsp;Cristina Giannattasio,&nbsp;Paolo Tarsia,&nbsp;Giovanna Travi,&nbsp;Francesco Scaglione,&nbsp;Fabrizio Colombo,&nbsp;Michaela Bertuzzi,&nbsp;Antonella Adinolfi,&nbsp;Maria Grazia Valsecchi,&nbsp;Claudio Rossetti,&nbsp;Oscar Massimiliano Epis","doi":"10.1007/s40261-023-01304-4","DOIUrl":"10.1007/s40261-023-01304-4","url":null,"abstract":"<p><strong>Background and objectives: </strong>Remdesivir is an antiviral agent, which was shown to be safe and effective in treating early COVID-19, but its favourable impact in hospitalised patients with non-critical disease is still under investigation. The present study aimed to assess the effectiveness and safety of remdesivir as a treatment for hospitalised patients with COVID-19 by a propensity score analysis of observational data.</p><p><strong>Methods: </strong>In this monocentric retrospective cohort study, the effectiveness and safety of a 5-day course of remdesivir (200 mg intravenously at Day 1, then 100 mg from Days 2-5) in association with the standard of care were assessed in comparison with the standard of care only. The primary endpoint was the proportion of recovery on Day 14.</p><p><strong>Results: </strong>Of 3662 eligible inpatients who tested positive for the severe acute respiratory syndrome coronavirus 2 genome by nasopharyngeal swab at admission, 861 (24%) non-critical patients were included in a propensity score analysis and 281 (33%) were exposed to remdesivir. In total, 242/281 (86.1%) and 435/580 (75.0%) patients recovered in exposed and non-exposed, respectively, with a relative improvement of 11.1% (95% CI + 5.8 to 16.5%; unadjusted odds ratio: 2.07, 95% CI 1.40-3.05, p = 0.0001; after adjustment by propensity score weighting, odds ratio: 1.92, 95% CI 1.30-2.83, p = 0.001). In treated patients, 1 (0.03%) anaphylactic reaction and 1 (0.03%) acute reaction during drug injection were reported, and 24 (8.5%) patients stopped the treatment due to adverse reactions. No significant differences were found with respect to the secondary efficacy endpoints (in-hospital all-cause death, need for intensive care treatments, clinical improvement score at Day 28) and safety endpoints (any and serious adverse reactions).</p><p><strong>Conclusion: </strong>A 5-day course of remdesivir in association with the standard of care effectively promoted recovery from COVID-19 among non-critical in-hospital patients and had an acceptable safety profile.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41109440","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
Tumor Lysis Syndrome with CD20 Monoclonal Antibodies for Chronic Lymphocytic Leukemia: Signals from the FDA Adverse Event Reporting System. CD20单克隆抗体治疗慢性淋巴细胞白血病的肿瘤溶解综合征:来自美国食品药品监督管理局不良事件报告系统的信号。
IF 3.2 3区 医学 Q2 Medicine Pub Date : 2023-10-01 Epub Date: 2023-09-27 DOI: 10.1007/s40261-023-01308-0
Shuang Xia, Jia-Ting Ma, Emanuel Raschi, Rui Ma, Bi-Kui Zhang, Linna Guo, Yoshihiro Noguchi, Mayur Sarangdhar, Hui Gong, Miao Yan

Background and objective: Although tumor lysis syndrome was reported with obinutuzumab and rituximab, the association with CD20 monoclonal antibodies for chronic lymphocytic leukemia is unclear.

Methods: A disproportionality analysis was conducted to investigate the link between CD20 monoclonal antibodies and tumor lysis syndrome by accounting for known confounders and comparing with other anticancer drugs, using data from the US Food and Drug Administration Adverse Event Reporting System. Reporting odds ratios and the information component were calculated as disproportionality measures. A stepwise sensitivity analysis was conducted to test the robustness of disproportionality signals. Bradford Hill criteria were adopted to globally assess the potential causal relationship.

Results: From 2004 to 2022, 197, 368, 41, and 14 tumor lysis syndrome reports were detected for obinutuzumab, rituximab, ofatumumab, and alemtuzumab (CD52 monoclonal antibody), respectively. Disproportionality signals were found for the above four monoclonal antibodies when compared with other anticancer drugs. Sensitivity analyses confirmed robust disproportionality signals for obinutuzumab, rituximab, and ofatumumab. The median onset time was 4.5, 1.5, and 2.5 days for rituximab, obinutuzumab, and ofatumumab, respectively. A potential causal relationship was fulfilled by assessing Bradford Hill criteria.

Conclusions: This pharmacovigilance study on the FDA Adverse Event Reporting System detected a plausible association between CD20 monoclonal antibodies (but not CD52) and tumor lysis syndrome by assessing the adapted Bradford Hill criteria. Urgent clarification of drug- and patient-related risk factors is needed through large comparative population-based studies.

背景和目的:尽管奥比努单抗和利妥昔单抗曾报道过肿瘤溶解综合征,但与CD20单克隆抗体治疗慢性淋巴细胞白血病的相关性尚不清楚。方法:利用美国食品药品监督管理局不良事件报告系统的数据,通过解释已知的混杂因素并与其他抗癌药物进行比较,进行歧化分析,研究CD20单克隆抗体与肿瘤溶解综合征之间的联系。报告比值比和信息部分被计算为不均衡性指标。进行了逐步灵敏度分析,以测试不均衡信号的稳健性。采用Bradford-Hill标准对潜在的因果关系进行全球评估。结果:从2004年到2022年,分别检测到197例、368例、41例和14例肿瘤溶解综合征报告中的奥比努单抗、利妥昔单抗、奥法图单抗和阿仑单抗(CD52单克隆抗体)。与其他抗癌药物相比,发现上述四种单克隆抗体的信号不成比例。敏感性分析证实了奥比努单抗、利妥昔单抗和奥法图单抗的稳健不均衡信号。利妥昔单抗、奥比努单抗和奥法图单抗的中位起效时间分别为4.5、1.5和2.5天。通过评估Bradford-Hill标准,可以确定潜在的因果关系。结论:这项针对美国食品药品监督管理局不良事件报告系统的药物警戒研究通过评估适用的Bradford-Hill标准,检测到CD20单克隆抗体(但不是CD52)与肿瘤溶解综合征之间的可能关联。迫切需要通过大规模的基于人群的比较研究来澄清药物和患者相关的风险因素。
{"title":"Tumor Lysis Syndrome with CD20 Monoclonal Antibodies for Chronic Lymphocytic Leukemia: Signals from the FDA Adverse Event Reporting System.","authors":"Shuang Xia,&nbsp;Jia-Ting Ma,&nbsp;Emanuel Raschi,&nbsp;Rui Ma,&nbsp;Bi-Kui Zhang,&nbsp;Linna Guo,&nbsp;Yoshihiro Noguchi,&nbsp;Mayur Sarangdhar,&nbsp;Hui Gong,&nbsp;Miao Yan","doi":"10.1007/s40261-023-01308-0","DOIUrl":"10.1007/s40261-023-01308-0","url":null,"abstract":"<p><strong>Background and objective: </strong>Although tumor lysis syndrome was reported with obinutuzumab and rituximab, the association with CD20 monoclonal antibodies for chronic lymphocytic leukemia is unclear.</p><p><strong>Methods: </strong>A disproportionality analysis was conducted to investigate the link between CD20 monoclonal antibodies and tumor lysis syndrome by accounting for known confounders and comparing with other anticancer drugs, using data from the US Food and Drug Administration Adverse Event Reporting System. Reporting odds ratios and the information component were calculated as disproportionality measures. A stepwise sensitivity analysis was conducted to test the robustness of disproportionality signals. Bradford Hill criteria were adopted to globally assess the potential causal relationship.</p><p><strong>Results: </strong>From 2004 to 2022, 197, 368, 41, and 14 tumor lysis syndrome reports were detected for obinutuzumab, rituximab, ofatumumab, and alemtuzumab (CD52 monoclonal antibody), respectively. Disproportionality signals were found for the above four monoclonal antibodies when compared with other anticancer drugs. Sensitivity analyses confirmed robust disproportionality signals for obinutuzumab, rituximab, and ofatumumab. The median onset time was 4.5, 1.5, and 2.5 days for rituximab, obinutuzumab, and ofatumumab, respectively. A potential causal relationship was fulfilled by assessing Bradford Hill criteria.</p><p><strong>Conclusions: </strong>This pharmacovigilance study on the FDA Adverse Event Reporting System detected a plausible association between CD20 monoclonal antibodies (but not CD52) and tumor lysis syndrome by assessing the adapted Bradford Hill criteria. Urgent clarification of drug- and patient-related risk factors is needed through large comparative population-based studies.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41112523","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: 1
Correction: Expanded Access Study of Palbociclib Plus Letrozole for Postmenopausal Women with HR+/HER2- Advanced Breast Cancer in Latin America for Whom Letrozole Therapy is Deemed Appropriate. 更正:Palbociclib联合来曲唑治疗拉丁美洲患有HR+/HER2-晚期癌症的绝经后妇女的扩大获取研究,来曲唑疗法被认为是合适的。
IF 3.2 3区 医学 Q2 Medicine Pub Date : 2023-09-01 DOI: 10.1007/s40261-023-01305-3
Luis Fein, Nicolas Lazaretti, Yamil López Chuken, J Rogelio González Ramírez Benfield, Max S Mano, Jose Lobaton, Ernesto Korbenfeld, Fernanda Damian, Dongrui R Lu, Ave Mori, Shem J Patyna, Sandra Franco
{"title":"Correction: Expanded Access Study of Palbociclib Plus Letrozole for Postmenopausal Women with HR+/HER2- Advanced Breast Cancer in Latin America for Whom Letrozole Therapy is Deemed Appropriate.","authors":"Luis Fein,&nbsp;Nicolas Lazaretti,&nbsp;Yamil López Chuken,&nbsp;J Rogelio González Ramírez Benfield,&nbsp;Max S Mano,&nbsp;Jose Lobaton,&nbsp;Ernesto Korbenfeld,&nbsp;Fernanda Damian,&nbsp;Dongrui R Lu,&nbsp;Ave Mori,&nbsp;Shem J Patyna,&nbsp;Sandra Franco","doi":"10.1007/s40261-023-01305-3","DOIUrl":"10.1007/s40261-023-01305-3","url":null,"abstract":"","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/44/c0/40261_2023_Article_1305.PMC10514132.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10200839","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
期刊
Clinical Drug Investigation
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