Pub Date : 2022-12-01Epub Date: 2022-10-20DOI: 10.1007/s40268-022-00405-3
Chaoying Hu, Dan Gao, Dandan Li, Dongli Zhou, Lan Zhang
Objective: We aimed to assess the bioequivalence, safety, and tolerability of Chinese- and French-manufactured Glucophage® immediate-release (GIR) tablets under fasted and fed conditions in healthy volunteers. A bioequivalence study was proposed to support the manufacturing transfer.
Methods: This was an open-label, randomized, two-period, two-sequence, crossover study. Subjects were randomly assigned to receive the test product (one 500 mg GIR tablet manufactured in China) or reference product (one 500 mg GIR tablet manufactured in France). The primary study endpoint was the area under the plasma concentration-time curve from time zero to the last sampling time (AUCt) and maximum observed concentration (Cmax).
Results: In total, 96 subjects were screened and 44 subjects were randomly assigned to treatment (fasted group, 26 subjects; fed group, 18 subjects). All 44 subjects received the study drug, completed the study, and were included in the pharmacokinetic (PK) and safety analysis sets. Under fasted or fed conditions, the mean AUCt and Cmax (primary PK parameters) were comparable between the test and reference products. Point estimates for both parameters were close to 100% and the corresponding 90% confidence intervals were within the specified 80-125% bioequivalence boundary. There were no hypoglycemia-related adverse events (AEs) in either treatment group. All AEs in the present study were mild in severity.
Conclusions: Bioequivalence between the test and reference GIR tablets was demonstrated under fasted and fed conditions and both were safe and well tolerated.
Clinical trials registration: This study was registered at ClinicalTrials.gov under the identifying number NCT03393208.
{"title":"Chinese- and French-Manufactured Immediate-Release Glucophage<sup>®</sup> Bioequivalence: A Randomized, Open-Label, Crossover Study.","authors":"Chaoying Hu, Dan Gao, Dandan Li, Dongli Zhou, Lan Zhang","doi":"10.1007/s40268-022-00405-3","DOIUrl":"https://doi.org/10.1007/s40268-022-00405-3","url":null,"abstract":"<p><strong>Objective: </strong>We aimed to assess the bioequivalence, safety, and tolerability of Chinese- and French-manufactured Glucophage<sup>®</sup> immediate-release (GIR) tablets under fasted and fed conditions in healthy volunteers. A bioequivalence study was proposed to support the manufacturing transfer.</p><p><strong>Methods: </strong>This was an open-label, randomized, two-period, two-sequence, crossover study. Subjects were randomly assigned to receive the test product (one 500 mg GIR tablet manufactured in China) or reference product (one 500 mg GIR tablet manufactured in France). The primary study endpoint was the area under the plasma concentration-time curve from time zero to the last sampling time (AUC<sub>t</sub>) and maximum observed concentration (C<sub>max</sub>).</p><p><strong>Results: </strong>In total, 96 subjects were screened and 44 subjects were randomly assigned to treatment (fasted group, 26 subjects; fed group, 18 subjects). All 44 subjects received the study drug, completed the study, and were included in the pharmacokinetic (PK) and safety analysis sets. Under fasted or fed conditions, the mean AUC<sub>t</sub> and C<sub>max</sub> (primary PK parameters) were comparable between the test and reference products. Point estimates for both parameters were close to 100% and the corresponding 90% confidence intervals were within the specified 80-125% bioequivalence boundary. There were no hypoglycemia-related adverse events (AEs) in either treatment group. All AEs in the present study were mild in severity.</p><p><strong>Conclusions: </strong>Bioequivalence between the test and reference GIR tablets was demonstrated under fasted and fed conditions and both were safe and well tolerated.</p><p><strong>Clinical trials registration: </strong>This study was registered at ClinicalTrials.gov under the identifying number NCT03393208.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/3a/ca/40268_2022_Article_405.PMC9700552.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40574857","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}
Pub Date : 2022-12-01Epub Date: 2022-09-22DOI: 10.1007/s40268-022-00402-6
Shuangyan Yang, Junfeng Zhang, Dan Chen, Jie Ding, Yanhong Zhang, Lili Song
Background and objectives: Aspirin is a common drug for the treatment of pre-eclampsia. We aimed to explore whether quercetin as a supplement to aspirin could enhance the therapeutic outcome in pre-eclampsia rat models. We further aimed to evaluate the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome as a potential pre-eclampsia-related molecular mechanism, which can be affected by quercetin treatment.
Methods: Rat pre-eclampsia models were established using an intravenous lipopolysaccharide injection after gestation. Rats were treated with aspirin and quercetin at 6-18 days after pregnancy. On day 20, blood, fetus, and placenta were harvested. Blood pressure and the level of proteinuria were measured every 4 days. Fetal outcomes were analyzed by pup body weight. Serum soluble Fms-like tyrosine kinase-1, PIGF, interleukin-6, and interleukin-10 levels were measured using the enzyme-linked immunosorbent assay. Caspase-1, NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain, and p-caspase-1 levels in the placenta were assessed using western blot or quantitative real-time polymerase chain reaction analyses.
Results: Pre-eclampsia rat models showed a pronounced increase in systolic blood pressure and proteinuria after 4 days of pregnancy, while aspirin, quercetin, and aspirin/quercetin combinatory treatment significantly attenuated the blood pressure and proteinuria abnormalities. Notably, the aspirin/quercetin combinatory treatment showed the highest efficacy in attenuating pre-eclampsia-like symptoms. Placental caspase-1 and NLRP3 levels also showed the greatest attenuation in pre-eclampsia rats after aspirin/quercetin treatment.
Conclusions: Our data suggested that quercetin supplementation to aspirin is more effective in attenuating symptoms of pre-eclampsia and improving pregnancy outcomes compared with quercetin or aspirin alone. Quercetin can ameliorate placental NLRP3 inflammasome activation, which might serve as an underlying mechanism for its therapeutic efficacies in pre-eclampsia.
{"title":"Quercetin Supplement to Aspirin Attenuates Lipopolysaccharide-Induced Pre-eclampsia-Like Impairments in Rats Through the NLRP3 Inflammasome.","authors":"Shuangyan Yang, Junfeng Zhang, Dan Chen, Jie Ding, Yanhong Zhang, Lili Song","doi":"10.1007/s40268-022-00402-6","DOIUrl":"https://doi.org/10.1007/s40268-022-00402-6","url":null,"abstract":"<p><strong>Background and objectives: </strong>Aspirin is a common drug for the treatment of pre-eclampsia. We aimed to explore whether quercetin as a supplement to aspirin could enhance the therapeutic outcome in pre-eclampsia rat models. We further aimed to evaluate the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome as a potential pre-eclampsia-related molecular mechanism, which can be affected by quercetin treatment.</p><p><strong>Methods: </strong>Rat pre-eclampsia models were established using an intravenous lipopolysaccharide injection after gestation. Rats were treated with aspirin and quercetin at 6-18 days after pregnancy. On day 20, blood, fetus, and placenta were harvested. Blood pressure and the level of proteinuria were measured every 4 days. Fetal outcomes were analyzed by pup body weight. Serum soluble Fms-like tyrosine kinase-1, PIGF, interleukin-6, and interleukin-10 levels were measured using the enzyme-linked immunosorbent assay. Caspase-1, NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain, and p-caspase-1 levels in the placenta were assessed using western blot or quantitative real-time polymerase chain reaction analyses.</p><p><strong>Results: </strong>Pre-eclampsia rat models showed a pronounced increase in systolic blood pressure and proteinuria after 4 days of pregnancy, while aspirin, quercetin, and aspirin/quercetin combinatory treatment significantly attenuated the blood pressure and proteinuria abnormalities. Notably, the aspirin/quercetin combinatory treatment showed the highest efficacy in attenuating pre-eclampsia-like symptoms. Placental caspase-1 and NLRP3 levels also showed the greatest attenuation in pre-eclampsia rats after aspirin/quercetin treatment.</p><p><strong>Conclusions: </strong>Our data suggested that quercetin supplementation to aspirin is more effective in attenuating symptoms of pre-eclampsia and improving pregnancy outcomes compared with quercetin or aspirin alone. Quercetin can ameliorate placental NLRP3 inflammasome activation, which might serve as an underlying mechanism for its therapeutic efficacies in pre-eclampsia.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/56/7a/40268_2022_Article_402.PMC9700538.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33470815","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}
Background and objectives: Irinotecan sometimes causes lethal septic shock but the risk factors remain unclear. This retrospective case-control study explored the potential risk factors for septic shock following irinotecan treatment.
Methods: All women who received irinotecan-containing chemotherapy for gynecologic malignancies at Shizuoka General Hospital from October 2014 to September 2020 were investigated. The clinical backgrounds and blood test results of those who developed septic shock after irinotecan-containing chemotherapy were compared with those who did not. Odds ratios (ORs) for developing septic shock after receiving irinotecan were calculated with 95% confidence intervals (CIs), using univariable logistic regression analysis.
Results: During the study period, 147 women received irinotecan-containing chemotherapy. Three women developed septic shock due to neutropenic enterocolitis after irinotecan treatment, and 144 did not. The three patients with septic shock had recurrent cervical cancer, heterozygous variants in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene (two patients had *1/*6, one had *1/*28 variants), a history of concurrent chemoradiation therapy, 50-60 Gy of pelvic irradiation, and platinum-combined chemotherapy. A history of pelvic irradiation was identified as a possible risk factor for developing septic shock after irinotecan-containing chemotherapy (OR 63.0, 95% CI 5.71-8635; p < 0.001). The OR of UGT1A1 polymorphism for septic shock was 9.09 (95% CI 0.86-1233; p = 0.070) in the complete case analysis.
Conclusion: Medical personnel involved in cancer therapy should consider the possible risk of septic shock developing due to neutropenic enterocolitis when administering irinotecan-containing chemotherapy in patients with a history of pelvic irradiation.
背景和目的:伊立替康有时会引起致命的感染性休克,但危险因素尚不清楚。本回顾性病例对照研究探讨伊立替康治疗后感染性休克的潜在危险因素。方法:对2014年10月至2020年9月在静冈县总医院接受伊立替康妇科恶性肿瘤化疗的所有女性进行调查。将伊立替康化疗后发生脓毒性休克的患者的临床背景和血检结果与未发生脓毒性休克的患者进行比较。采用单变量logistic回归分析,计算伊立替康治疗后感染性休克发生的比值比(ORs), 95%置信区间(ci)。结果:在研究期间,147名妇女接受了含伊立替康的化疗。伊立替康治疗后,3名妇女因中性粒细胞减少性小肠结肠炎发生感染性休克,144名妇女没有发生感染性休克。3例脓毒性休克患者均有宫颈癌复发、尿苷二磷酸葡萄糖醛基转移酶1A1 (UGT1A1)基因杂合变异(2例为*1/*6,1例为*1/*28)、同步放化疗史、50-60 Gy盆腔照射、铂联合化疗。盆腔照射史被认为是伊立替康化疗后发生感染性休克的可能危险因素(OR 63.0, 95% CI 5.71-8635;结论:参与癌症治疗的医务人员在对有盆腔照射史的患者进行含伊立替康化疗时,应考虑因中性粒细胞减少性小肠结肠炎发生脓毒性休克的可能风险。
{"title":"Risk Factors for Septic Shock After Irinotecan-Containing Chemotherapy: An Exploratory Case-Control Study.","authors":"Maki Umemiya, Yoshihide Inayama, Eiji Nakatani, Kenta Ito, Mitsuru Tsuji, Teruki Yoshida, Sae Yu, Rei Gou, Naoki Horikawa, Hirohiko Tani, Kenzo Kosaka","doi":"10.1007/s40268-022-00399-y","DOIUrl":"https://doi.org/10.1007/s40268-022-00399-y","url":null,"abstract":"<p><strong>Background and objectives: </strong>Irinotecan sometimes causes lethal septic shock but the risk factors remain unclear. This retrospective case-control study explored the potential risk factors for septic shock following irinotecan treatment.</p><p><strong>Methods: </strong>All women who received irinotecan-containing chemotherapy for gynecologic malignancies at Shizuoka General Hospital from October 2014 to September 2020 were investigated. The clinical backgrounds and blood test results of those who developed septic shock after irinotecan-containing chemotherapy were compared with those who did not. Odds ratios (ORs) for developing septic shock after receiving irinotecan were calculated with 95% confidence intervals (CIs), using univariable logistic regression analysis.</p><p><strong>Results: </strong>During the study period, 147 women received irinotecan-containing chemotherapy. Three women developed septic shock due to neutropenic enterocolitis after irinotecan treatment, and 144 did not. The three patients with septic shock had recurrent cervical cancer, heterozygous variants in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene (two patients had *1/*6, one had *1/*28 variants), a history of concurrent chemoradiation therapy, 50-60 Gy of pelvic irradiation, and platinum-combined chemotherapy. A history of pelvic irradiation was identified as a possible risk factor for developing septic shock after irinotecan-containing chemotherapy (OR 63.0, 95% CI 5.71-8635; p < 0.001). The OR of UGT1A1 polymorphism for septic shock was 9.09 (95% CI 0.86-1233; p = 0.070) in the complete case analysis.</p><p><strong>Conclusion: </strong>Medical personnel involved in cancer therapy should consider the possible risk of septic shock developing due to neutropenic enterocolitis when administering irinotecan-containing chemotherapy in patients with a history of pelvic irradiation.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/30/47/40268_2022_Article_399.PMC9700533.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40627141","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}
Pub Date : 2022-12-01Epub Date: 2022-08-24DOI: 10.1007/s40268-022-00400-8
Matthew W McCarthy
On 4 September, 2020, the US National Institutes of Health launched a new clinical trial, "A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic and Additional Strategies in Hospitalized Adults with COVID-19." This open-label, placebo-controlled, multicenter, adaptive platform study was designed to evaluate therapeutic options for patients hospitalized with mild, moderate, or severe COVID-19. A variety of drugs and drug classes were selected, including heparin, the monoclonal antibody crizanlizumab, sodium-glucose cotransporter-2 inhibitors, and purinergic signaling receptor Y12 inhibitors. These medications have been widely used in the treatment of other conditions, from sick cell disease to type 2 diabetes mellitus and some forms of cardiovascular disease, but their inclusion in a study of COVID-19 was somewhat unexpected. This article examines the rationale behind the use of these disparate agents in the treatment and prevention of adverse outcomes in patients with COVID-19 and explores how these strategies may be utilized in the future to address the severe acute respiratory syndrome coronavirus 2 pandemic.
{"title":"Novel Strategies for the Treatment of COVID-19.","authors":"Matthew W McCarthy","doi":"10.1007/s40268-022-00400-8","DOIUrl":"https://doi.org/10.1007/s40268-022-00400-8","url":null,"abstract":"<p><p>On 4 September, 2020, the US National Institutes of Health launched a new clinical trial, \"A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic and Additional Strategies in Hospitalized Adults with COVID-19.\" This open-label, placebo-controlled, multicenter, adaptive platform study was designed to evaluate therapeutic options for patients hospitalized with mild, moderate, or severe COVID-19. A variety of drugs and drug classes were selected, including heparin, the monoclonal antibody crizanlizumab, sodium-glucose cotransporter-2 inhibitors, and purinergic signaling receptor Y<sub>12</sub> inhibitors. These medications have been widely used in the treatment of other conditions, from sick cell disease to type 2 diabetes mellitus and some forms of cardiovascular disease, but their inclusion in a study of COVID-19 was somewhat unexpected. This article examines the rationale behind the use of these disparate agents in the treatment and prevention of adverse outcomes in patients with COVID-19 and explores how these strategies may be utilized in the future to address the severe acute respiratory syndrome coronavirus 2 pandemic.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/90/85/40268_2022_Article_400.PMC9398904.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40632756","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}
Pub Date : 2022-12-01Epub Date: 2022-10-07DOI: 10.1007/s40268-022-00404-4
Christopher Hawthorne, Martin Shaw, Ruaraidh Campbell, Nicholas Sutcliffe, Shiona McKelvie, Stefan Schraag
Background and objective: Pharmacokinetic or pharmacokinetic-pharmacodynamic models have been instrumental in facilitating the clinical use of propofol in target-controlled infusion systems in anaesthetic practice. There has been debate over which model should be recommended for practice. The covariates model is an updated pharmacokinetic model for propofol. The aim of this study was to prospectively validate this model in an adult population.
Methods: Twenty-nine patients were included, with a range of ages to assess model performance in younger and older individuals. Subjects received propofol through a target-controlled infusion device programmed with the covariates model. Subjects were randomised to one of two increasing/decreasing regimes of propofol plasma target concentrations between 2 and 5 μg.mL-1. After the start of the infusion, arterial and venous blood samples were drawn at pre-specified timepoints between 1.5 and 20 min and between 1.5 and 45 min, respectively. Predictive performance was assessed using established methodology.
Results: The model achieved a bias of 9 (- 45 to 82) and precision of 24 (9-82) for arterial samples and bias of - 8 (- 64 to 70) and precision of 23 (9-70) for venous samples. Predicted concentrations tended to be higher than the measured concentrations in female individuals but lower in male individuals. There was no clear systematic difference in the bias between younger and older patients.
Conclusions: The covariates propofol pharmacokinetic model achieved an acceptable level of predictive performance, as assessed by both arterial and venous sampling, for use in target-controlled infusion in clinical practice.
{"title":"Clinical Validation of the Covariates Pharmacokinetic Model for Propofol in an Adult Population.","authors":"Christopher Hawthorne, Martin Shaw, Ruaraidh Campbell, Nicholas Sutcliffe, Shiona McKelvie, Stefan Schraag","doi":"10.1007/s40268-022-00404-4","DOIUrl":"https://doi.org/10.1007/s40268-022-00404-4","url":null,"abstract":"<p><strong>Background and objective: </strong>Pharmacokinetic or pharmacokinetic-pharmacodynamic models have been instrumental in facilitating the clinical use of propofol in target-controlled infusion systems in anaesthetic practice. There has been debate over which model should be recommended for practice. The covariates model is an updated pharmacokinetic model for propofol. The aim of this study was to prospectively validate this model in an adult population.</p><p><strong>Methods: </strong>Twenty-nine patients were included, with a range of ages to assess model performance in younger and older individuals. Subjects received propofol through a target-controlled infusion device programmed with the covariates model. Subjects were randomised to one of two increasing/decreasing regimes of propofol plasma target concentrations between 2 and 5 μg.mL<sup>-1</sup>. After the start of the infusion, arterial and venous blood samples were drawn at pre-specified timepoints between 1.5 and 20 min and between 1.5 and 45 min, respectively. Predictive performance was assessed using established methodology.</p><p><strong>Results: </strong>The model achieved a bias of 9 (- 45 to 82) and precision of 24 (9-82) for arterial samples and bias of - 8 (- 64 to 70) and precision of 23 (9-70) for venous samples. Predicted concentrations tended to be higher than the measured concentrations in female individuals but lower in male individuals. There was no clear systematic difference in the bias between younger and older patients.</p><p><strong>Conclusions: </strong>The covariates propofol pharmacokinetic model achieved an acceptable level of predictive performance, as assessed by both arterial and venous sampling, for use in target-controlled infusion in clinical practice.</p><p><strong>Clinical trial registration: </strong>NCT01492712 (15 December, 2011).</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/26/4e/40268_2022_Article_404.PMC9700536.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33494376","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}
Pub Date : 2022-11-17DOI: 10.1007/s40268-022-00409-z
Not Available Not Available
{"title":"Acknowledgement to Referees","authors":"Not Available Not Available","doi":"10.1007/s40268-022-00409-z","DOIUrl":"https://doi.org/10.1007/s40268-022-00409-z","url":null,"abstract":"","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43497698","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}
Pub Date : 2022-09-01Epub Date: 2022-06-20DOI: 10.1007/s40268-022-00391-6
Angela Genge, Benjamin Rix Brooks, Björn Oskarsson, Alexander Kalin, Ming Ji, Stephen Apple, Laura Bower
Background: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease with no curative therapies. Edaravone (Radicava®) (Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan), approved in the United States (US) for ALS in adults in 2017, was shown in a clinical trial to slow the rate of physical functional decline in ALS and is administered intravenously. The aim of this paper is to summarize the observed safety profile from real-world patient use during the first 3 years of edaravone availability in the US.
Methods: Edaravone usage data were collected, and adverse events (AEs) were identified from a postmarketing safety database from August 8, 2017 through August 7, 2020 (cutoff date).
Results: As of October 3, 2020, 5207 ALS patients had been treated with edaravone. As of August 7, 2020, the most commonly reported AEs included death (not specified), drug ineffective, disease progression, therapeutic response unexpected, fall, asthenia, fatigue, muscular weakness, gait disturbance, and dyspnea. The most commonly reported serious AEs (SAEs) included death (not specified), pneumonia, disease progression, ALS, fall, dyspnea, respiratory failure, device-related infection, hospitalization, and injection-site infection. There were 687 deaths, with 494 reported as death without specifying the cause. Deaths were most commonly attributed to ALS, disease progression, respiratory failure, or pneumonia. Review for administration-site reactions revealed 95 AEs, including 34 site infections, with 22 SAEs (all non-fatal). Five non-fatal SAEs of anaphylaxis were reported.
Conclusion: In the postmarketing reporting to date, no new safety signals were identified beyond those already known from the edaravone clinical trial program.
背景:肌萎缩性侧索硬化症(ALS)是一种进行性、致死性神经肌肉疾病,目前尚无治愈方法。依达拉奉(Radicava®)(Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan)于2017年在美国(US)获批用于成人ALS,一项临床试验显示,依达拉奉可减缓ALS患者身体功能下降的速度,并可静脉给药。本文的目的是总结在依达拉奉在美国上市的前3年,从实际患者使用中观察到的安全性概况。方法:收集依达拉奉使用数据,并从2017年8月8日至2020年8月7日(截止日期)的上市后安全数据库中确定不良事件(ae)。结果:截至2020年10月3日,5207名ALS患者接受了依达拉奉治疗。截至2020年8月7日,最常见的ae报告包括死亡(未指定)、药物无效、疾病进展、治疗反应出乎意料、跌倒、乏力、疲劳、肌肉无力、步态障碍和呼吸困难。最常见的严重ae (SAEs)包括死亡(未指明)、肺炎、疾病进展、ALS、跌倒、呼吸困难、呼吸衰竭、器械相关感染、住院和注射部位感染。共有687人死亡,其中494人报告死亡但未说明死因。死亡最常见的原因是ALS、疾病进展、呼吸衰竭或肺炎。对给药部位反应的回顾显示95例ae,包括34例部位感染,22例SAEs(均非致命)。报告了5例非致死性过敏性休克。结论:在迄今为止的上市后报告中,除了依达拉奉临床试验项目中已知的安全信号外,没有发现新的安全信号。
{"title":"Analysis of the US Safety Data for Edaravone (Radicava<sup>®</sup>) From the Third Year After Launch.","authors":"Angela Genge, Benjamin Rix Brooks, Björn Oskarsson, Alexander Kalin, Ming Ji, Stephen Apple, Laura Bower","doi":"10.1007/s40268-022-00391-6","DOIUrl":"https://doi.org/10.1007/s40268-022-00391-6","url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease with no curative therapies. Edaravone (Radicava<sup>®</sup>) (Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan), approved in the United States (US) for ALS in adults in 2017, was shown in a clinical trial to slow the rate of physical functional decline in ALS and is administered intravenously. The aim of this paper is to summarize the observed safety profile from real-world patient use during the first 3 years of edaravone availability in the US.</p><p><strong>Methods: </strong>Edaravone usage data were collected, and adverse events (AEs) were identified from a postmarketing safety database from August 8, 2017 through August 7, 2020 (cutoff date).</p><p><strong>Results: </strong>As of October 3, 2020, 5207 ALS patients had been treated with edaravone. As of August 7, 2020, the most commonly reported AEs included death (not specified), drug ineffective, disease progression, therapeutic response unexpected, fall, asthenia, fatigue, muscular weakness, gait disturbance, and dyspnea. The most commonly reported serious AEs (SAEs) included death (not specified), pneumonia, disease progression, ALS, fall, dyspnea, respiratory failure, device-related infection, hospitalization, and injection-site infection. There were 687 deaths, with 494 reported as death without specifying the cause. Deaths were most commonly attributed to ALS, disease progression, respiratory failure, or pneumonia. Review for administration-site reactions revealed 95 AEs, including 34 site infections, with 22 SAEs (all non-fatal). Five non-fatal SAEs of anaphylaxis were reported.</p><p><strong>Conclusion: </strong>In the postmarketing reporting to date, no new safety signals were identified beyond those already known from the edaravone clinical trial program.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c0/8f/40268_2022_Article_391.PMC9433633.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40070552","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}
Pub Date : 2022-09-01Epub Date: 2022-08-07DOI: 10.1007/s40268-022-00393-4
Roman Borišek, André Mischo, Ida Šmid
Aim: The purpose of this study was to evaluate the extended physicochemical and biological stability of Sandoz Rixathon®/Riximyo® (SDZ-RTX) after exposure to out-of-fridge (OOF) conditions.
Materials and methods: The impact of the short-term temperature excursion on stability parameters of SDZ-RTX was simulated by subsequently exposing the three batches of SDZ-RTX (100 and 500 mg) to OOF conditions, (I) 25 ± 2 °C/60 ± 5% relative humidity (RH) and (II) 30 ± 2 °C/65 ± 5% RH, for up to 21 days after more than the claimed 36-month shelf-life storage in long-term conditions (5 ± 3 °C). Analytical methods used included the cation exchange chromatography (CEX), size exclusion chromatography (SEC), and non-reducing capillary electrophoresis-sodium dodecyl sulfate (nrCE-SDS), as well as biological activity by complement-dependent cytotoxicity (CDC)-bioactivity as well as further methods, for example, related to identity and pharmacopoeia test methods.
Results: No notable changes were observed across all batches with respect to identity (charge and primary structure), pharmaceutical tests (clarity, visible and subvisible particles analytics, container appearance, degree of coloration, pH, osmolality, extractable volume, and container closure integrity testing), protein content by UV and microbiological parameters (sterility and bacterial endotoxins) under both OOF conditions. Only minor changes were observed for parameters evaluated via SEC, CEX, and nrCE-SDS. For potency (CDC-bioactivity) only one of the batches showed a relevant change. Even for these stability-indicating test methods, all analyzed parameters complied with the shelf-life specifications.
Conclusion: SDZ-RTX is safe for use even under worst-case conditions, for example, after subjecting it for up to 21 days at OOF conditions (25 ± 2 °C/60 ± 5% RH or 30 ± 2 °C/65 ± 5% RH) after the batches had reached an age that was already beyond the claimed shelf-life.
{"title":"Study of the Stability of Sandoz Rituximab Biosimilar Rixathon<sup>®</sup>/Riximyo<sup>®</sup> When Subjected for up to 21 Days to Ambient Storage.","authors":"Roman Borišek, André Mischo, Ida Šmid","doi":"10.1007/s40268-022-00393-4","DOIUrl":"https://doi.org/10.1007/s40268-022-00393-4","url":null,"abstract":"<p><strong>Aim: </strong>The purpose of this study was to evaluate the extended physicochemical and biological stability of Sandoz Rixathon®/Riximyo® (SDZ-RTX) after exposure to out-of-fridge (OOF) conditions.</p><p><strong>Materials and methods: </strong>The impact of the short-term temperature excursion on stability parameters of SDZ-RTX was simulated by subsequently exposing the three batches of SDZ-RTX (100 and 500 mg) to OOF conditions, (I) 25 ± 2 °C/60 ± 5% relative humidity (RH) and (II) 30 ± 2 °C/65 ± 5% RH, for up to 21 days after more than the claimed 36-month shelf-life storage in long-term conditions (5 ± 3 °C). Analytical methods used included the cation exchange chromatography (CEX), size exclusion chromatography (SEC), and non-reducing capillary electrophoresis-sodium dodecyl sulfate (nrCE-SDS), as well as biological activity by complement-dependent cytotoxicity (CDC)-bioactivity as well as further methods, for example, related to identity and pharmacopoeia test methods.</p><p><strong>Results: </strong>No notable changes were observed across all batches with respect to identity (charge and primary structure), pharmaceutical tests (clarity, visible and subvisible particles analytics, container appearance, degree of coloration, pH, osmolality, extractable volume, and container closure integrity testing), protein content by UV and microbiological parameters (sterility and bacterial endotoxins) under both OOF conditions. Only minor changes were observed for parameters evaluated via SEC, CEX, and nrCE-SDS. For potency (CDC-bioactivity) only one of the batches showed a relevant change. Even for these stability-indicating test methods, all analyzed parameters complied with the shelf-life specifications.</p><p><strong>Conclusion: </strong>SDZ-RTX is safe for use even under worst-case conditions, for example, after subjecting it for up to 21 days at OOF conditions (25 ± 2 °C/60 ± 5% RH or 30 ± 2 °C/65 ± 5% RH) after the batches had reached an age that was already beyond the claimed shelf-life.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/af/60/40268_2022_Article_393.PMC9433506.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40686131","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}
Pub Date : 2022-09-01Epub Date: 2022-08-03DOI: 10.1007/s40268-022-00396-1
Andrea Chiricozzi, Niccolò Gori, Alessandra Narcisi, Anna Balato, Alessio Gambardella, Michela Ortoncelli, Angelo Valerio Marzano, Riccardo Balestri, Giovanni Palazzo, Michele Pellegrino, Marco Romanelli, Giovanni Tripepi, Ketty Peris, Antonio Costanzo
Background: The efficacy and safety of upadacitinib in atopic dermatitis (AD) have been defined in clinical trials, but no real-world data are currently available. We aimed to assess the safety and effectiveness of upadacitinib in a real-world AD patient cohort that mostly included patients who failed the available systemic therapies, including dupilumab.
Methods: Prospective cohort study collecting data on upadacitinib-treated AD adult patients completing at least 16 weeks of therapy.
Results: Forty-three patients showed rapid and marked response to upadacitinib with significant reduction of all disease severity scores since the first follow-up visit. At week 16, Eczema Area and Severity Index (EASI) 75, EASI 90, and EASI 100 response was observed in 97.5%, 82.1%, and 69.2% of patients, respectively. EASI 90 response reflected the achievement of a clear or almost clear condition (POEM 0-2), self-evaluated by 79.5% of patients. Patients' quality of life improved as suggested by the achievement of DLQI 0/1 by 38.5% of patients at week 4, and by 76.9% at week 16.
Conclusion: Elevated effectiveness and favorable safety of upadacitinib were confirmed in patients unresponsive to dupilumab, who were not included in upadacitinib trials.
{"title":"Effectiveness and Safety of Upadacitinib in the Treatment of Moderate-Severe Atopic Dermatitis: A Multicentric, Prospective, Real-World, Cohort Study.","authors":"Andrea Chiricozzi, Niccolò Gori, Alessandra Narcisi, Anna Balato, Alessio Gambardella, Michela Ortoncelli, Angelo Valerio Marzano, Riccardo Balestri, Giovanni Palazzo, Michele Pellegrino, Marco Romanelli, Giovanni Tripepi, Ketty Peris, Antonio Costanzo","doi":"10.1007/s40268-022-00396-1","DOIUrl":"https://doi.org/10.1007/s40268-022-00396-1","url":null,"abstract":"<p><strong>Background: </strong>The efficacy and safety of upadacitinib in atopic dermatitis (AD) have been defined in clinical trials, but no real-world data are currently available. We aimed to assess the safety and effectiveness of upadacitinib in a real-world AD patient cohort that mostly included patients who failed the available systemic therapies, including dupilumab.</p><p><strong>Methods: </strong>Prospective cohort study collecting data on upadacitinib-treated AD adult patients completing at least 16 weeks of therapy.</p><p><strong>Results: </strong>Forty-three patients showed rapid and marked response to upadacitinib with significant reduction of all disease severity scores since the first follow-up visit. At week 16, Eczema Area and Severity Index (EASI) 75, EASI 90, and EASI 100 response was observed in 97.5%, 82.1%, and 69.2% of patients, respectively. EASI 90 response reflected the achievement of a clear or almost clear condition (POEM 0-2), self-evaluated by 79.5% of patients. Patients' quality of life improved as suggested by the achievement of DLQI 0/1 by 38.5% of patients at week 4, and by 76.9% at week 16.</p><p><strong>Conclusion: </strong>Elevated effectiveness and favorable safety of upadacitinib were confirmed in patients unresponsive to dupilumab, who were not included in upadacitinib trials.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/a5/e9/40268_2022_Article_396.PMC9362214.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40598046","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}
Pub Date : 2022-09-01Epub Date: 2022-08-02DOI: 10.1007/s40268-022-00394-3
Manuel Román Martinez, Eva García Aguilar, Samuel Martin Vílchez, Javier González García, Sergio Luquero-Bueno, Paola Camargo-Mamani, Gina Mejia-Abril, Laura García-Castro, Alejandro de Miguel-Cáceres, Paula Saz-Leal, Francisco Abad-Santos, Concepcion Nieto Magro, Dolores Ochoa Mazarro
Background: Melatonin is an endogenous substance which plays a key role in sleep induction by reducing sleep onset latency; it has been approved by the European Food Safety Authority as a food supplement for exogenous administration. Oniria® is a food supplement formulated as 1.98 mg of prolonged-release melatonin tablets; it displays a dual dissolution profile in vitro.
Objectives: The main objective of the present study was to evaluate the relative oral bioavailability of Oniria®, in comparison with immediate-release tablets (IRT) with a similar melatonin content as a reference. We also attempted to characterize the circadian rhythm of endogenous melatonin.
Methods: We performed an open-label, cross-over, randomized, phase I clinical study with two sequences and three periods involving 14 healthy volunteers. We characterized the endogenous melatonin circadian profile (period 1) and pharmacokinetics (PK) of both Oniria® and the reference melatonin (periods 2 and 3).
Results: Two phases were clearly differentiated in the PK profile of Oniria®. An initial one, from dosing up to 2 h, and a delayed one from 2 to 11 h post-administration. During the initial phase, both melatonin formulations were equivalent, with a Cmax value close to 4000 pg/mL. However, in the delayed phase, Oniria® showed significantly higher melatonin concentrations than the IRT (three times higher at 4-6 h post-administration). Moreover, Oniria® exhibited concentrations above the endogenous melatonin peak of 80 pg/mL for up to 2.5 h versus the reference formulation, potentially suggesting an effect of Oniria®, not only in the induction of sleep, but also in the maintenance.
Conclusion: Oniria® could be a highly promising food supplement, not only for sleep induction but also for the maintenance of sleep.
{"title":"Bioavailability of Oniria<sup>®</sup>, a Melatonin Prolonged-Release Formulation, Versus Immediate-Release Melatonin in Healthy Volunteers.","authors":"Manuel Román Martinez, Eva García Aguilar, Samuel Martin Vílchez, Javier González García, Sergio Luquero-Bueno, Paola Camargo-Mamani, Gina Mejia-Abril, Laura García-Castro, Alejandro de Miguel-Cáceres, Paula Saz-Leal, Francisco Abad-Santos, Concepcion Nieto Magro, Dolores Ochoa Mazarro","doi":"10.1007/s40268-022-00394-3","DOIUrl":"10.1007/s40268-022-00394-3","url":null,"abstract":"<p><strong>Background: </strong>Melatonin is an endogenous substance which plays a key role in sleep induction by reducing sleep onset latency; it has been approved by the European Food Safety Authority as a food supplement for exogenous administration. Oniria<sup>®</sup> is a food supplement formulated as 1.98 mg of prolonged-release melatonin tablets; it displays a dual dissolution profile in vitro.</p><p><strong>Objectives: </strong>The main objective of the present study was to evaluate the relative oral bioavailability of Oniria<sup>®</sup>, in comparison with immediate-release tablets (IRT) with a similar melatonin content as a reference. We also attempted to characterize the circadian rhythm of endogenous melatonin.</p><p><strong>Methods: </strong>We performed an open-label, cross-over, randomized, phase I clinical study with two sequences and three periods involving 14 healthy volunteers. We characterized the endogenous melatonin circadian profile (period 1) and pharmacokinetics (PK) of both Oniria<sup>®</sup> and the reference melatonin (periods 2 and 3).</p><p><strong>Results: </strong>Two phases were clearly differentiated in the PK profile of Oniria<sup>®</sup>. An initial one, from dosing up to 2 h, and a delayed one from 2 to 11 h post-administration. During the initial phase, both melatonin formulations were equivalent, with a C<sub>max</sub> value close to 4000 pg/mL. However, in the delayed phase, Oniria<sup>®</sup> showed significantly higher melatonin concentrations than the IRT (three times higher at 4-6 h post-administration). Moreover, Oniria<sup>®</sup> exhibited concentrations above the endogenous melatonin peak of 80 pg/mL for up to 2.5 h versus the reference formulation, potentially suggesting an effect of Oniria<sup>®</sup>, not only in the induction of sleep, but also in the maintenance.</p><p><strong>Conclusion: </strong>Oniria<sup>®</sup> could be a highly promising food supplement, not only for sleep induction but also for the maintenance of sleep.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/fa/ef/40268_2022_Article_394.PMC9433621.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40665668","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}