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Prediction Model for Severe Thrombocytopenia Induced by Gemcitabine Plus Cisplatin Combination Therapy in Patients with Urothelial Cancer 吉西他滨加顺铂联合疗法诱发泌尿系统癌症患者严重血小板减少症的预测模型
IF 3.2 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-04-29 DOI: 10.1007/s40261-024-01361-3
Noriaki Matsumoto, Tomohiro Mizuno, Yosuke Ando, Koki Kato, Masanori Nakanishi, Tsuyoshi Nakai, Jeannie K. Lee, Yoshitaka Kameya, Wataru Nakamura, Kiyoshi Takahara, Ryoichi Shiroki, Shigeki Yamada

Background

Chemotherapy-induced thrombocytopenia is often a use-limiting adverse reaction to gemcitabine and cisplatin (GC) combination chemotherapy, reducing therapeutic intensity, and, in some cases, requiring platelet transfusion.

Objective

A retrospective cohort study was conducted on patients with urothelial cancer at the initiation of GC combination therapy and the objective was to develop a prediction model for the incidence of severe thrombocytopenia using machine learning.

Methods

We performed receiver operating characteristic analysis to determine the cut-off values of the associated factors. Multivariate analyses were conducted to identify risk factors associated with the occurrence of severe thrombocytopenia. The prediction model was constructed from an ensemble model and gradient-boosted decision trees to estimate the risk of an outcome using the risk factors associated with the occurrence of severe thrombocytopenia.

Results

Of 186 patients included in this study, 46 (25%) experienced severe thrombocytopenia induced by GC therapy. Multivariate analyses revealed that platelet count ≤ 21.4 (×104/µL) [odds ratio 7.19, p < 0.01], hemoglobin ≤ 12.1 (g/dL) [odds ratio 2.41, p = 0.03], lymphocyte count ≤ 1.458 (×103/µL) [odds ratio 2.47, p = 0.02], and dose of gemcitabine ≥ 775.245 (mg/m2) [odds ratio 4.00, p < 0.01] were risk factors of severe thrombocytopenia. The performance of the prediction model using these associated factors was high (area under the curve 0.76, accuracy 0.82, precision 0.68, recall 0.50, and F-measure 0.58).

Conclusions

Platelet count, hemoglobin level, lymphocyte count, and gemcitabine dose contributed to the development of a novel prediction model to identify the incidence of GC-induced severe thrombocytopenia.

背景化疗引起的血小板减少通常是限制吉西他滨和顺铂(GC)联合化疗的不良反应,会降低治疗强度,在某些情况下还需要输注血小板。方法 我们进行了接受者操作特征分析,以确定相关因素的临界值。我们进行了接受者操作特征分析,以确定相关因素的临界值;进行了多变量分析,以确定与严重血小板减少症发生相关的风险因素。预测模型由集合模型和梯度提升决策树构建而成,利用与严重血小板减少症发生相关的风险因素来估计结果的风险。多变量分析显示,血小板计数≤ 21.4 (×104/µL) [几率比 7.19, p < 0.01]、血红蛋白≤ 12.1 (g/dL) [几率比 2.41, p = 0.03]、淋巴细胞计数≤ 1.458 (×103/µL) [几率比 2.47, p = 0.02],吉西他滨剂量≥ 775.245 (mg/m2) [几率比 4.00, p <0.01]是严重血小板减少的危险因素。结论血小板计数、血红蛋白水平、淋巴细胞计数和吉西他滨剂量有助于建立一个新的预测模型,以确定 GC 诱导的严重血小板减少症的发生率。
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引用次数: 0
Safety, Tolerability, and Pharmacokinetics of Oral BI 1358894 in Healthy Japanese Male Volunteers 口服 BI 1358894 对日本男性健康志愿者的安全性、耐受性和药代动力学研究
IF 3.2 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-04-24 DOI: 10.1007/s40261-024-01357-z
Jangsoo Yoon, Vikas Sharma, Akiko Harada

Background and Objectives

BI 1358894, a novel small-molecule inhibitor of transient receptor potential canonical ion channels, is under development for treatment of major depressive disorder. Phase I trials assessing the safety and pharmacokinetics of BI 1358894 in Caucasian male healthy volunteers (HVs) have been performed. This Phase I, double-blind, placebo-controlled, parallel-group trial assessed the safety, tolerability and pharmacokinetics of BI 1358894 in Japanese male HVs.

Methods

Male HVs were randomized to receive oral BI 1358894 (n = 18) or placebo (n = 6) after a high-fat, high-calorie meal within three dose groups (50 mg, 100 mg, 200 mg), administered sequentially in dose-ascending order. The primary endpoint was number of HVs with drug-related adverse events (DRAEs). Secondary endpoints were the pharmacokinetic parameters of BI 1358894.

Results

Overall, 24 male HVs entered the trial [mean (standard deviation) age: 30.0 (7.6) years]. DRAEs occurred in 3/18 HVs (BI 1358894 100 mg group: one HV experienced dizziness and headache; BI 1358894 200 mg group: one HV experienced headache, another reported sleep disorder). BI 1358894 exposure increased dose dependently and proportionally, peaking 4–6 h after administration before declining in a multiphasic manner with a terminal elimination half-life of ~70 h in the 50 mg and 100 mg dose groups, and 203 h in the 200 mg dose group.

Conclusion

BI 1358894 was well tolerated with a favorable pharmacokinetic profile in Japanese male HVs, similar to findings from a previous study in Caucasian male HVs.

Trial Registration

ClinicalTrials.gov (NCT03875001; 08-Mar-2019).

背景和目标BI 1358894是一种新型小分子瞬时受体电位离子通道抑制剂,目前正在开发用于治疗重度抑郁症。已在白种男性健康志愿者(HVs)中进行了 I 期试验,评估 BI 1358894 的安全性和药代动力学。该 I 期双盲安慰剂对照平行组试验评估了 BI 1358894 在日本男性健康志愿者中的安全性、耐受性和药代动力学。主要终点是发生药物相关不良事件(DRAE)的 HV 人数。结果共有 24 名男性 HV 参与试验[平均(标准差)年龄:30.0(7.6)岁]。3/18 名 HV 出现了 DRAE(BI 1358894 100 毫克组:一名 HV 出现头晕和头痛;BI 1358894 200 毫克组:一名 HV 出现头痛,另一名报告出现睡眠障碍)。结论BI 1358894在日本男性HV中耐受性良好,药代动力学特征良好,与之前在高加索男性HV中的研究结果相似。
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引用次数: 0
Risk of Cardiovascular Events in Schizophrenic Patients Treated with Paliperidone Palmitate Once-Monthly Injection (PP1M): A Population-Based Retrospective Cohort Study in Taiwan 帕潘立酮棕榈酸酯每月一次注射液(PP1M)治疗精神分裂症患者发生心血管事件的风险:台湾一项基于人群的回顾性队列研究
IF 3.2 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-04-15 DOI: 10.1007/s40261-024-01358-y
Shih-Pei Shen, Li Yan, Tao Wu, Min-Wei Huang, Kuan-Chih Huang, Hong Qiu, Yongjing Zhang, Chao-Hsiun Tang

Background

Schizophrenia is one of the leading causes of disability. Paliperidone palmitate once-monthly injection (PP1M) was developed to provide consistent drug delivery and improve medication adherence for maintenance treatment. It is well known that patients with schizophrenia have higher cardiovascular risks, however little is known about the cardiovascular risks of patients with schizophrenia treated with PP1M in Asia.

Objective

This study aimed to estimate the incidence of cardiovascular events after initiating PP1M treatment and evaluate the cardiovascular risk associations compared with oral second-generation antipsychotics (SGAs).

Methods

Data from Taiwan’s National Health Insurance Research Database were used to identify a cohort of adult patients with schizophrenia who received any SGAs from 1 March 2012 to 31 December 2018. Patients who initiated PP1M treatment were enrolled for descriptive analysis of incidence rates. PP1M patients were propensity matched 1:1 to patients initiating a new oral SGA, for comparative analysis based on demographics, clinical characteristics and treatment history at baseline, in three-step matching procedures, following the prevalent new-user design to enhance comparability. Follow-up ended at the end of the treatment episode of index drug, death, last record available, or end of the study (31 December 2019). Study endpoints included serious cardiovascular events (including severe ventricular arrhythmia and sudden death), expanded serious cardiovascular events (which further included acute myocardial infarction and ischemic stroke), and cardiovascular hospitalizations. Risks of study endpoints between matched cohorts were compared using Cox regression.

Results

Overall, 11,023 patients initiating PP1M treatment were identified (49.5% were females; mean age of 43.2 [12.2] years). Overall incidences for serious cardiovascular events, expanded serious cardiovascular events, and cardiovascular hospitalizations were 3.92, 7.88 and 51.96 per 1000 person-years, respectively. In matched cohort analysis (N = 10,115), the hazard ratios (HRs) between initiating PP1M and a new oral SGA for serious cardiovascular events, expanded serious cardiovascular events, and cardiovascular hospitalizations were 0.86 (95% confidence interval [CI] 0.55–1.36), 0.88 (95% CI 0.63–1.21), and 0.78 (95% CI 0.69–0.89), respectively.

Conclusion

This study reported the population-based incidence of cardiovascular events in schizophrenic patients initiating PP1M treatment. PP1M was not associated with increased risks of serious cardiovascular events but was potentially associated with lower risks of cardiovascular hospitalizations compared with oral SGAs.

背景精神分裂症是导致残疾的主要原因之一。帕潘立酮棕榈酸酯每月一次注射液(PP1M)的开发旨在为维持治疗提供稳定的给药方式并提高用药依从性。众所周知,精神分裂症患者的心血管风险较高,但在亚洲,人们对接受帕利哌酮棕榈酸酯注射液治疗的精神分裂症患者的心血管风险知之甚少。本研究旨在估算开始接受帕利哌酮棕榈酸酯注射液治疗后心血管事件的发生率,并评估与口服第二代抗精神病药物(SGAs)相比的心血管风险关联。方法利用台湾国民健康保险研究数据库的数据,对2012年3月1日至2018年12月31日期间接受过任何SGAs治疗的成年精神分裂症患者进行队列识别。开始接受 PP1M 治疗的患者被纳入其中,用于对发病率进行描述性分析。根据基线时的人口统计学特征、临床特征和治疗史,将 PP1M 患者与新开始口服 SGA 的患者进行 1:1 的倾向性匹配,通过三步匹配程序进行比较分析,采用普遍的新用户设计以提高可比性。随访结束于指数药物治疗疗程结束、死亡、有最后记录或研究结束(2019 年 12 月 31 日)。研究终点包括严重心血管事件(包括严重室性心律失常和猝死)、扩大严重心血管事件(进一步包括急性心肌梗死和缺血性中风)和心血管住院治疗。采用 Cox 回归法比较了匹配队列间研究终点的风险。结果共发现 11,023 名开始接受 PP1M 治疗的患者(49.5% 为女性;平均年龄为 43.2 [12.2] 岁)。严重心血管事件、扩大严重心血管事件和心血管住院治疗的总发生率分别为每千人年 3.92 例、7.88 例和 51.96 例。在配对队列分析中(N = 10,115),开始使用 PP1M 和新的口服 SGA 对严重心血管事件、扩大的严重心血管事件和心血管住院治疗的危险比(HRs)分别为 0.结论本研究报告了开始接受 PP1M 治疗的精神分裂症患者心血管事件的人群发生率。与口服 SGAs 相比,PP1M 与严重心血管事件风险增加无关,但与心血管住院风险降低可能有关。
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引用次数: 0
Pharmacokinetic Interactions Between Tegoprazan and the Combination of Clarithromycin, Amoxicillin and Bismuth in Healthy Chinese Subjects: An Open-Label, Single-Center, Multiple-Dosage, Self-Controlled, Phase I Trial 中国健康受试者特戈普拉赞与克拉霉素、阿莫西林和铋剂复方制剂之间的药代动力学相互作用:一项开放标签、单中心、多剂量、自我控制的 I 期试验
IF 3.2 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-04-13 DOI: 10.1007/s40261-024-01359-x
Yujing Du, Lixiu Yu, Bin Deng, Qinying Li, Junrui Hu, Linjie Li, Yusen Xu, Liangwei Song, Fang Xie, Yinghui Wang, Yuhao Chen, Chengxin Liu, Xuejia Zhai, Yongning Lu

Background

Tegoprazan is a potassium-competitive acid blocker that inhibits gastric acid and which may be used for eradicating Helicobacter pylori. This study focuses on the pharmacokinetic interaction and safety between tegoprazan and the combination of clarithromycin, amoxicillin and bismuth in healthy Chinese subjects.

Methods

An open-label, three-period, single-center, multiple-dosage, single-sequence, phase I trial was conducted in 22 healthy subjects. In period 1, the subjects took tegoprazan 50 mg twice daily for 7 days, and in period 2 they were administered clarithromycin 500 mg, amoxicillin 1000 mg and bismuth potassium citrate 600 mg twice daily for 7 days (days 14–20). Tegoprazan, clarithromycin, amoxicillin and bismuth potassium citrate were then administered in combination for 7 days (days 21–27) in period 3. Blood samples were collected up to 12 h after the last dose of each period. Safety assessments were performed in each period.

Results

The geometric mean ratios (GMRs) [90% confidence interval (CI)] of maximum plasma concentration at steady state (Cmax,ss) and area under the plasma concentration–time curve over the dosing interval (AUCτ) at steady state were 195.93% (175.52–218.71%) and 287.54% (263.28–314.04%) for tegoprazan and 423.23% (382.57–468.22%) and 385.61% (354.62–419.30%) for tegoprazan metabolite M1, respectively. The GMRs (90% CI) of Cmax,ss and AUCτ were 83.69% (77.44–90.45%) and 110.30% (102.74–118.41%) for clarithromycin, 126.25% (114.73–138.93%) and 146.94% (135.33–159.55%) for 14-hydroxyclarithromycin, 75.89% (69.73–82.60%) and 94.34% (87.94–101.20%) for amoxicillin, and 158.43% (125.43–200.11%) and 183.63% (156.42–215.58%) for bismuth, respectively. All reported adverse events were mild. The frequency of adverse events during the coadministration stage was not higher than that during the single- or triple-drug administration stages.

Conclusion

The plasma exposure of tegoprazan, M1, 14-hydroxyclarithromycin and bismuth was increased after the coadministration of tegoprazan, clarithromycin, amoxicillin and bismuth. The coadministration exhibited favorable safety and tolerability.

Clinical Trials Registration

CTR20230643.

背景特戈普拉赞是一种钾竞争性胃酸阻滞剂,能抑制胃酸,可用于根除幽门螺旋杆菌。本研究主要探讨特戈普拉赞与克拉霉素、阿莫西林和铋剂复方制剂在中国健康受试者中的药代动力学相互作用及安全性。方法在 22 名健康受试者中进行了一项开放标签、三期、单中心、多剂量、单序的 I 期试验。在第一阶段,受试者服用特戈普拉赞 50 毫克,每天两次,共 7 天;在第二阶段,受试者服用克拉霉素 500 毫克、阿莫西林 1000 毫克和枸橼酸铋钾 600 毫克,每天两次,共 7 天(第 14-20 天)。然后,在第 3 期中联合使用替戈普拉赞、克拉霉素、阿莫西林和枸橼酸铋钾,共 7 天(第 21-27 天)。在每个疗程的最后一次用药后 12 小时内采集血液样本。结果 稳定状态下最大血浆浓度(Cmax,ss)和给药间隔血浆浓度-时间曲线下面积(AUCτ)的几何平均比(GMRs)[90%置信区间(CI)]分别为 195.分别为195.93% (175.52-218.71%)和287.54% (263.28-314.04%);替戈普拉赞代谢物M1分别为423.23% (382.57-468.22%)和385.61% (354.62-419.30%)。克拉霉素的 Cmax、ss 和 AUCτ 的 GMRs(90% CI)分别为 83.69%(77.44-90.45%)和 110.30%(102.74-118.41%),14-羟基克拉霉素的 Cmax、ss 和 AUCτ 的 GMRs(90% CI)分别为 126.25%(114.73-138.93%)和 146.94%(135.33-159.55%)。55%),阿莫西林分别为 75.89%(69.73-82.60%)和 94.34%(87.94-101.20%),铋剂分别为 158.43%(125.43-200.11%)和 183.63%(156.42-215.58%)。所有报告的不良反应均为轻微。结论联合应用替戈普拉嗪、克拉霉素、阿莫西林和铋剂后,替戈普拉嗪、M1、14-羟基克拉霉素和铋剂的血浆暴露量增加。联合用药具有良好的安全性和耐受性。
{"title":"Pharmacokinetic Interactions Between Tegoprazan and the Combination of Clarithromycin, Amoxicillin and Bismuth in Healthy Chinese Subjects: An Open-Label, Single-Center, Multiple-Dosage, Self-Controlled, Phase I Trial","authors":"Yujing Du, Lixiu Yu, Bin Deng, Qinying Li, Junrui Hu, Linjie Li, Yusen Xu, Liangwei Song, Fang Xie, Yinghui Wang, Yuhao Chen, Chengxin Liu, Xuejia Zhai, Yongning Lu","doi":"10.1007/s40261-024-01359-x","DOIUrl":"https://doi.org/10.1007/s40261-024-01359-x","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Tegoprazan is a potassium-competitive acid blocker that inhibits gastric acid and which may be used for eradicating <i>Helicobacter pylori</i>. This study focuses on the pharmacokinetic interaction and safety between tegoprazan and the combination of clarithromycin, amoxicillin and bismuth in healthy Chinese subjects.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>An open-label, three-period, single-center, multiple-dosage, single-sequence, phase I trial was conducted in 22 healthy subjects. In period 1, the subjects took tegoprazan 50 mg twice daily for 7 days, and in period 2 they were administered clarithromycin 500 mg, amoxicillin 1000 mg and bismuth potassium citrate 600 mg twice daily for 7 days (days 14–20). Tegoprazan, clarithromycin, amoxicillin and bismuth potassium citrate were then administered in combination for 7 days (days 21–27) in period 3. Blood samples were collected up to 12 h after the last dose of each period. Safety assessments were performed in each period.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>The geometric mean ratios (GMRs) [90% confidence interval (CI)] of maximum plasma concentration at steady state (<i>C</i><sub>max,ss</sub>) and area under the plasma concentration–time curve over the dosing interval (AUC<sub>τ</sub>) at steady state were 195.93% (175.52–218.71%) and 287.54% (263.28–314.04%) for tegoprazan and 423.23% (382.57–468.22%) and 385.61% (354.62–419.30%) for tegoprazan metabolite M1, respectively. The GMRs (90% CI) of <i>C</i><sub>max,ss</sub> and AUC<sub>τ</sub> were 83.69% (77.44–90.45%) and 110.30% (102.74–118.41%) for clarithromycin, 126.25% (114.73–138.93%) and 146.94% (135.33–159.55%) for 14-hydroxyclarithromycin, 75.89% (69.73–82.60%) and 94.34% (87.94–101.20%) for amoxicillin, and 158.43% (125.43–200.11%) and 183.63% (156.42–215.58%) for bismuth, respectively. All reported adverse events were mild. The frequency of adverse events during the coadministration stage was not higher than that during the single- or triple-drug administration stages.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>The plasma exposure of tegoprazan, M1, 14-hydroxyclarithromycin and bismuth was increased after the coadministration of tegoprazan, clarithromycin, amoxicillin and bismuth. The coadministration exhibited favorable safety and tolerability.</p><h3 data-test=\"abstract-sub-heading\">Clinical Trials Registration</h3><p>CTR20230643.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":"93 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140581427","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
Impact of Viloxazine Extended-Release Capsules (Qelbree®) on Select Cytochrome P450 Enzyme Activity and Evaluation of CYP2D6 Genetic Polymorphisms on Viloxazine Pharmacokinetics 维洛氮平缓释胶囊(Qelbree®)对某些细胞色素 P450 酶活性的影响以及评估 CYP2D6 基因多态性对维洛氮平药代动力学的影响
IF 3.2 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-04-10 DOI: 10.1007/s40261-024-01356-0
Zhao Wang, Tesfaye Liranso, Zulane Maldonado-Cruz, Alisa R. Kosheleff, Azmi Nasser

Background and Objective

Viloxazine extended-release (ER) [Qelbree®] is a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment. In vitro studies suggested potential for viloxazine to inhibit cytochrome 450 (CYP) enzymes 1A2, 2B6, 2D6 and 3A4. This clinical study therefore evaluated viloxazine ER effects on index substrates for CYP1A2, 2D6, and 3A4, and secondarily evaluated the impact of CYP2D6 polymorphisms on viloxazine pharmacokinetics.

Methods

Thirty-seven healthy subjects received a modified Cooperstown cocktail (MCC; caffeine 200 mg, dextromethorphan 30 mg, midazolam 0.025 mg/kg) on Day 1, viloxazine ER 900 mg/day on Days 3–5, and a combination of viloxazine ER 900 mg and MCC on Day 6. Viloxazine ER effects on MCC substrates were evaluated using analysis of variance. The impact of CYP2D6 genetic polymorphisms on steady-state viloxazine plasma concentrations was evaluated using Student’s t test assessing pharmacokinetic parameter differences between poor versus extensive metabolizers.

Results

The least squares geometric mean ratio [GMR%] (90% CI) of MCC substrate + viloxazine ER/MCC substrate alone for caffeine maximum concentration (Cmax), area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUCt), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC) was 99.11 (95.84–102.49), 436.15 (398.87–476.92), and 583.35 (262.41–1296.80), respectively; 150.76 (126.03–180.35), 185.76 (155.01–222.61), and 189.71 (160.37–224.42) for dextromethorphan Cmax, AUCt, and AUC, respectively; and 112.81 (104.71–121.54), 167.56 (153.05–183.45), and 168.91 (154.38–184.80) for midazolam Cmax, AUCt, and AUC, respectively. At steady state, viloxazine least squares GMR (90% CI) for poor/extensive CYP2D6 metabolizers were Cmax 120.70 (102.33–142.37) and area under the plasme concentration-time curve from time 0 to 24 hours (AUC0–24 125.66 (105.36–149.87)).

Conclusion

Viloxazine ER is a strong CYP1A2 inhibitor and a weak CYP2D6 and CYP3A4 inhibitor. CYP2D6 polymorphisms did not meaningfully alter the viloxazine ER pharmacokinetic profile.

背景和目的维洛沙嗪缓释片(ER)[Qelbree®]是一种非刺激性的注意力缺陷/多动症(ADHD)治疗药物。体外研究表明,维洛沙嗪可能会抑制细胞色素450(CYP)酶1A2、2B6、2D6和3A4。因此,本临床研究评估了维洛沙嗪 ER 对 CYP1A2、2D6 和 3A4 指数底物的影响,其次评估了 CYP2D6 多态性对维洛沙嗪药代动力学的影响。方法37名健康受试者在第1天服用改良库珀斯敦鸡尾酒(MCC;咖啡因200毫克、右美沙芬30毫克、咪达唑仑0.025毫克/千克),第3-5天服用维洛嗪ER 900毫克/天,第6天服用维洛嗪ER 900毫克和MCC的组合。使用方差分析评估了维洛嗪ER对MCC底物的影响。采用学生 t 检验评估代谢差与代谢广的药代动力学参数差异,评估 CYP2D6 基因多态性对稳态维洛沙嗪血浆浓度的影响。结果对于咖啡因最大浓度(Cmax)、从时间 0 到最后可定量浓度的血浆浓度-时间曲线下面积(AUCt)以及从时间 0 推断至无穷大的血浆浓度-时间曲线下面积(AUC∞),MCC 底物 + 维罗沙嗪 ER/MCC 底物单独的最小二乘几何平均比[GMR%](90% CI)为 99.11(95.84-102.49)、436.15(398.87-476.92)和 583.35(262.41-1296.80);右美沙芬为 150.76(126.03-180.35)、185.76(155.01-222.61)和 189.71(160.37-224.右美沙芬的 Cmax、AUCt 和 AUC∞分别为 112.81(104.71-121.54)、167.56(153.05-183.45)和 168.91(154.38-184.80);咪达唑仑的 Cmax、AUCt 和 AUC∞分别为 112.81(104.71-121.54)、167.56(153.05-183.45)和 168.91(154.38-184.80)。在稳态时,CYP2D6代谢差/广谱的维洛沙嗪最小二乘法GMR(90% CI)为Cmax 120.70(102.33-142.37)和从0到24小时的血浆浓度-时间曲线下面积(AUC0-24 125.66(105.36-149.87))。CYP2D6 多态性并不会显著改变维洛沙嗪 ER 的药代动力学特征。
{"title":"Impact of Viloxazine Extended-Release Capsules (Qelbree®) on Select Cytochrome P450 Enzyme Activity and Evaluation of CYP2D6 Genetic Polymorphisms on Viloxazine Pharmacokinetics","authors":"Zhao Wang, Tesfaye Liranso, Zulane Maldonado-Cruz, Alisa R. Kosheleff, Azmi Nasser","doi":"10.1007/s40261-024-01356-0","DOIUrl":"https://doi.org/10.1007/s40261-024-01356-0","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background and Objective</h3><p>Viloxazine extended-release (ER) [Qelbree<sup>®</sup>] is a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment. In vitro studies suggested potential for viloxazine to inhibit cytochrome 450 (CYP) enzymes 1A2, 2B6, 2D6 and 3A4. This clinical study therefore evaluated viloxazine ER effects on index substrates for CYP1A2, 2D6, and 3A4, and secondarily evaluated the impact of CYP2D6 polymorphisms on viloxazine pharmacokinetics.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Thirty-seven healthy subjects received a modified Cooperstown cocktail (MCC; caffeine 200 mg, dextromethorphan 30 mg, midazolam 0.025 mg/kg) on Day 1, viloxazine ER 900 mg/day on Days 3–5, and a combination of viloxazine ER 900 mg and MCC on Day 6. Viloxazine ER effects on MCC substrates were evaluated using analysis of variance. The impact of CYP2D6 genetic polymorphisms on steady-state viloxazine plasma concentrations was evaluated using Student’s <i>t</i> test assessing pharmacokinetic parameter differences between poor versus extensive metabolizers.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>The least squares geometric mean ratio [GMR%] (90% CI) of MCC substrate + viloxazine ER/MCC substrate alone for caffeine maximum concentration (<i>C</i><sub>max</sub>), area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC<sub><i>t</i></sub>), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC<sub>∞</sub>) was 99.11 (95.84–102.49), 436.15 (398.87–476.92), and 583.35 (262.41–1296.80), respectively; 150.76 (126.03–180.35), 185.76 (155.01–222.61), and 189.71 (160.37–224.42) for dextromethorphan <i>C</i><sub>max</sub>, AUC<sub>t,</sub> and AUC<sub>∞</sub>, respectively; and 112.81 (104.71–121.54), 167.56 (153.05–183.45), and 168.91 (154.38–184.80) for midazolam <i>C</i><sub>max</sub>, AUC<sub><i>t</i>,</sub> and AUC<sub>∞</sub>, respectively. At steady state, viloxazine least squares GMR (90% CI) for poor/extensive CYP2D6 metabolizers were <i>C</i><sub>max</sub> 120.70 (102.33–142.37) and area under the plasme concentration-time curve from time 0 to 24 hours (AUC<sub>0–24</sub> 125.66 (105.36–149.87)).</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>Viloxazine ER is a strong CYP1A2 inhibitor and a weak CYP2D6 and CYP3A4 inhibitor. CYP2D6 polymorphisms did not meaningfully alter the viloxazine ER pharmacokinetic profile.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":"38 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140581489","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
An Open-Label Study to Assess Monthly Risperidone Injections (180 mg) Following Switch from Daily Oral Risperidone (6 mg) in Stable Schizophrenic Patients. 一项开放标签研究,评估稳定期精神分裂症患者从每日口服利培酮(6 毫克)改为每月注射利培酮(180 毫克)的效果。
IF 3.2 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-04-01 Epub Date: 2024-02-22 DOI: 10.1007/s40261-024-01347-1
David P Walling, Sunita N Shinde, Janice M Pogoda, Jahnavi Kharidia, Celine M Laffont

Background and objective: Long-acting injectable antipsychotics have shown benefits over oral medications with reduced hospitalization rates and improved health-related quality of life. RBP-7000 (PERSERIS®) is a monthly risperidone formulation (90 or 120 mg) for the treatment of schizophrenia administered by subcutaneous abdominal injection. The objective of this study was to assess a higher dose of 180 mg RBP-7000 and an alternate injection site.

Methods: Following stabilization on 6 mg/day (3 mg twice daily) oral risperidone, clinically stable schizophrenic participants received 3 monthly doses of 180 mg RBP-7000 in the abdomen followed by a fourth monthly dose of 180 mg RBP-7000 in the upper arm (each dose administered as two 90-mg injections). The primary endpoint was the steady-state average plasma concentration (Cavg(ss)) of risperidone and total active moiety after oral and RBP-7000 administration. Secondary endpoints included measures of clinical efficacy (Positive and Negative Syndrome Scale, Clinical Global Impression Scale for Severity of Illness), safety, and local injection-site tolerability to assess the switch from oral risperidone and compare injection sites.

Results: In all, 23 participants received at least one dose of RBP-7000, 16 received all four doses, and 15 completed the study. Monthly doses of 180 mg RBP-7000 provided similar Cavg(ss) of total active moiety compared with 6 mg/day oral risperidone. The pharmacokinetics of RBP-7000 were similar after injection in the abdomen versus upper arm. Clinical efficacy measures remained stable throughout the study. All RBP-7000 injections were well tolerated with no unexpected safety findings.

Conclusions: The results support the use of 180 mg RBP-7000 in schizophrenic patients stable on 6 mg/day oral risperidone and a second injection site in the upper arm.

Trial registration: ClinicalTrials.gov identifier: NCT03978832.

背景和目的:与口服药物相比,长效注射用抗精神病药物具有降低住院率和改善健康相关生活质量的优势。RBP-7000(PERSERIS®)是一种利培酮制剂(90 或 120 毫克),用于治疗精神分裂症,每月一次,腹部皮下注射给药。本研究的目的是评估 180 毫克 RBP-7000 的高剂量和替代注射部位:临床稳定的精神分裂症患者在每天口服 6 毫克(3 毫克,每天两次)利培酮的情况稳定后,每月在腹部注射 3 次 180 毫克 RBP-7000,然后每月在上臂注射第 4 次 180 毫克 RBP-7000(每次注射 2 次,每次 90 毫克)。主要终点是口服和RBP-7000给药后利培酮和总活性分子的稳态平均血浆浓度(Cavg(ss))。次要终点包括临床疗效(阳性和阴性综合征量表、疾病严重程度临床总体印象量表)、安全性和局部注射部位耐受性,以评估从口服利培酮的转换情况并比较注射部位:共有 23 名参与者至少接受了一剂 RBP-7000,16 人接受了全部四剂,15 人完成了研究。与每天6毫克的口服利培酮相比,每月180毫克的RBP-7000可提供相似的总活性分子Cavg(ss)。腹部注射与上臂注射后,RBP-7000 的药代动力学相似。临床疗效指标在整个研究期间保持稳定。所有RBP-7000注射剂的耐受性都很好,没有意外的安全性发现:研究结果支持在口服利培酮6毫克/天且病情稳定的精神分裂症患者中使用180毫克RBP-7000,第二个注射部位为上臂:试验注册:ClinicalTrials.gov identifier:NCT03978832。
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引用次数: 0
Experience of Tofacitinib Use in Pregnancy in Patients with Ulcerative Colitis. 妊娠期溃疡性结肠炎患者使用托法替尼的经验。
IF 3.2 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-04-01 Epub Date: 2024-03-19 DOI: 10.1007/s40261-024-01353-3
María Chaparro, Daniel Ceballos, Raquel Vicente, Javier P Gisbert
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引用次数: 0
Effectiveness of Dose Increase in Upadacitinib from 15 mg to 30 mg for Patients with Moderate-to-Severe Atopic Dermatitis: A Real-World Clinical Practice in Japan. 中重度特应性皮炎患者将乌达帕替尼的剂量从 15 毫克增加到 30 毫克的效果:日本真实世界的临床实践。
IF 3.2 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-04-01 Epub Date: 2024-03-06 DOI: 10.1007/s40261-024-01352-4
Teppei Hagino, Risa Hamada, Mai Yoshida, Hidehisa Saeki, Eita Fujimoto, Naoko Kanda

Background: Atopic dermatitis is characterized by persistent eczema and pruritus. Janus kinase inhibitors, including upadacitinib, are effective treatments for moderate-to-severe atopic dermatitis. If patients do not respond well to a certain dose of a Janus kinase inhibitor, increasing the dose may improve their treatment responsiveness.

Objectives: We assessed the outcomes of a dose increase in upadacitinib from 15 mg to 30 mg for Japanese patients with moderate-to-severe atopic dermatitis.

Methods: In 23 patients who showed insufficient responses to upadacitinib 15-mg treatment, the dose of upadacitinib was increased to 30 mg. We evaluated total Eczema Area and Severity Index (EASI), EASI on the head and neck, trunk, upper, or lower limbs, EASI of erythema, edema/papulation, excoriation, or lichenification, and Peak Pruritus Numerical-Rating Scale at baseline (onset of upadactinib 15 mg), week 0 (time of increase), and weeks 4 and 12 after the increase.

Results: Total EASI, EASI on each anatomical site, EASI of each clinical sign, and Peak Pruritus Numerical-Rating Scale were markedly reduced at weeks 4 or 12 compared with week 0. After the dose increase, the achievement rates of EASI 75 and EASI 90 significantly improved; EASI 75 4.3%, 68.2%, and 66.7%; EASI 90 0%, 18.2%, and 38.1% at weeks 0, 4, and 12, respectively.

Conclusions: These results suggest that upadacitinib 30 mg can ameliorate rash and pruritus insufficiently improved by upadacitinib 15 mg, and that the dose increase to 30 mg may be considered as a treatment option for patients with atopic dermatitis with a limited response to upadacitinib 15 mg.

背景:特应性皮炎的特征是持续性湿疹和瘙痒。包括乌达替尼在内的Janus激酶抑制剂是治疗中重度特应性皮炎的有效药物。如果患者对一定剂量的Janus激酶抑制剂反应不佳,增加剂量可能会改善他们的治疗反应:我们评估了日本中重度特应性皮炎患者将达达替尼的剂量从 15 毫克增加到 30 毫克的效果:方法:在23名对高达替尼15毫克治疗反应不足的患者中,将高达替尼的剂量增加到30毫克。我们评估了基线(开始使用达帕替尼 15 毫克)、第 0 周(剂量增加时)以及剂量增加后第 4 周和第 12 周的湿疹面积和严重程度指数(EASI)、头颈部、躯干、上肢或下肢的 EASI、红斑、水肿/丘疹、脱屑或苔藓化的 EASI 以及瘙痒峰值数字评分量表:结果:与第0周相比,第4周或第12周的总EASI、各解剖部位的EASI、各临床体征的EASI以及瘙痒峰值数字评分量表均明显降低。剂量增加后,EASI 75 和 EASI 90 的达标率显著提高;在第 0、4 和 12 周,EASI 75 的达标率分别为 4.3%、68.2% 和 66.7%;EASI 90 的达标率分别为 0%、18.2% 和 38.1%:这些结果表明,奥达帕替尼30毫克可改善奥达帕替尼15毫克不能充分改善的皮疹和瘙痒症状,对于奥达帕替尼15毫克疗效有限的特应性皮炎患者,可考虑将剂量增加到30毫克。
{"title":"Effectiveness of Dose Increase in Upadacitinib from 15 mg to 30 mg for Patients with Moderate-to-Severe Atopic Dermatitis: A Real-World Clinical Practice in Japan.","authors":"Teppei Hagino, Risa Hamada, Mai Yoshida, Hidehisa Saeki, Eita Fujimoto, Naoko Kanda","doi":"10.1007/s40261-024-01352-4","DOIUrl":"10.1007/s40261-024-01352-4","url":null,"abstract":"<p><strong>Background: </strong>Atopic dermatitis is characterized by persistent eczema and pruritus. Janus kinase inhibitors, including upadacitinib, are effective treatments for moderate-to-severe atopic dermatitis. If patients do not respond well to a certain dose of a Janus kinase inhibitor, increasing the dose may improve their treatment responsiveness.</p><p><strong>Objectives: </strong>We assessed the outcomes of a dose increase in upadacitinib from 15 mg to 30 mg for Japanese patients with moderate-to-severe atopic dermatitis.</p><p><strong>Methods: </strong>In 23 patients who showed insufficient responses to upadacitinib 15-mg treatment, the dose of upadacitinib was increased to 30 mg. We evaluated total Eczema Area and Severity Index (EASI), EASI on the head and neck, trunk, upper, or lower limbs, EASI of erythema, edema/papulation, excoriation, or lichenification, and Peak Pruritus Numerical-Rating Scale at baseline (onset of upadactinib 15 mg), week 0 (time of increase), and weeks 4 and 12 after the increase.</p><p><strong>Results: </strong>Total EASI, EASI on each anatomical site, EASI of each clinical sign, and Peak Pruritus Numerical-Rating Scale were markedly reduced at weeks 4 or 12 compared with week 0. After the dose increase, the achievement rates of EASI 75 and EASI 90 significantly improved; EASI 75 4.3%, 68.2%, and 66.7%; EASI 90 0%, 18.2%, and 38.1% at weeks 0, 4, and 12, respectively.</p><p><strong>Conclusions: </strong>These results suggest that upadacitinib 30 mg can ameliorate rash and pruritus insufficiently improved by upadacitinib 15 mg, and that the dose increase to 30 mg may be considered as a treatment option for patients with atopic dermatitis with a limited response to upadacitinib 15 mg.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"261-269"},"PeriodicalIF":3.2,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140038885","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
Real-World Effectiveness of Once-Weekly Glucagon-Like Peptide-1 Receptor Agonists (OW GLP-1RAs) in Comparison with Dipeptidyl Peptidase-4 Inhibitors (DPP-4is) for Glycemic Control and Weight Outcomes in Type 2 Diabetes Mellitus (RELATE). 每周一次的胰高血糖素样肽-1 受体激动剂(OW GLP-1RAs)与二肽基肽酶-4 抑制剂(DPP-4is)对 2 型糖尿病患者血糖控制和体重结果的实际效果比较 (RELATE)。
IF 3.2 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-04-01 Epub Date: 2024-03-20 DOI: 10.1007/s40261-024-01354-2
Xi Tan, Victoria Divino, James Amamoo, Lin Xie, Katharine B Coyle, Cory L Gamble, Mico Guevarra, Yurek Paprocki, Aaron A King

Background: The efficacy of once-weekly (OW) glucagon-like peptide-1 receptor agonists (GLP-1RAs) has been established in several trials in people with type 2 diabetes mellitus (T2DM); however, real-world evidence on their effectiveness is limited. This study evaluated the effectiveness of OW GLP-1RA regarding glycemic and weight outcomes, and relative to DPP-4i in a comparator analysis.

Methods: This observational cohort study evaluated glycated hemoglobin (HbA1c) and weight outcomes in people with T2DM with two or more prescription claims for the same OW GLP-1RA using a pre-post study design (including for a semaglutide OW T2DM subgroup, hereafter referred to as semaglutide). Comparator analysis for the same outcome was performed for OW GLP-1RAs versus DPP-4i and semaglutide subgroup versus DPP-4i. A linked patient population from the IQVIA PharMetrics® Plus database and the Ambulatory Electronic Medical Records (AEMR) database was analyzed using data from January 2017 to April 2022. HbA1c and weight were assessed at baseline and at the end of the 12-month post-index period. Inverse probability of treatment weighting (IPTW) was used to adjust for imbalances in baseline patient characteristics in the comparator analysis.

Results: In the pre-post analysis, a greater numerical reduction in HbA1c and weight was observed for the semaglutide subgroup (N = 354) relative to the OW GLP-1RA cohort (N = 921). In the semaglutide subgroup, 52.5% and 34.2% of patients achieved HbA1c of < 7.0% and ≥ 5% weight loss, respectively. For the comparator analysis, the OW GLP-1RAs (N = 651) were significantly more effective (p < 0.001) in reducing HbA1c (- 1.5% vs. -  1.0%) and weight (- 3.2 kg vs. -  1.0 kg) than the DPP-4is (N = 431). Similarly, the semaglutide cohort (N = 251) also displayed more effectiveness (p < 0.001) in reducing HbA1c (- 1.7% vs. -  0.9%) and weight (- 4.1 kg vs. -  1.3 kg) than the respective DPP-4i cohort (N = 417). Patients initiating OW GLP-1RAs, including the semaglutide cohort, were at least twice as likely to achieve HbA1c and weight outcomes as well as composite outcomes compared with those initiating DPP-4is.

Conclusion: The study reinforces that OW GLP-1RAs are more effective in glycemic control and weight reduction compared with DPP-4is in people with T2DM in the real-world setting. These findings align with the recommendation in the current guidelines for utilizing glucose-lowering treatment regimens that support weight-management goals in people with T2DM.

背景:每周一次(OW)胰高血糖素样肽-1受体激动剂(GLP-1RA)在2型糖尿病(T2DM)患者中的疗效已在多项试验中得到证实;然而,有关其疗效的实际证据却很有限。本研究评估了OW GLP-1RA在血糖和体重结果方面的有效性,以及在对比分析中与DPP-4i相比的有效性:这项观察性队列研究采用前-后研究设计,评估了T2DM患者的糖化血红蛋白(HbA1c)和体重结果,这些患者有两次或两次以上处方申请使用同一种OW GLP-1RA(包括semaglutide OW T2DM亚组,以下简称semaglutide)。针对同一结果,还进行了OW GLP-1RA与DPP-4i以及semaglutide亚组与DPP-4i的比较分析。利用2017年1月至2022年4月的数据分析了来自IQVIA PharMetrics® Plus数据库和非住院电子病历(AEMR)数据库的关联患者群体。HbA1c和体重在基线和指数后12个月期末进行评估。在对比分析中,采用了逆概率治疗加权法(IPTW)来调整基线患者特征的不平衡:结果:在前后分析中观察到,与OW GLP-1RA队列(N = 921)相比,塞马鲁肽亚组(N = 354)的HbA1c和体重下降幅度更大。在semaglutide亚组中,分别有52.5%和34.2%的患者实现了HbA1c<7.0%和体重下降≥5%。在对比分析中,OW GLP-1RAs(N = 651)在降低 HbA1c(- 1.5% vs. - 1.0%)和减轻体重(- 3.2 kg vs. - 1.0 kg)方面的效果(p < 0.001)明显优于 DPP-4is(N = 431)。同样,在降低 HbA1c(- 1.7% vs. - 0.9%)和减轻体重(- 4.1 kg vs. - 1.3 kg)方面,semaglutide 组(N = 251)也比相应的 DPP-4i 组(N = 417)更有效(p < 0.001)。与开始使用DPP-4i的患者相比,开始使用OW GLP-1RAs(包括semaglutide队列)的患者达到HbA1c和体重结果以及综合结果的可能性至少是开始使用DPP-4i患者的两倍:结论:本研究证实,在现实环境中,OW GLP-1RA 与 DPP-4is 相比,对 T2DM 患者的血糖控制和体重减轻更有效。这些研究结果与现行指南中的建议一致,即对 T2DM 患者采用支持体重管理目标的降糖治疗方案。
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引用次数: 0
Should Glucokinase be Given a Chance in Diabetes Therapeutics? A Clinical-Pharmacological Review of Dorzagliatin and Lessons Learned So Far. 在糖尿病治疗中是否应该给葡萄糖激酶一个机会?Dorzagliatin的临床药理学回顾及迄今为止的经验教训。
IF 3.2 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-04-01 Epub Date: 2024-03-09 DOI: 10.1007/s40261-024-01351-5
Upinder Kaur, Bhairav Kumar Pathak, Tharik Jalal Meerashahib, Dondapati Venkata Vamshi Krishna, Sankha Shubhra Chakrabarti
<p><p>Despite advances in the management of type 2 diabetes mellitus (T2DM), one-third of patients with diabetes do not achieve the desired glycemic goal. Considering this inadequacy, many agents that activate glucokinase have been investigated over the last two decades but were withdrawn before submission for marketing permission. Dorzagliatin is the first glucokinase activator that has been granted approval for T2DM, only in China. As overstimulation of glucokinase is linked with pathophysiological disturbances such as fatty liver and cardiovascular issues and a loss of therapeutic efficacy with time. This review aims to highlight the benefits of glucokinase activators vis-à-vis the risks associated with chronic enzymatic activation. We discuss the multisystem disturbances expected with chronic activation of the enzyme, the lessons learned with glucokinase activators of the past, the major efficacy and safety findings with dorzagliatin and its pharmacological properties, and the status of other glucokinase activators in the pipeline. The approval of dorzagliatin in China was based on the SEED and the DAWN trials, the major pivotal phase III trials that enrolled patients with T2DM with a mean glycosylated hemoglobin of 8.3-8.4%, and a mean age of 53-54.5 years from multiple sites in China. Patients with uncontrolled diabetes, cardiac diseases, organ dysfunction, and a history of severe hypoglycemia were excluded. Both trials had a randomized double-blind placebo-controlled phase of 24 weeks followed by an open-label phase of 28 weeks with dorzagliatin. Drug-naïve patients with T2DM with a disease duration of 11.7 months were enrolled in the SEED trial while the DAWN trial involved patients with T2DM with a mean duration of 71.5 months and receiving background metformin therapy. Compared with placebo, the decline in glycosylated hemoglobin at 24 weeks was more with dorzagliatin with an estimated treatment difference of - 0.57% in the SEED trial and - 0.66% in the DAWN trial. The desired glycosylated hemoglobin (< 7%) was also attained at more than two times higher rates with dorzagliatin. The glycemic improvement was sustained in the SEED trial but decreased over 52 weeks in the DAWN trial. Hyperlipidemia was observed in 12-14% of patients taking dorzagliatin versus 9-11% of patients receiving a placebo. Additional adverse effects noticed over 52 weeks with dorzagliatin included an elevation in liver enzymes, hyperuricemia, hyperlacticacidemia, renal dysfunction, and cardiovascular disturbances. Considering the statistically significant improvement in glycosylated hemoglobin with dorzagliatin in patients with T2DM, the drug may be given a chance in treatment-naïve patients with a shorter disease history. However, with the waning therapeutic efficacy witnessed in patients with long-standing diabetes, which was also one of the potential concerns with previously tested molecules, extended studies involving patients with chronic and uncontrolled diab
尽管 2 型糖尿病(T2DM)的治疗取得了进展,但仍有三分之一的糖尿病患者无法达到预期的血糖目标。考虑到这一不足,在过去二十年中,许多激活葡萄糖激酶的药物被研究出来,但在提交上市申请之前就被撤回。多扎格雷丁是第一个获准用于治疗 T2DM 的葡萄糖激酶激活剂,但只在中国获批。由于葡萄糖激酶的过度刺激与病理生理紊乱(如脂肪肝和心血管问题)有关,而且随着时间的推移,疗效也会下降。本综述旨在强调葡萄糖激酶激活剂的益处与长期酶激活相关风险的对比。我们将讨论长期激活葡萄糖激酶可能引起的多系统紊乱、过去使用葡萄糖激酶激活剂的经验教训、多沙格列汀的主要疗效和安全性研究结果及其药理特性,以及正在研发中的其他葡萄糖激酶激活剂的现状。多扎格拉汀在中国获批上市是基于 SEED 和 DAWN 试验,这两项主要的关键性 III 期试验在中国多个地点招募了平均糖化血红蛋白为 8.3%-8.4%、平均年龄为 53-54.5 岁的 T2DM 患者。未控制的糖尿病患者、心脏病患者、器官功能障碍患者和有严重低血糖病史的患者被排除在外。这两项试验都有一个为期 24 周的随机双盲安慰剂对照阶段,随后是一个为期 28 周的多扎格列汀开放标签阶段。SEED 试验招募了病程为 11.7 个月的 T2DM 患者,他们对药物一无所知;而 DAWN 试验则招募了平均病程为 71.5 个月的 T2DM 患者,他们正在接受二甲双胍治疗。与安慰剂相比,多扎格雷汀在 24 周时的糖化血红蛋白下降幅度更大,SEED 试验中的估计治疗差异为-0.57%,DAWN 试验中的估计治疗差异为-0.66%。理想的糖化血红蛋白(
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引用次数: 0
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Clinical Drug Investigation
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