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。
{"title":"Prediction Model for Severe Thrombocytopenia Induced by Gemcitabine Plus Cisplatin Combination Therapy in Patients with Urothelial Cancer","authors":"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","doi":"10.1007/s40261-024-01361-3","DOIUrl":"https://doi.org/10.1007/s40261-024-01361-3","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>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.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>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.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>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.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Of 186 patients included in this study, 46 (25%) experienced severe thrombocytopenia induced by GC therapy. Multivariate analyses revealed that platelet count ≤ 21.4 (×10<sup>4</sup>/µL) [odds ratio 7.19, <i>p</i> < 0.01], hemoglobin ≤ 12.1 (g/dL) [odds ratio 2.41, <i>p</i> = 0.03], lymphocyte count ≤ 1.458 (×10<sup>3</sup>/µL) [odds ratio 2.47, <i>p</i> = 0.02], and dose of gemcitabine ≥ 775.245 (mg/m<sup>2</sup>) [odds ratio 4.00, <i>p</i> < 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).</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>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.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":"9 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140828569","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}
Pub Date : 2024-04-24DOI: 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。
{"title":"Safety, Tolerability, and Pharmacokinetics of Oral BI 1358894 in Healthy Japanese Male Volunteers","authors":"Jangsoo Yoon, Vikas Sharma, Akiko Harada","doi":"10.1007/s40261-024-01357-z","DOIUrl":"https://doi.org/10.1007/s40261-024-01357-z","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background and Objectives</h3><p>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.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Male HVs were randomized to receive oral BI 1358894 (<i>n</i> = 18) or placebo (<i>n</i> = 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.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>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.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>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.</p><h3 data-test=\"abstract-sub-heading\">Trial Registration</h3><p>ClinicalTrials.gov (NCT03875001; 08-Mar-2019).</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":"19 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140804833","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}
Pub Date : 2024-04-15DOI: 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.
{"title":"Risk of Cardiovascular Events in Schizophrenic Patients Treated with Paliperidone Palmitate Once-Monthly Injection (PP1M): A Population-Based Retrospective Cohort Study in Taiwan","authors":"Shih-Pei Shen, Li Yan, Tao Wu, Min-Wei Huang, Kuan-Chih Huang, Hong Qiu, Yongjing Zhang, Chao-Hsiun Tang","doi":"10.1007/s40261-024-01358-y","DOIUrl":"https://doi.org/10.1007/s40261-024-01358-y","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>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.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>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).</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>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.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>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 (<i>N</i> = 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.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>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.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":"49 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140602541","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}
Pub Date : 2024-04-13DOI: 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.
{"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}
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.
{"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}
Pub Date : 2024-04-01Epub Date: 2024-02-22DOI: 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.
{"title":"An Open-Label Study to Assess Monthly Risperidone Injections (180 mg) Following Switch from Daily Oral Risperidone (6 mg) in Stable Schizophrenic Patients.","authors":"David P Walling, Sunita N Shinde, Janice M Pogoda, Jahnavi Kharidia, Celine M Laffont","doi":"10.1007/s40261-024-01347-1","DOIUrl":"10.1007/s40261-024-01347-1","url":null,"abstract":"<p><strong>Background and objective: </strong>Long-acting injectable antipsychotics have shown benefits over oral medications with reduced hospitalization rates and improved health-related quality of life. RBP-7000 (PERSERIS<sup>®</sup>) 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.</p><p><strong>Methods: </strong>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 (C<sub>avg(ss)</sub>) 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.</p><p><strong>Results: </strong>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 C<sub>avg(ss)</sub> 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.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov identifier: NCT03978832.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"251-260"},"PeriodicalIF":3.2,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10980608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139930364","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}
Pub Date : 2024-04-01Epub Date: 2024-03-19DOI: 10.1007/s40261-024-01353-3
María Chaparro, Daniel Ceballos, Raquel Vicente, Javier P Gisbert
{"title":"Experience of Tofacitinib Use in Pregnancy in Patients with Ulcerative Colitis.","authors":"María Chaparro, Daniel Ceballos, Raquel Vicente, Javier P Gisbert","doi":"10.1007/s40261-024-01353-3","DOIUrl":"10.1007/s40261-024-01353-3","url":null,"abstract":"","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"285-288"},"PeriodicalIF":3.2,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10980649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140157731","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}
Pub Date : 2024-04-01Epub Date: 2024-03-06DOI: 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.
{"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}
Pub Date : 2024-04-01Epub Date: 2024-03-20DOI: 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.
{"title":"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).","authors":"Xi Tan, Victoria Divino, James Amamoo, Lin Xie, Katharine B Coyle, Cory L Gamble, Mico Guevarra, Yurek Paprocki, Aaron A King","doi":"10.1007/s40261-024-01354-2","DOIUrl":"10.1007/s40261-024-01354-2","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>This observational cohort study evaluated glycated hemoglobin (HbA<sub>1c</sub>) 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<sup>®</sup> Plus database and the Ambulatory Electronic Medical Records (AEMR) database was analyzed using data from January 2017 to April 2022. HbA<sub>1c</sub> 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.</p><p><strong>Results: </strong>In the pre-post analysis, a greater numerical reduction in HbA<sub>1c</sub> 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 HbA<sub>1c</sub> 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 HbA<sub>1c</sub> (- 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 HbA<sub>1c</sub> (- 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 HbA<sub>1c</sub> and weight outcomes as well as composite outcomes compared with those initiating DPP-4is.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"271-284"},"PeriodicalIF":3.2,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10980663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140174015","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}
<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
{"title":"Should Glucokinase be Given a Chance in Diabetes Therapeutics? A Clinical-Pharmacological Review of Dorzagliatin and Lessons Learned So Far.","authors":"Upinder Kaur, Bhairav Kumar Pathak, Tharik Jalal Meerashahib, Dondapati Venkata Vamshi Krishna, Sankha Shubhra Chakrabarti","doi":"10.1007/s40261-024-01351-5","DOIUrl":"10.1007/s40261-024-01351-5","url":null,"abstract":"<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","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"223-250"},"PeriodicalIF":3.2,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140068208","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}