Journal of clinical pharmacology最新文献_第7页

Core Entrustable Professional Activities in Clinical Pharmacology for Entering Residency: Biologics. 进入住院医师的临床药理学核心可信赖的专业活动:生物制剂。

IF 2.9 4区医学

Journal of clinical pharmacology Pub Date : 2017-08-01 Epub Date: 2017-06-14 DOI: 10.1002/jcph.938

Vera S Donnenberg, Maja Mandic, John C Rhee, Timothy F Burns, Bernd Meibohm, Joan M Korth-Bradley

引用次数: 3

Pharmacokinetics of Macitentan in Patients With Pulmonary Arterial Hypertension and Comparison With Healthy Subjects. 马西坦在肺动脉高压患者体内的药动学及与健康人的比较。

IF 2.9 4区医学

Journal of clinical pharmacology Pub Date : 2017-08-01 Epub Date: 2017-04-05 DOI: 10.1002/jcph.888

Milena Issac, Jasper Dingemanse, Patricia N Sidharta

{"title":"Pharmacokinetics of Macitentan in Patients With Pulmonary Arterial Hypertension and Comparison With Healthy Subjects.","authors":"Milena Issac, Jasper Dingemanse, Patricia N Sidharta","doi":"10.1002/jcph.888","DOIUrl":"https://doi.org/10.1002/jcph.888","url":null,"abstract":"Macitentan is a worldwide approved dual endothelin receptor antagonist that has demonstrated efficacy in the treatment of pulmonary arterial hypertension (PAH) in a phase 3 clinical trial, SERAPHIN, at a dose of 10 mg once daily. During this trial, trough plasma concentrations (Ctrough ) of macitentan and its active metabolite, ACT-132577, were obtained at steady state in 242 patients, indicating that mean Ctrough of both analytes was about 2-fold higher in PAH patients than in healthy subjects. To further investigate the pharmacokinetics (PK) of macitentan and its active metabolite, ACT-132577, a 24-hour PK profile was recorded at steady state in 20 PAH patients in the open-label extension of SERAPHIN. A cross-study comparison showed that although Ctrough in PAH patients is higher when compared with a historical reference group of healthy subjects, with geometric mean ratios of 1.45 and 1.36 for macitentan and ACT-132577, respectively, this does not translate to a significant difference in exposure expressed as maximum plasma concentration (Cmax ) or area under the plasma concentration-time curve over a dosing interval (AUCτ ). Geometric mean ratios for Cmax and AUCτ were 1.08 and 1.22, respectively, for macitentan and 1.24 and 1.31, respectively, for ACT-132577. Therefore, overall exposure at steady state to macitentan and ACT-132577 in PAH patients is considered similar to that in healthy subjects.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 8","pages":"997-1004"},"PeriodicalIF":2.9,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.888","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34887171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 5

Influence of Meals and Glycemic Changes on QT Interval Dynamics. 膳食和血糖变化对 QT 间期动态的影响

IF 2.9 4区医学

Journal of clinical pharmacology Pub Date : 2017-08-01 Epub Date: 2017-05-22 DOI: 10.1002/jcph.933

Brenda Cirincione, Philip T Sager, Donald E Mager

{"title":"Influence of Meals and Glycemic Changes on QT Interval Dynamics.","authors":"Brenda Cirincione, Philip T Sager, Donald E Mager","doi":"10.1002/jcph.933","DOIUrl":"10.1002/jcph.933","url":null,"abstract":"Thorough QT/QTc studies have become an integral part of early drug development programs, with major clinical and regulatory implications. This analysis expands on existing pharmacodynamic models of QT interval analysis by incorporating the influence of glycemic changes on the QT interval in a semimechanistic manner. A total of 21 healthy subjects enrolled in an open-label phase 1 pilot study and provided continuous electrocardiogram monitoring and plasma glucose and insulin concentrations associated with a 24-hour baseline assessment. The data revealed a transient decrease in QTc, with peak suppression occurring approximately 3 hours after the meal. A semimechanistic modeling approach was applied to evaluate temporal delays between meals and subsequent changes that might influence QT measurements. The food effect was incorporated into a model of heart rate dynamics, and additional delayed effects of the meal on QT were incorporated using a glucose-dependent hypothetical transit compartment. The final model helps to provide a foundation for the future design and analysis of QT studies that may be confounded by meals. This study has significant implications for QT study assessment following a meal or when a cohort is receiving a medication that influences postprandial glucose concentrations.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 8","pages":"966-976"},"PeriodicalIF":2.9,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c5/60/JCPH-57-966.PMC5518218.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35027255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Population-Based Pharmacokinetic and Exposure-Efficacy Analyses of Peginterferon Beta-1a in Patients With Relapsing Multiple Sclerosis. 聚乙二醇干扰素β -1a在复发性多发性硬化症患者中基于人群的药代动力学和暴露-疗效分析

IF 2.9 4区医学

Journal of clinical pharmacology Pub Date : 2017-08-01 Epub Date: 2017-04-10 DOI: 10.1002/jcph.883

Xiao Hu, Yaming Hang, Yue Cui, Jie Zhang, Shifang Liu, Ali Seddighzadeh, Aaron Deykin, Ivan Nestorov

{"title":"Population-Based Pharmacokinetic and Exposure-Efficacy Analyses of Peginterferon Beta-1a in Patients With Relapsing Multiple Sclerosis.","authors":"Xiao Hu, Yaming Hang, Yue Cui, Jie Zhang, Shifang Liu, Ali Seddighzadeh, Aaron Deykin, Ivan Nestorov","doi":"10.1002/jcph.883","DOIUrl":"https://doi.org/10.1002/jcph.883","url":null,"abstract":"Peginterferon beta-1a reduced annualized relapse rate as compared with placebo and was approved to treat multiple sclerosis patients. A population pharmacokinetic and an exposure-efficacy model were developed to establish the quantitative relationship between pharmacokinetics and annualized relapse rate. The pharmacokinetics was well described by a 1-compartment model with first-order absorption and linear elimination kinetics. Body mass index was the most significant covariate that impacted both clearance and volume of distribution, which in turn impacted area under the curve and maximum serum concentration. Cumulative monthly area under the curve and annualized relapse rate were best described by a Poisson-gamma (negative binomial) model, demonstrating that the improved efficacy of every-2-weeks dosing was driven by greater drug exposure. The results supported the superior efficacy of the every-2-week dosing regimen compared with the every-4-weeks dosing regimen.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 8","pages":"1005-1016"},"PeriodicalIF":2.9,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.883","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34900505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 7

Population Pharmacokinetics and Target Engagement of Natalizumab in Patients With Multiple Sclerosis. Natalizumab在多发性硬化症患者中的群体药代动力学和靶标参与。

IF 2.9 4区医学

Journal of clinical pharmacology Pub Date : 2017-08-01 Epub Date: 2017-04-11 DOI: 10.1002/jcph.894

Kumar Kandadi Muralidharan, Geoffrey Kuesters, Tatiana Plavina, Meena Subramanyam, Daniel D Mikol, Sreeja Gopal, Ivan Nestorov

{"title":"Population Pharmacokinetics and Target Engagement of Natalizumab in Patients With Multiple Sclerosis.","authors":"Kumar Kandadi Muralidharan, Geoffrey Kuesters, Tatiana Plavina, Meena Subramanyam, Daniel D Mikol, Sreeja Gopal, Ivan Nestorov","doi":"10.1002/jcph.894","DOIUrl":"https://doi.org/10.1002/jcph.894","url":null,"abstract":"Natalizumab (humanized immunoglobulin G4 antibody targeting alpha-4 integrins) is a highly efficacious treatment for relapsing-remitting multiple sclerosis (RRMS) that has been in clinical use since 2006. However, natalizumab pharmacokinetic (PK) characteristics and concentration alpha-4 integrin saturation relationships have not been well described in the scientific literature. Therefore, clinical data from 11 studies were pooled and analyzed to characterize the PK and pharmacodynamic (PD) properties of natalizumab in RRMS subjects. Natalizumab PK was best described using a 2-compartment model with linear first-order and Michaelis-Menten elimination. Subcutaneous absorption of natalizumab was characterized using first-order absorption with lag time. The relationship between natalizumab concentration and alpha-4 integrin saturation (PD) was best described by a direct response model with a sigmoidal effect on alpha-4 integrin saturation mediated by a maximum effect relationship with natalizumab concentrations. Covariate analysis showed that body weight, product formulations, and the presence of antinatalizumab antibodies were the main covariates affecting natalizumab PK, whereas age and formulations affected PD. The use of simulations based on a pharmacokinetic-pharmacodynamic model showed that covariates, although statistically significant, are not expected to have any clinical impact at the approved clinical dosing regimen of natalizumab (300 mg once every 4 weeks).","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 8","pages":"1017-1030"},"PeriodicalIF":2.9,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.894","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34904004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 28

Model-Based Evaluation of Exenatide Effects on the QT Interval in Healthy Subjects Following Continuous IV Infusion. 基于模型的持续静脉输注艾塞那肽对健康受试者QT间期影响的评价

IF 2.9 4区医学

Journal of clinical pharmacology Pub Date : 2017-08-01 Epub Date: 2017-05-22 DOI: 10.1002/jcph.882

Brenda Cirincione, Frank LaCreta, Philip Sager, Donald E Mager

{"title":"Model-Based Evaluation of Exenatide Effects on the QT Interval in Healthy Subjects Following Continuous IV Infusion.","authors":"Brenda Cirincione, Frank LaCreta, Philip Sager, Donald E Mager","doi":"10.1002/jcph.882","DOIUrl":"https://doi.org/10.1002/jcph.882","url":null,"abstract":"Investigation of the cardiovascular proarrhythmic potential of a new chemical entity is now an integral part of drug development. Studies suggest that meals and glycemic changes can influence QT intervals, and a semimechanistic model has been developed that incorporates the effects of changes in glucose concentrations on heart rate (HR) and QT intervals. This analysis aimed to adapt the glucose-HR-QT model to incorporate the effects of exenatide, a drug that reduces postprandial increases in glucose concentrations. The final model includes stimulatory drug effects on glucose elimination and HR perturbations. The targeted and constant exenatide plasma concentrations (>200 pg/mL), via intravenous infusions at multiple dose levels, resulted in significant inhibition of glucose concentrations. The exenatide concentration associated with 50% of the stimulation of HR production was 584 pg/mL. After accounting for exenatide effects on glucose and HR, no additional drug effects were required to explain observed changes in the QT interval. Resulting glucose, HR, and QT profiles at all exenatide concentrations were adequately described. For therapeutic agents that alter glycemic conditions, particularly those that alter postprandial glucose, the QT interval cannot be directly compared to that with placebo without first accounting for confounding factors (eg, glucose) either through mathematical modeling or careful consideration of mealtime placement in the study design.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 8","pages":"956-965"},"PeriodicalIF":2.9,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.882","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35028671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Population Pharmacokinetics of Nusinersen in the Cerebral Spinal Fluid and Plasma of Pediatric Patients With Spinal Muscular Atrophy Following Intrathecal Administrations. 鞘内给药后小儿脊髓肌萎缩患者脑脊液和血浆中Nusinersen的群体药代动力学

IF 2.9 4区医学

Journal of clinical pharmacology Pub Date : 2017-08-01 Epub Date: 2017-03-29 DOI: 10.1002/jcph.884

Kenneth T Luu, Daniel A Norris, Rudy Gunawan, Scott Henry, Richard Geary, Yanfeng Wang

{"title":"Population Pharmacokinetics of Nusinersen in the Cerebral Spinal Fluid and Plasma of Pediatric Patients With Spinal Muscular Atrophy Following Intrathecal Administrations.","authors":"Kenneth T Luu, Daniel A Norris, Rudy Gunawan, Scott Henry, Richard Geary, Yanfeng Wang","doi":"10.1002/jcph.884","DOIUrl":"https://doi.org/10.1002/jcph.884","url":null,"abstract":"Nusinersen is an antisense oligonucleotide intended for the treatment of spinal muscular atrophy. The pharmacokinetics of nusinersen, following intrathecal administrations, in the cerebrospinal fluid (CSF) and plasma of 72 pediatric patients (3 months to 17 years) with spinal muscular atrophy across 5 clinical trials was analyzed via population-based modeling. With sparse data in the CSF and profile data in the plasma, a linear 4-compartment model simultaneously described the time-concentration profiles in both matrices. The typical population parameters were: Qp = 0.572 L/h, QCSF = 0.069 L/h, CLp = 2.50 L/h, CLCSF = 0.133 L/hr, VCSF = 0.441 L, Vp = 32.0 L, Vsystemic_tissue = 429 L, and VCNS_tissue = 258 L. A full covariate modeling approach identified baseline body weight to be a statistically and clinically relevant covariate on VCSF , Vp , and CLp . The model predicted that the CSF volume of distribution increased steadily with age from 0 to 2 years but became relatively steady for children >2 years. Simulations from the final model showed that age-based dosing in children under 2 years ensured a more comparable exposure (peak concentration and area under the concentration-time curve) across subjects in the population relative to a fixed dosing scheme. However, because no dose-limiting toxicity has been reported in any of the trials, a fixed-dose scheme (12 mg across all age groups) was recommended. The median terminal half-life of nusinersen in the CSF was determined from the model to be 163 days, which supported infrequent dosing, once every 4 to 6 months in pediatric patients with spinal muscular atrophy.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 8","pages":"1031-1041"},"PeriodicalIF":2.9,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.884","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34879680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 33

Regulatory and Ethical Issues in Pediatric Clinical Research: Recommendations From a Panel Discussion. 儿科临床研究中的监管和伦理问题:来自小组讨论的建议。

IF 2.9 4区医学

Journal of clinical pharmacology Pub Date : 2017-08-01 Epub Date: 2017-05-17 DOI: 10.1002/jcph.916

Nilima Kshirsagar, Soumya Swaminathan, Pramod Jog, Samir Dalwai, Roli Mathur, Chandra Shekhar, Bernd Meibohm, Y K Gupta, Nusrat Shafiq, Gangadhar Sunkara, V G Somani, Prasad Kulkarni, Brian Tseng, Dhvani Mehta

引用次数: 6

Modeling and Simulation of Pivotal Clinical Trials Using Linked Models for Multiple Endpoints in Chronic Obstructive Pulmonary Disease With Roflumilast. 使用罗氟司特治疗慢性阻塞性肺疾病多终点关联模型的关键临床试验建模和模拟

IF 2.9 4区医学

Journal of clinical pharmacology Pub Date : 2017-08-01 Epub Date: 2017-04-17 DOI: 10.1002/jcph.885

Axel Facius, Andreas Krause, Laurent Claret, Rene Bruno, Gezim Lahu

{"title":"Modeling and Simulation of Pivotal Clinical Trials Using Linked Models for Multiple Endpoints in Chronic Obstructive Pulmonary Disease With Roflumilast.","authors":"Axel Facius, Andreas Krause, Laurent Claret, Rene Bruno, Gezim Lahu","doi":"10.1002/jcph.885","DOIUrl":"https://doi.org/10.1002/jcph.885","url":null,"abstract":"Roflumilast is a selective phosphodiesterase 4 inhibitor (PDE4i) for the treatment of severe chronic obstructive pulmonary disease (COPD). In 2 large phase 3 trials in a broader population of COPD patients (BY217/M2-111, ClinicalTrials.gov: NCT00076089 and BY217/M2-112, ClinicalTrials.gov: NCT00430729), treatment with roflumilast reduced the rate of exacerbations; however, the reduction did not reach statistical significance. Two linked dose-response models for the primary (annualized COPD exacerbation counts) and secondary (change from baseline in forced expiratory volume in 1 second [FEV1 ]) end points were therefore developed to characterize and quantify effect sizes and the patient characteristics influencing them. The models showed that disease severity and bronchitis, particularly the severity of bronchitis expressed in cough-and-sputum scores, were good predictors of exacerbation rates and differential benefit of roflumilast in exacerbation reduction. The models were used to support the rational design of 2 phase 3 randomized, placebo-controlled clinical trials (BY217/M2-124, ClinicalTrials.gov: NCT00297102 and BY217/M2-125, ClinicalTrials.gov: NCT00297115) by identifying the most appropriate patient population using clinical trial simulations. Model predictions for both end points were found to be highly accurate - as confirmed by the results from these trials, which led to the approval of roflumilast as the first oral PDE4i for the treatment of COPD in patients associated with chronic bronchitis and a history of exacerbations.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 8","pages":"1042-1052"},"PeriodicalIF":2.9,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.885","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34922279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 6

Antimuscarinic Use in Females With Overactive Bladder Syndrome Increases the Risk of Depressive Disorder: A 3-Year Follow-up Study. 女性膀胱过度活动综合征患者使用抗蛇毒碱增加抑郁障碍的风险:一项3年随访研究

IF 2.9 4区医学

Journal of clinical pharmacology Pub Date : 2017-08-01 Epub Date: 2017-04-05 DOI: 10.1002/jcph.890

Shiu-Dong Chung, Sung-Shun Weng, Chao-Yuan Huang, Herng-Ching Lin, Li-Ting Kao

{"title":"Antimuscarinic Use in Females With Overactive Bladder Syndrome Increases the Risk of Depressive Disorder: A 3-Year Follow-up Study.","authors":"Shiu-Dong Chung, Sung-Shun Weng, Chao-Yuan Huang, Herng-Ching Lin, Li-Ting Kao","doi":"10.1002/jcph.890","DOIUrl":"https://doi.org/10.1002/jcph.890","url":null,"abstract":"To date, the relationship between antimuscarinics for overactive bladder (OAB) syndrome and depressive disorder still remains unclear. Therefore, this retrospective cohort study examined the association between antimuscarinic use and the subsequent risk of depressive disorder using a population-based data set. This study used data from the Taiwan Longitudinal Health Insurance Database 2005. We selected 1952 OAB women who received antimuscarinics as the study cohort and 9760 OAB women who did not receive antimuscarinics as the comparison cohort. Each subject was tracked for 3 years from her index date to determine all those who were subsequently diagnosed with depressive disorder. Results indicated that the adjusted hazard ratio (HR) for depressive disorder in OAB women who received antimuscarinics was 1.38 (95% confidence interval [CI], 1.15-1.64) compared with those OAB women who did not receive antimuscarinics. In addition, the adjusted HRs for subsequent depressive disorder for OAB women aged 18-39, 40-59, and ≥60 years who received antimuscarinics were 1.83 (95%CI, 1.27-2.64), 1.36 (95%CI, 1.03-1.81), and 1.16 (95%CI, 0.86-1.56), respectively, compared with those OAB women who did not receive antimuscarinics. We concluded that women with OAB who received antimuscarinics had a significantly higher risk of subsequent depressive disorder compared with those OAB women who did not receive antimuscarinics. Accordingly, clinicians should be alert to the relationship between antimuscarinics usage and depressive disorder in OAB women and provide appropriate instructions for these patients.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 8","pages":"1064-1070"},"PeriodicalIF":2.9,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.890","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34887170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4