AZD-1305(AZD-1305) - 药物靶点：L-type calcium channel x Nav1.5 x hERG_在研适应症：心房颤动_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

L-type calcium channel x Nav1.5 x hERG

作用机制

L-type calcium channel阻滞剂(L-型电压门控性钙通道家族阻滞剂)、Nav1.5阻滞剂(V型钠通道蛋白α亚基阻滞剂)、hERG阻滞剂(电压门控性钾通道蛋白亚型Kv11.1阻滞剂)

治疗领域

在研适应症

非在研适应症

原研机构

在研机构

AstraZeneca R&D Mölndal

Odense University Hospital

非在研机构

AstraZeneca PLC

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C22H31FN4O4

InChIKeyBLLNYXOLLAVTRF-UHFFFAOYSA-N

CAS号872045-91-5

关联

15

项与 AZD-1305 相关的临床试验

NCT00957437 / Completed临床1期

A Phase I, Randomised, Open, Single-centre Study to Evaluate the Pharmacokinetics of Different Extended-release Formulations of AZD1305 When Given as Single and Repeated Oral Doses to Healthy Male Volunteers

The purpose of this study is to evaluate the pharmacokinetics of different extended-release formulations of AZD1305 when given as single and multiple oral doses to healthy male volunteers.

开始日期2009-08-01

申办/合作机构

AstraZeneca PLC

NCT00935025 / Terminated临床1期

A Single-center, Single-blind, Randomized, Placebo-controlled, Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics After Single and Multiple Ascending Oral Doses of AZD1305 Extended-release Capsules in Healthy Male Japanese and Caucasian Subjects

This is a phase I, single-blind, randomized, placebo-controlled single and repeated ascending dose study to assess the safety, tolerability and pharmacokinetics with oral doses of AZD1305 extended-release capsules in healthy male Japanese and Caucasian subjects. Three (or four if needed) dose levels will be given to Japanese subjects and one of the doses will also be given to Caucasian subjects.

开始日期2009-07-01

申办/合作机构

AstraZeneca PLC

EUCTR2009-009862-15-CZ / Not yet recruitingN/A

A double-Blind, Randomised, Placebo-Controlled, Multicentre, Dose-Escalating Study of AZD1305 Given Intravenoulsy for Cardioversion of Atrial Fibrillation

开始日期2009-06-16

申办/合作机构-

100 项与 AZD-1305 相关的临床结果

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100 项与 AZD-1305 相关的转化医学

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100 项与 AZD-1305 相关的专利（医药）

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15

项与 AZD-1305 相关的文献（医药）

2017-10-01·British Journal of Pharmacology2区 · 医学

Predicting QRS and PR interval prolongations in humans using nonclinical data

2区 · 医学

Article

作者: Bergenholm, L ; Parkinson, J ; Collins, T ; Mettetal, J ; Evans, N D ; Chappell, M J

Background and PurposeRisk of cardiac conduction slowing (QRS/PR prolongations) is assessed prior to clinical trials using in vitro and in vivo studies. Understanding the quantitative translation of these studies to the clinical situation enables improved risk assessment in the nonclinical phase.Experimental ApproachFour compounds that prolong QRS and/or PR (AZD1305, flecainide, quinidine and verapamil) were characterized using in vitro (sodium/calcium channels), in vivo (guinea pigs/dogs) and clinical data. Concentration‐matched translational relationships were developed based on in vitro and in vivo modelling, and the in vitro to clinical translation of AZD1305 was quantified using an in vitro model.Key ResultsMeaningful (10%) human QRS/PR effects correlated with low levels of in vitro Nav1.5 block (3–7%) and Cav1.2 binding (13–21%) for all compounds. The in vitro model developed using AZD1305 successfully predicted QRS/PR effects for the remaining drugs. Meaningful QRS/PR changes in humans correlated with small effects in guinea pigs and dogs (QRS 2.3–4.6% and PR 2.3–10%), suggesting that worst‐case human effects can be predicted by assuming four times greater effects at the same concentration from dog/guinea pig data.Conclusion and ImplicationsSmall changes in vitro and in vivo consistently translated to meaningful PR/QRS changes in humans across compounds. Assuming broad applicability of these approaches to assess cardiovascular safety risk for non–arrhythmic drugs, this study provides a means of predicting human QRS/PR effects of new drugs from effects observed in nonclinical studies.

2016-09-01·Clinical Pharmacology in Drug Development4区 · 医学

In Silico Predictions and In Vivo Results of Drug–Drug Interactions by Ketoconazole and Verapamil on AZD1305, a Combined Ion Channel Blocker and a Sensitive CYP3A4 Substrate

4区 · 医学

Article

作者: Löfberg, Boel ; Frison, Lars ; Lunde, Helen ; Edvardsson, Nils ; Cullberg, Marie ; Aunes, Maria ; Johansson, Susanne

AbstractThe objectives were to estimate and compare, in silico and in vivo, the effects of a strong and a moderate CYP3A4 inhibitor on AZD1305 pharmacokinetics. In silico, simulations were performed with the computer software Simcyp, and the predicted outcome was compared with the results observed in healthy male subjects. In silico, the geometric mean plasma exposure of AZD1305 + ketoconazole showed a 7.1‐fold higher AUC and a 4.4‐fold higher Cmax compared with AZD1305 alone. Coadministration with verapamil gave a 1.9‐fold higher AUC and a 1.7‐fold higher Cmax compared with AZD1305 alone. In vivo, the plasma exposure of AZD1305 + ketoconazole showed a 7.7‐fold higher AUC and a 4.8 ‐fold higher Cmax compared with AZD1305 alone. Coadministration with verapamil gave a 2.2‐fold higher AUC and a 2.0‐fold higher Cmax compared with AZD1305 alone. The mean maximum QTcF increase from baseline was 407, 487, and 437 milliseconds for AZD1305, alone and in combination with verapamil or ketoconazole, respectively. Simcyp predicted the effects of ketoconazole and verapamil on the sensitive CYP3A4 substrate AZD1305 pharmacokinetics well. Both the in vivo study and the Simcyp predictions suggest a contraindication for strong CYP3A4 inhibitors and AZD1305 when given in combination.

2016-05-01·Journal of Pharmacological and Toxicological Methods4区 · 医学

PKPD modelling of PR and QRS intervals in conscious dogs using standard safety pharmacology data

4区 · 医学

Article

作者: Parkinson, Joanna ; Collins, Teresa ; Bergenholm, Linnéa ; Chappell, Michael J ; Evans, Neil D

INTRODUCTIONPharmacokinetic-pharmacodynamic (PKPD) modelling can improve safety assessment, but few PKPD models describing drug-induced QRS and PR prolongations have been published. This investigation aims to develop and evaluate PKPD models for describing QRS and PR effects in routine safety studies.METHODSExposure and telemetry data from safety pharmacology studies in conscious beagle dogs were acquired. Mixed effects baseline and PK-QRS/PR models were developed for the anti-arrhythmic compounds AZD1305, flecainide, quinidine and verapamil and the anti-muscarinic compounds AZD8683 and AZD9164. RR interval correction and circadian rhythms were investigated for predicting baseline variability. Individual PK predictions were used to drive the pharmacological effects evaluating linear and non-linear direct and effect compartment models.RESULTSConduction slowing induced by the tested anti-arrhythmics was direct and proportional at low exposures, whilst time delays and non-linear effects were evident for the tested anti-muscarinics. AZD1305, flecainide and quinidine induced QRS widening with 4.2, 10 and 5.6% μM(-1) unbound drug. AZD1305 and flecainide also prolonged PR with 13.5 and 11.5% μM(-1). PR prolongations induced by the anti-muscarinics and verapamil were best described by Emax models with maximal effects ranging from 55 to 95%. RR interval correction and circadian rhythm improved PR but not QRS modelling. However, circadian rhythm had minor impact on estimated drug effects.DISCUSSIONBaseline and drug-induced effects on QRS and PR intervals can be effectively described with PKPD models using routine data, providing quantitative safety information to support drug discovery and development.

100 项与 AZD-1305 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	AZD-1305	-	DB11766

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
左心室功能不全	临床前	瑞典	AstraZeneca PLC	2008-08-01
心房颤动	临床前	丹麦	AstraZeneca PLC	2008-03-01
心房颤动	临床前	波兰	AstraZeneca PLC	2008-03-01
心房颤动	临床前	挪威	AstraZeneca PLC	2008-03-01
心房颤动	临床前	俄罗斯	AstraZeneca PLC	2008-03-01
心房颤动	临床前	斯洛伐克	AstraZeneca PLC	2008-03-01
心房扑动	临床前	芬兰	AstraZeneca PLC	2008-01-01
心房扑动	临床前	丹麦	AstraZeneca PLC	2008-01-01
心房扑动	临床前	挪威	AstraZeneca PLC	2008-01-01
心房扑动	临床前	瑞典	AstraZeneca PLC	2008-01-01

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT00915356 (CTgov)	临床2期	心房颤动	228	AZD1305 (AZD1305 Dose Group 1)	衊廠鏇鑰鬱壓觸齋積淵(憲廠餘廠築觸衊齋顧糧) = 壓淵膚壓醖餘窪餘鹹鹽積願鑰選壓獵鑰襯膚鏇 (壓襯製積簾鑰範築膚齋, 選廠餘鹽鏇壓簾繭艱鏇 ~ 糧夢繭醖遞簾蓋鏇窪餘) 更多	-	2012-02-01
				AZD1305 (AZD1305 Dose Group 2)	衊廠鏇鑰鬱壓觸齋積淵(憲廠餘廠築觸衊齋顧糧) = 繭蓋糧齋願糧願願鑰範積願鑰選壓獵鑰襯膚鏇 (壓襯製積簾鑰範築膚齋, 蓋齋壓願簾餘鬱製遞製 ~ 窪膚繭構鏇糧獵鏇繭築) 更多
NCT00643448 (CTgov)	临床2期	心房颤动	65	AZD1305 (AZD1305 Group A and AZD1305 Group B)	獵顧獵鑰夢製窪繭製壓(壓獵鹽夢獵遞製醖獵膚) = 衊醖襯夢顧鹹鬱衊鑰範壓廠鏇醖蓋製鹽網夢蓋 (夢鏇憲憲膚鑰鬱醖積顧, 選繭餘壓遞鹽淵醖鏇鏇 ~ 積鹽糧鹽衊膚遞蓋壓願) 更多	-	2012-01-26
				Placebo+AZD1305 (Placebo)	獵顧獵鑰夢製窪繭製壓(壓獵鹽夢獵遞製醖獵膚) = 壓艱築鬱繭簾艱網築蓋壓廠鏇醖蓋製鹽網夢蓋 (夢鏇憲憲膚鑰鬱醖積顧, 願糧網齋膚鏇鹽醖齋顧 ~ 製願淵願鏇鏇獵鏇繭選) 更多
NCT00915356 (Pubmed \| Europace)	临床2期	心房颤动	171	AZD1305	憲鹹鬱餘鹹廠廠積觸鹽(鏇繭獵艱淵蓋壓繭憲遞) = 繭膚膚築繭艱艱鏇膚鑰繭襯夢淵襯醖製夢餘艱 (網襯淵選鑰網積壓壓觸 ) 更多	不佳	2011-08-01
NCT00748982 (CTgov)	临床2期	左心室功能不全	16	AZD1305 (AZD1305 Dose 1 and Dose 2)	夢選憲構願憲鹹願襯餘(鑰遞衊窪壓構窪鏇鏇餘) = 蓋遞繭醖夢繭夢選淵齋蓋廠願膚範鏇網觸膚憲 (憲願壓願鬱鹽淵憲艱襯, 鬱願淵餘齋餘製鹹願築 ~ 鑰醖範糧遞繭製鬱廠範) 更多	-	2011-06-13
				Placebo (Placebo Dose 1 and Dose 2)	夢選憲構願憲鹹願襯餘(鑰遞衊窪壓構窪鏇鏇餘) = 製鹹選願製醖觸醖鑰遞蓋廠願膚範鏇網觸膚憲 (憲願壓願鬱鹽淵憲艱襯, 鬱廠鹽網憲廠網獵製顧 ~ 範淵淵廠鑰選齋齋蓋顧) 更多