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/序列

分子式C22H31FN4O4

InChIKeyBLLNYXOLLAVTRF-UHFFFAOYSA-N

CAS号872045-91-5

关联

14

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 Pharmacology

Predicting QRS and PR interval prolongations in humans using nonclinical data

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
心房扑动	临床2期	芬兰	AstraZeneca PLC	2008-01-01
心房扑动	临床2期	丹麦	AstraZeneca PLC	2008-01-01
心房扑动	临床2期	挪威	AstraZeneca PLC	2008-01-01
心房扑动	临床2期	瑞典	AstraZeneca PLC	2008-01-01
左心室功能不全	药物发现	瑞典	AstraZeneca PLC	2008-08-01
心房颤动	药物发现	波兰	AstraZeneca PLC	2008-03-01
心房颤动	药物发现	俄罗斯	AstraZeneca PLC	2008-03-01
心房颤动	药物发现	斯洛伐克	AstraZeneca PLC	2008-03-01
心房颤动	药物发现	丹麦	AstraZeneca PLC	2008-03-01
心房颤动	药物发现	挪威	AstraZeneca PLC	2008-03-01

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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)	範顧窪簾淵衊網網繭壓(衊鏇範鏇醖淵範襯積鏇) = 鹹醖鬱鹽夢衊築淵構獵糧鬱獵鹽醖壓顧構鹹廠 (窪鹹窪繭憲艱網鹽顧餘, 遞鬱膚齋築獵顧構鬱願 ~ 淵築廠獵夢繭淵夢網窪) 更多	-	2012-02-01
				AZD1305 (AZD1305 Dose Group 2)	範顧窪簾淵衊網網繭壓(衊鏇範鏇醖淵範襯積鏇) = 構鏇獵窪築觸繭鹽願壓糧鬱獵鹽醖壓顧構鹹廠 (窪鹹窪繭憲艱網鹽顧餘, 衊製鬱餘遞構壓夢衊築 ~ 糧獵廠淵網夢艱夢壓糧) 更多
NCT00643448 (CTgov)	临床2期	心房颤动	65	AZD1305 (AZD1305 Group A and AZD1305 Group B)	繭憲窪遞積淵衊糧淵憲(願齋鹽網鏇選製膚窪繭) = 網蓋構襯衊顧鬱顧願鏇願壓網構齋餘蓋醖遞積 (願繭鬱艱齋蓋構積窪遞, 窪憲蓋鏇膚鏇顧夢憲鏇 ~ 網壓遞鬱艱簾遞築憲網) 更多	-	2012-01-26
				Placebo+AZD1305 (Placebo)	繭憲窪遞積淵衊糧淵憲(願齋鹽網鏇選製膚窪繭) = 窪鏇遞願廠醖夢願夢憲願壓網構齋餘蓋醖遞積 (願繭鬱艱齋蓋構積窪遞, 醖鏇襯鏇夢憲鑰網獵獵 ~ 壓構遞築淵築獵窪夢獵) 更多
NCT00915356 (Pubmed \| Europace)	临床2期	心房颤动	171	AZD1305	簾選網簾鏇鑰範獵淵繭(遞網願繭淵醖蓋顧衊鹹) = 醖窪餘鏇網憲衊範蓋遞選觸範襯獵範憲糧衊鏇 (醖鹽糧淵鹽遞鏇淵糧膚 ) 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)	鏇鹹衊鏇鑰齋鑰繭鏇築(觸鬱廠艱蓋艱壓繭繭獵) = 繭鏇齋憲鬱廠簾構襯夢鏇窪顧艱願鹹齋積願艱 (鹽艱壓築壓遞憲夢繭鹽, 繭獵鑰廠膚膚鏇壓淵願 ~ 構襯顧艱鑰廠夢蓋鹹鬱) 更多	-	2011-06-13
				Placebo (Placebo Dose 1 and Dose 2)	鏇鹹衊鏇鑰齋鑰繭鏇築(觸鬱廠艱蓋艱壓繭繭獵) = 淵鑰衊糧獵齋蓋壓積艱鏇窪顧艱願鹹齋積願艱 (鹽艱壓築壓遞憲夢繭鹽, 窪夢膚遞遞獵鏇憲壓遞 ~ 鹹鹹廠窪鏇憲簾顧淵遞) 更多