Delving into the Latest Updates on AZD-1305 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

Mechanism

L-type calcium channel blockers(Voltage-gated L-type calcium channel blockers), Nav1.5 blockers(Sodium channel protein type V alpha subunit blockers), hERG blockers(Voltage-gated potassium channel subunit Kv11.1 blockers)

Therapeutic Areas

Cardiovascular Diseases

Active Indication

Atrial Fibrillation

Inactive Indication

Atrial FlutterVentricular Dysfunction, Left

Originator Organization

AstraZeneca Pharmaceuticals Co. Ltd.

Active Organization

AstraZeneca R&D Mölndal

Odense University Hospital

Inactive Organization

AstraZeneca PLC

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC22H31FN4O4

InChIKeyBLLNYXOLLAVTRF-UHFFFAOYSA-N

CAS Registry872045-91-5

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.

Start Date01 Jul 2009

Sponsor / Collaborator

AstraZeneca PLC

EUCTR2009-009862-15-CZ / Not yet recruitingNot Applicable

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

Start Date16 Jun 2009

Sponsor / Collaborator-

100 Clinical Results associated with AZD-1305

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100 Translational Medicine associated with AZD-1305

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100 Patents (Medical) associated with AZD-1305

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15

Literatures (Medical) associated with AZD-1305

01 Oct 2017·British Journal of PharmacologyQ2 · MEDICINE

Predicting QRS and PR interval prolongations in humans using nonclinical data

Q2 · MEDICINE

Article

Author: 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.

01 Sep 2016·Clinical Pharmacology in Drug DevelopmentQ4 · MEDICINE

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

Q4 · MEDICINE

Article

Author: 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.

01 May 2016·Journal of Pharmacological and Toxicological MethodsQ4 · MEDICINE

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

Q4 · MEDICINE

Article

Author: 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 Deals associated with AZD-1305

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External Link

KEGG	Wiki	ATC	Drug Bank
-	AZD-1305	-	DB11766

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Ventricular Dysfunction, Left	Phase 2	SE	AstraZeneca PLC	01 Aug 2008
Atrial Fibrillation	Phase 2	RU	AstraZeneca PLC	01 Mar 2008
Atrial Fibrillation	Phase 2	NO	AstraZeneca PLC	01 Mar 2008
Atrial Fibrillation	Phase 2	SK	AstraZeneca PLC	01 Mar 2008
Atrial Fibrillation	Phase 2	PL	AstraZeneca PLC	01 Mar 2008
Atrial Fibrillation	Phase 2	DK	AstraZeneca PLC	01 Mar 2008
Atrial Flutter	Phase 2	SE	AstraZeneca PLC	01 Jan 2008
Atrial Flutter	Phase 2	NO	AstraZeneca PLC	01 Jan 2008
Atrial Flutter	Phase 2	FI	AstraZeneca PLC	01 Jan 2008
Atrial Flutter	Phase 2	DK	AstraZeneca PLC	01 Jan 2008

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00915356 (CTgov)	Phase 2	Atrial Fibrillation	228	AZD1305 (AZD1305 Dose Group 1)	fijnxzjfyf(sfmntargnc) = rwpdqigktt gjpahqozdz (bdbciqubbv, xoltdmndjb - nqxpmmxqlq) View more	-	01 Feb 2012
				AZD1305 (AZD1305 Dose Group 2)	fijnxzjfyf(sfmntargnc) = mpkymyploy gjpahqozdz (bdbciqubbv, jchcqcnlcr - wepixwzrxb) View more
NCT00643448 (CTgov)	Phase 2	Atrial Fibrillation	65	AZD1305 (AZD1305 Group A and AZD1305 Group B)	hwehmtiljb(xybwmnlqbb) = wqfozryrie yxsbnwlmat (fqfdkjzefl, jyxkivcagn - orwnqearvo) View more	-	26 Jan 2012
				Placebo+AZD1305 (Placebo)	hwehmtiljb(xybwmnlqbb) = onjhfcspfh yxsbnwlmat (fqfdkjzefl, awsxkgkgzu - npttdvcksd) View more
NCT00915356 (Pubmed \| Europace)	Phase 2	Atrial Fibrillation	171	AZD1305	vvdyabrols(zlhrwjomno) = oqkzcdwfiu adxofpexlo (pmommmzkzz ) View more	Negative	01 Aug 2011
NCT00748982 (CTgov)	Phase 2	Ventricular Dysfunction, Left	16	AZD1305 (AZD1305 Dose 1 and Dose 2)	izftqnnqso(tbtdigwpzg) = xkmmuandbe kszfalqsyj (wlowdcvanf, kyaszjeszm - yrjiuugqsc) View more	-	13 Jun 2011
				Placebo (Placebo Dose 1 and Dose 2)	izftqnnqso(tbtdigwpzg) = nuyxycvmpj kszfalqsyj (wlowdcvanf, ibgskkyrkq - qcuzmspwad) View more