Olaparib does not cause clinically relevant QT/QTc interval prolongation in patients with advanced solid tumours: results from two phase I studies

Swaisland, Helen; Plummer, Ruth; So, Karen; Garnett, Sally; Fabre, Marc-Antoine; Dota, Corina; Fielding, Anitra

doi:10.1007/s00280-016-3124-5

Cited by 18 publications

(7 citation statements)

References 19 publications

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“…In addition to ABT-888, olaparib may represent a suitable candidate. Olaparib is used in phase III clinical trials for the treatment of metastatic breast cancers and has no effect on QT/QTc interval 47,48 . Another potential therapeutic option to protect against AF-induced remodeling could be to replenish the NAD + pool by supplementation with NAD + or its precursors, such as nicotinamide and nicotinamide riboside.…”

Section: Discussionmentioning

confidence: 99%

DNA damage-induced PARP1 activation confers cardiomyocyte dysfunction through NAD+ depletion in experimental atrial fibrillation

Zhang

et al. 2019

Nat Commun

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Atrial fibrillation (AF) is the most common clinical tachyarrhythmia with a strong tendency to progress in time. AF progression is driven by derailment of protein homeostasis, which ultimately causes contractile dysfunction of the atria. Here we report that tachypacing-induced functional loss of atrial cardiomyocytes is precipitated by excessive poly(ADP)-ribose polymerase 1 (PARP1) activation in response to oxidative DNA damage. PARP1-mediated synthesis of ADP-ribose chains in turn depletes nicotinamide adenine dinucleotide (NAD+), induces further DNA damage and contractile dysfunction. Accordingly, NAD+ replenishment or PARP1 depletion precludes functional loss. Moreover, inhibition of PARP1 protects against tachypacing-induced NAD+ depletion, oxidative stress, DNA damage and contractile dysfunction in atrial cardiomyocytes and Drosophila. Consistently, cardiomyocytes of persistent AF patients show significant DNA damage, which correlates with PARP1 activity. The findings uncover a mechanism by which tachypacing impairs cardiomyocyte function and implicates PARP1 as a possible therapeutic target that may preserve cardiomyocyte function in clinical AF.

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Section: Discussionmentioning

confidence: 99%

DNA damage-induced PARP1 activation confers cardiomyocyte dysfunction through NAD+ depletion in experimental atrial fibrillation

Zhang

et al. 2019

Nat Commun

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“…For example, the PARP1 inhibitor olaparib is already in phase III clinical trials for the treatment of metastatic breast cancer (62) and ABT-888 in phase I/II clinical trials for the treatment of ovarian cancers presenting BRCA mutations ( Table 1). Olaparib is a favorable drug as it presents with high potency, low toxicity, and limited influence on QT/QTc interval (63). The second promising therapeutic strategy to prevent cardiomyocyte malfunction due to energetic failure is exogenous replenishment of NAD + by its precursors nicotinamide riboside and nicotinamide (12,30).…”

Section: Intervention At the Dna Damage-parp1-nad + Axis As A Novel Tmentioning

confidence: 99%

DNA Damage, an Innocent Bystander in Atrial Fibrillation and Other Cardiovascular Diseases?

Ramos

Brundel

2020

Front. Cardiovasc. Med.

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Atrial Fibrillation (AF) is the most common clinical tachyarrhythmia with a strong tendency to progress in time. AF is difficult to treat and therefore there is a great need to dissect root causes of AF with the ultimate goal to develop mechanism-based (drug) therapies. New findings related to mechanisms driving AF progression indicate a prime role for DNA damage-induced metabolic remodeling. A recent study uncovered that AF results in oxidative DNA damage and consequently excessive poly-ADP-ribose polymerase 1 (PARP1) activation and nicotinamide adenine dinucleotide (NAD +) depletion and finally atrial cardiomyocyte electrical and contractile dysfunction. This newly elucidated role of DNA damage in AF opens opportunities for novel therapeutic strategies. Recently developed PARP inhibitors, such as ABT-888 and olaparib, provide beneficial effects in limiting experimental AF, and are also found to limit atherosclerotic coronary artery disease and heart failure. Another therapeutic option to protect against AF is to replenish the NAD + pool by supplementation with NAD + or its precursors, such as nicotinamide and nicotinamide riboside. In this review, we describe the role of DNA damage-mediated metabolic remodeling in AF and other cardiovascular diseases, discuss novel druggable targets for AF and highlight future directions for clinical trials with drugs directed at PARP1-NAD + pathway with the ultimate aim to preserve quality of life and to attenuate severe complications such as heart failure or stroke in patients with AF.

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“…6 Evidence from two phase I studies in adult patients afflicted with refractory/resistant advanced solid tumours do not support a clinically relevant change in QT interval. 7…”

Section: Pharmacodynamic Properties Of Olaparibmentioning

confidence: 99%

“…Highlighted pharmacokinetic data from olaparib tablet dose finding study and summary of product characteristics. 6,7 Capsule 400 mg BID (N¼18) Tablet 300 mg BID (N¼18) A summary of pharmacokinetic data has been reported in Table 1. 6,8…”

Section: Pharmacokinetics Properties Of Olaparibmentioning

confidence: 99%

Pharmacological issues concerning olaparib capsule and tablet formulations in treating ovarian cancer: Are they really the same drug?

Perego

Nozza

Oggionni

et al. 2020

J Oncol Pharm Pract

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Olaparib is a first-in-class PARP inhibitor that has demonstrated efficacy as maintenance therapy in patients with ovarian cancer. It has been approved as a capsule formulation and after the publication of data from SOLO2 study became available also as tablet formulation. Due to different pharmacokinetic properties, these different formulations cannot be considered bioequivalent nor interchangeable. The tablet formulation has improved bioavailability, reducing pill burden and offering a more convenient dosage regimen. Furthermore, olaparib tablet formulation had a manageable tolerability profile if compared to capsule one, with most of adverse events of mild or moderate severity. Under this light, olaparib tablet formulation is a useful maintenance strategy for recurrent, platinum-sensitive ovarian cancer, providing a more convenient dosing option than the capsule formulation.

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Olaparib does not cause clinically relevant QT/QTc interval prolongation in patients with advanced solid tumours: results from two phase I studies

Abstract: Olaparib tablets administered as multiple or single doses had no clinically significant effect on QT/QTc interval.

Cited by 18 publications

References 19 publications

DNA damage-induced PARP1 activation confers cardiomyocyte dysfunction through NAD+ depletion in experimental atrial fibrillation

DNA damage-induced PARP1 activation confers cardiomyocyte dysfunction through NAD+ depletion in experimental atrial fibrillation

DNA Damage, an Innocent Bystander in Atrial Fibrillation and Other Cardiovascular Diseases?

Pharmacological issues concerning olaparib capsule and tablet formulations in treating ovarian cancer: Are they really the same drug?

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