Validation of a population‐based method to assess drug‐induced alterations in the QT interval: a self‐controlled crossover study

Iribarren, Carlos; Round, Alfred D; Peng, Jonathan A.; Lü, Meng; Zaroff, Jonathan G.; Holve, Taylor J.; Prasad, Amit; Stang, Paul

doi:10.1002/pds.3479

Cited by 23 publications

(42 citation statements)

References 72 publications

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“…However, in a recently controlled crossover study for 90 drugs with 59,467 subjects (42) aripiprazole showed a mean QTc prolongation of 7.6 ms, that is similar to our data. In addition, Torsade de Pointes (a form of ventricular tachycardia) was reported in a patient without history of cardiovascular risk after administration of 2.5 mg of aripiprazole (43).…”

Section: Pharmacodynamicssupporting

confidence: 82%

Evaluation of the Relationship Between Pharmacokinetics and the Safety of Aripiprazole and Its Cardiovascular Effects in Healthy Volunteers

Belmonte¹,

Ochoa²,

Román³

et al. 2016

J Clin Psychopharmacol

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Esta es la versión de autor del artículo publicado en: This is an author produced version of a paper published in: El acceso a la versión del editor puede requerir la suscripción del recurso Access to the published version may require subscription Aripiprazole treatment produced a decrease of blood pressure (9.3 mmHg on systolic and 6.2 mmHg on diastolic pressure) and an increase in heart rate (12.1 bpm) and QTc interval (9.1 ms). There were sex differences in blood pressure, heart rate and QTc interval.Women and subjects with higher AUC and Cmax values were more prone to suffer adverse drug reactions (ADRs) and gastrointestinal adverse reactions. AUC was related with systolic blood pressure (SBP) and diastolic blood pressure (DBP) decrease and heart rate (HR) increase but there was no relationship between aripiprazole concentrations and QTc increase.Conclusions -Aripiprazole decreases blood pressure and increases heart rate and QTc interval. Pharmacokinetics, pharmacodynamics and safety of aripiprazole are affected by sex. There is a directly proportional relationship between pharmacokinetic parameters and ADRs and effect on BP and HR.

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Section: Pharmacodynamicssupporting

confidence: 82%

Evaluation of the Relationship Between Pharmacokinetics and the Safety of Aripiprazole and Its Cardiovascular Effects in Healthy Volunteers

Belmonte¹,

Ochoa²,

Román³

et al. 2016

J Clin Psychopharmacol

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“…From the heat maps in Fig 3, it is evident that compounds with half-lives greater than 1 hour (especially compounds with half-lives between 12 and 24 hours) are enriched in this KEGG pathway. The serotonergic synapse pathway ( hsa04726 ) is affected by trimipramine, an important antihistamine and sedative with an exact half-life of 23–24 hours [97, 98]. Fig 3 also shows that compounds with half-lives between 12 and 24 hours are enriched in this KEGG pathway, which supports the accuracy and efficacy of our prediction.…”

Section: Resultssupporting

confidence: 69%

The Use of Gene Ontology Term and KEGG Pathway Enrichment for Analysis of Drug Half-Life

et al. 2016

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A drug’s biological half-life is defined as the time required for the human body to metabolize or eliminate 50% of the initial drug dosage. Correctly measuring the half-life of a given drug is helpful for the safe and accurate usage of the drug. In this study, we investigated which gene ontology (GO) terms and biological pathways were highly related to the determination of drug half-life. The investigated drugs, with known half-lives, were analyzed based on their enrichment scores for associated GO terms and KEGG pathways. These scores indicate which GO terms or KEGG pathways the drug targets. The feature selection method, minimum redundancy maximum relevance, was used to analyze these GO terms and KEGG pathways and to identify important GO terms and pathways, such as sodium-independent organic anion transmembrane transporter activity (GO:0015347), monoamine transmembrane transporter activity (GO:0008504), negative regulation of synaptic transmission (GO:0050805), neuroactive ligand-receptor interaction (hsa04080), serotonergic synapse (hsa04726), and linoleic acid metabolism (hsa00591), among others. This analysis confirmed our results and may show evidence for a new method in studying drug half-lives and building effective computational methods for the prediction of drug half-lives.

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“…The data from a large number (n = 2005) of users in a clinic setting found that venlafaxine use was associated with a significantly increase in QTc. 31 The probability of a person having a dangerously prolonged QTc is greater in women and older person. The ability of venlafaxine to increase QTc is supported by cases of patients with markedly prolonged QT with venlafaxine treatment, 62 and with venlafaxine overdose.…”

Section: Venlafaxinementioning

confidence: 99%

“…30 In the Kaiser Permanente Medical Care Program of Northern California, there were significant increases in QTc for HPD, thioridazine, imipramine, citalopram, venlafaxine, clozapine, ziprasidone, sertraline quetiapine, nortriptyline, and risperidone. 31 In a meta-analysis, using a Bayesian-framework with both direct and indirect comparisons of randomized controlled trials comparing 15 antipsychotics and placebo in the acute treatment of schizophrenia, Leucht et al 32 found that most antipsychotics were associated with an increase in QTc. However, there are considerable differences in the magnitude of the increase in QTc between drugs.…”

Section: Psychotropics and Qtc Prolongationmentioning

confidence: 99%

Impact of Age and Sex on QT Prolongation in Patients Receiving Psychotropics

Rabkin

2015

Can J Psychiatry

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Objective: To assess older age and female sex, 2 of the major risk factors for potentially fatal cardiac arrhythmias or sudden cardiac death in patients prescribed psychotropics, within the context of electrocardiographic evidence of time between start of Q wave and end of T wave (QT) interval prolongation, which is an indicator of an increased risk for potentially fatal cardiac arrhythmias. Method:The literature on the relation between age, sex, and QT interval with respect to psychotropic drugs was reviewed. Results:The QT interval must be corrected (QTc) for heart rate. Because slower heart rates prolong and faster heart rates shorten the QT interval, people with faster heart rates may have a prolonged QT interval that is not apparent until the correction is performed. QTc values for apparently healthy post-pubertal people are less than 450 ms for males and less than 470 ms for females. The longer QT intervals in women may account for their increased risk of potentially fatal cardiac arrhythmias on psychotropics. QTc increases with increasing age. Assessment of QTc in older people is especially important to identify people with a longer QTc who are more likely to attain a serious QT level with drugs that prolong QTc. The age-related increase in QTc is more evident in men than women, suggesting that male sex does not afford protection against potentially fatal arrhythmias at older age. Conclusion:The association of increasing age and female sex with greater QT intervals indicates the need to have an increased awareness of the QTc prior to use of these psychotropics and to evaluate the QTc after initiation of therapy.W W W L'effet de l'âge et du sexe sur l'allongement de l'intervalle QT chez des patients recevant des psychotropes Objectif : Évaluer l'âge avancé et le sexe féminin, 2 des facteurs de risque majeurs pour des arythmies cardiaques potentiellement fatales ou une mort subite d'origine cardiaque chez des patients à qui l'on a prescrit des psychotropes, dans le contexte d'une preuve électrocardiographique du temps de l'allongement de l'intervalle (QT) entre le début de l'onde Q et la fin de l'onde T, ce qui est un indicateur du risque accru d'arythmies cardiaques potentiellement fatales.Méthode : La littérature sur la relation entre l'âge, le sexe, et l'intervalle QT en ce qui conerne les psychotropes a été recensée.Résultats : L'intervalle QT doit être corrigé (QTc) pour la fréquence cardiaque. Parce que des fréquences cardiaques plus lentes allongent l'intervalle QT et que des fréquences cardiaques plus rapides le racourcissent, les personnes dont la fréquence cardiaque est plus rapide peuvent avoir un intervalle QT allongé qui n'est pas apparent jusqu'à l'exécution de la correction. Les valeurs QTc pour des personnes postpubertaires apparemment en santé sont moins que 450 ms pour les hommes et moins que 470 ms pour les femmes. Les intervalles QT plus longs chez les femmes peuvent expliquer leur risque accru d'arythmies cardiaques potentiellement fatales avec les psychotropes. L'intervalle QTc s'accro...

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Validation of a population‐based method to assess drug‐induced alterations in the QT interval: a self‐controlled crossover study

Abstract: QT prolonging effects were common and varied in strength. Our results lend support to past Food and Drug Administration regulatory actions and support the role for ongoing surveillance of drug-induced QT prolongation.

Cited by 23 publications

References 72 publications

Evaluation of the Relationship Between Pharmacokinetics and the Safety of Aripiprazole and Its Cardiovascular Effects in Healthy Volunteers

Evaluation of the Relationship Between Pharmacokinetics and the Safety of Aripiprazole and Its Cardiovascular Effects in Healthy Volunteers

The Use of Gene Ontology Term and KEGG Pathway Enrichment for Analysis of Drug Half-Life

Impact of Age and Sex on QT Prolongation in Patients Receiving Psychotropics

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