Purpose: Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic oral p53 activator. The aim of this analysis is to examine the potential of idasanutlin to prolong the corrected QT (QTc) interval by evaluating the relationship between plasma idasanutlin concentration and QTc interval.
Method: Intensive plasma concentration QTc interval data were collected at the same timepoints, from three idasanutlin (RO5503781) phase 1 studies in patients with solid tumors and AML. QTc data in absolute values and changes from baseline (Δ) were analyzed for a potential association with plasma idasanutlin concentrations with a linear mixed effect model. Categorical analysis was also performed.
Results: A total of 282 patients were exposed to idasanutlin and had at least one observation of QTc and idasanutlin plasma concentration. There was no apparent increase of QTcF or ΔQTcF in a wide idasanutlin plasma concentration range, even at concentrations exceeding the exposure matching the dose adopted in the ongoing phase 3 study (300-mg BID). Categorical analysis did not detect a potential signal of QT prolongation.
Conclusion: The concentration-QTc analysis indicates that idasanutlin does not prolong the QT interval within the targeted concentration range currently in consideration for clinical development.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1007/s00280-018-3534-7 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
From spermatogenesis to fertilisation: the role of melatonin on ram spermatozoa.
Domest Anim Endocrinol
January 2025
BIOFITER-IUCA, Universidad de Zaragoza, Facultad de Veterinaria, Miguel Servet 177, 50013 Zaragoza, Spain. Electronic address:
This review presents recent findings on the effect of melatonin on ram spermatozoa. This hormone regulates seasonal reproduction in the ovine species through the hypothalamic-pituitary-gonadal axis, but it also exerts direct effects on spermatogenesis, seminal quality and fertility. In the testis, melatonin stimulates blood flow to this organ, but it also appears to be involved in the differentiation of spermatogonial stem cells and the secretion of testosterone through the MT1 and MT2 receptors.
View Article and Find Full Text PDFQuantitative Assessment of the Effect of Chronic Kidney Disease on Plasma P-Tau217 Concentrations.
Neurology
February 2025
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
Background And Objectives: Chronic kidney disease (CKD) is known to be associated with increased plasma phosphorylated tau217 (p-tau217) concentrations, potentially confounding the utility of plasma p-tau217 measurements as a marker of amyloid pathology in individuals with suspected Alzheimer disease (AD). In this study, we quantitatively investigate the relationship of plasma p-tau217 concentrations vs estimated glomerular filtration rate (eGFR) in individuals with CKD with and without amyloid pathology.
Methods: This was a retrospective examination of data from 2 observational cohorts from either the Mayo Clinic Study of Aging or the Alzheimer's Disease Research Center cohorts.
Critical Insights into LEAP2 Biology and Physiological Functions: Potential Roles Beyond Ghrelin Antagonism.
Endocrinology
January 2025
Grupo de Neurofisiología- Instituto Multidisciplinario de Biología Celular (IMBICE) (Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de La Plata, Comisión de Investigaciones Científicas de la Provincia de Buenos Aires), La Plata, Argentina.
Liver-expressed antimicrobial peptide 2 (LEAP2) has recently emerged as a novel hormone that reduces food intake and glycemia by acting through the growth hormone secretagogue receptor (GHSR), also known as the ghrelin receptor. This discovery has led to a fundamental reconceptualization of GHSR's functional dynamics, now understood to be under a dual and opposing regulation. LEAP2 exhibits several distinctive features.
View Article and Find Full Text PDFBiomarkers of RV Dysfunction in HFrEF Identified by Direct Tissue Proteomics: Extracellular Proteins Fibromodulin and Fibulin-5.
Circ Heart Fail
January 2025
First Faculty of Medicine, Biotechnology and Biomedicine Center of the Academy of Sciences and Charles University (BIOCEV), Charles University, Prague, Czech Republic. (M.B., D.L., O.V., J.P.).
Background: Right ventricular dysfunction (RVD) is common in patients with heart failure with reduced ejection fraction, and it is associated with poor prognosis. However, no biomarker reflecting RVD is available for routine clinical use.
Methods: Proteomic analysis of myocardium from the left ventricle and right ventricle (RV) of patients with heart failure with reduced ejection fraction with (n=10) and without RVD (n=10) who underwent heart transplantation was performed.
Evaluating platelet concentrates by platelet indices, thromboelastography, and flow cytometry.
Asian J Transfus Sci
May 2023
Department of Hematology, All India Institute of Medical Sciences, New Delhi, India.
Introduction: Platelet transfusion has been therapeutically used in patients with thrombocytopenia and platelet function defects over the years. The use of advanced techniques may add value in assessing the quality of platelet products. The aim of the study was to assess stored platelet concentrates (PCs) prepared in blood banks for platelet indices, clot strength, and platelet function.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!