AI Article Synopsis
- Idasanutlin (RG7388) is a p53-MDM2 antagonist being studied for cancer treatment, but there was a notable decrease in its plasma levels after repeated doses in monkeys.
- Research indicated that this decrease was primarily due to increased metabolism of RG7388 in the gut of monkeys, linked to the induction of specific liver enzymes (CYP3A8).
- Further studies confirmed that this metabolic induction is specific to monkeys and does not occur in humans, aligning with human pharmacokinetic data that showed no significant changes in drug metabolism.
Article Abstract
1. Idasanutlin (RG7388) is a potent p53-MDM2 antagonist currently in clinical development for treatment of cancer. The purpose of the present studies was to investigate the cause of marked decrease in plasma exposure after repeated oral administration of RG7388 in monkeys and whether the autoinduction observed in monkeys is relevant to humans. 2. In monkey liver and intestinal microsomes collected after repeated oral administration of RG7388 to monkeys, significantly increased activities of homologue CYP3A8 were observed (ex vivo). Investigation using a physiologically based pharmacokinetic (PBPK) model suggested that the loss of exposure was primarily due to induction of metabolism in the gut of monkeys. 3. Studies in monkey and human primary hepatocytes showed that CYP3A induction by RG7388 only occurred in monkey hepatocytes but not in human hepatocytes, which suggests the observed CYP3A induction is monkey specific. 4. The human PK data obtained from the first cohorts confirmed the lack of relevant induction as predicted by the human hepatocytes and the PBPK modelling based on no induction in humans.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.3109/00498254.2015.1110761 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Effectiveness of an 8-week neck exercise training on pain, jaw function, and oral health-related quality of life in women with chronic temporomandibular disorders: a randomized controlled trial.
J Oral Facial Pain Headache
March 2024
Faculty of business and Social Sciences, University of Applied Sciences, 49076 Osnabrück, Germany.
To test the effectiveness of an 8-week exercise program targeted to the neck muscles compared to manual therapy, and placebo treatments on orofacial pain intensity, jaw function, oral health-related quality of life (OHRQoL), and jaw range of motion (ROM) in women with Temporomandibular Disorders (TMD). In this randomized controlled trial, fifty-four women (between 18-45 years old) with a diagnosis of myofascial or mixed TMD according to the Research Diagnostic Criteria for TMD (RDC/TMD) were randomized into three groups: Neck motor control training (NTG), Manual Therapy Group (MTG), and Placebo Group (PG). All patients were evaluated with the Visual Analog Scale, Mandibular Function Impairment Questionnaire, Oral Health Impact Profile-14, and jaw Range of Motion (ROM) at baseline, immediately after treatment (after 8 weeks of treatment), one month, and three-month follow-up.
View Article and Find Full Text PDFObservational Study of Best Supportive Care With or Without Oral Capecitabine in Patients With Metastatic Gallbladder Carcinoma at a Tertiary Center in India.
JCO Glob Oncol
January 2025
Department of Radiotherapy, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
Purpose: To compare overall survival (OS), toxicity, and quality of life (QOL) in patients with metastatic gallbladder cancer receiving oral capecitabine (X) with best supportive care (BSC) and BSC alone.
Materials And Methods: Patients with metastatic gallbladder cancer and Karnofsky Performance Status (KPS) ≥70 were accrued and assigned to either arm A or B. Assignment to these two arms was based on physician/patient discretion.
A weight of evidence review on the mode of action, adversity, and the human relevance of xylene's observed thyroid effects in rats.
Crit Rev Toxicol
January 2025
Product Stewardship, Science & Regulatory, Shell Global Solutions International B.V. The Hague, the Netherlands.
Xylene substances have wide industrial and consumer uses and are currently undergoing dossier and substance evaluation under Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) for further toxicological testing including consideration of an additional neurotoxicological testing cohort to an extended one-generation reproduction toxicity (EOGRT) study. New repeated dose study data on xylenes identify the thyroid as a potential target tissue, and therefore a weight of evidence review is provided to investigate whether or not xylene-mediated changes on the hypothalamus-pituitary-thyroid (HPT) axis are secondary to liver enzymatic induction and are of a magnitude that is relevant for neurological human health concerns. Multiple published studies confirm xylene-mediated increases in liver weight, hepatocellular hypertrophy, and liver enzymatic induction the oral or inhalation routes, including an increase in uridine 5'-diphospho-glucuronosyltransferase (UDP-GT) activity, the key step in thyroid hormone metabolism in rodents.
View Article and Find Full Text PDFImpact of multimodal intervention on cognitive function and nutritional status in older adults with oral frailty: Post‐hoc sub‐group analyses of the J‐MINT study.
Alzheimers Dement
December 2024
National Center for Geriatrics and Gerontology, Obu, Aichi, Japan
Background: In Japan, effective interventions to prevent low nutrition in older people with oral frailty have not been well established. This post‐hoc sub‐group analysis of the Japan‐multimodal intervention trial for the prevention of dementia (J‐MINT) aimed to examine the efficacy of the multidomain intervention in older adults with and without oral frailty.
Methods: J‐MINT was an 18‐month randomized controlled trial in which participants aged 65‐85 years with mild cognitive impairment were randomized to a multimodal intervention group (physical exercise, nutrition counseling, cognitive training, and vascular risk factor management) and a control group.
Blarcamesine in Early Alzheimer Disease Phase 2b/3 Randomized Clinical Trial.
Alzheimers Dement
December 2024
Anavex Life Sciences Corp., New York, NY, USA
Background: There are no approved oral disease‐modifying treatments for Alzheimer disease (AD). This study was intended to assess efficacy and safety of blarcamesine (ANAVEX2‐73), an orally available small‐molecule activator of the sigma‐1 receptor (SIGMAR1) designed to exert neuroprotection through restoration of cellular homeostasis including autophagy enhancement.
Method: ANAVEX2‐73‐AD‐004 is a multicenter (52 medical research centers/hospitals in 5 countries), randomized, double‐blind, placebo‐controlled, 48‐week phase 2b/3 trial that enrolled 508 participants with early AD (mild cognitive impairment/mild dementia) from July 2018 to June 2021 (last patient visit in June 2022).
Want 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!