A randomized trial of safety and pharmacodynamic interactions between a selective glucocorticoid receptor antagonist, PT150, and ethanol in healthy volunteers

Abstract

PT150, a novel competitive glucocorticoid receptor (GR) antagonist, has proven safe in animal models, healthy volunteers, and people with depression. Our study is the first to investigate PT150’s safety with alcohol use. The primary objective of this study was to evaluate pharmacodynamic interactions between ethanol and PT150 in healthy subjects. This single-site, Phase I pilot trial consisted of community-recruited, healthy, alcohol-experienced participants aged 21–64 years. Of 32 participants screened, 11 were enrolled and randomized, one of which withdrew before intervention. PT150 (900 mg/day) was administered orally to all participants for five days. All participants received two beverage challenges on Day 1 (before PT150 administration) and Day 5 (after PT150 administration). On challenge days, they received both alcohol (16% ethanol) and placebo (1% ethanol) beverages in random order. Primary outcomes included breath alcohol level, blood pressure, heart rate, adverse events, and electrocardiogram changes. There were no statistically significant differences in vital signs or estimated blood alcohol concentrations between PT150 non-exposed and exposed groups during the ethanol challenge. There were no clinically significant abnormal electrocardiograms or serious adverse events. These data show that administration of PT150 with concurrent alcohol use is safe and well-tolerated. This study supports a future pharmacokinetic interaction study between PT150 and alcohol.Trial Registration ClinicalTrials.gov Identifier: NCT03548714.

Neuroprotective Efficacy of the Glucocorticoid Receptor Modulator PT150 in the Rotenone Mouse Model of Parkinson’s Disease

“…Treatment dosage of the experimental drug, PT150 (supplied by Palisadse Therapeutics/Pop Test Oncology, LLC), was calculated using dosing schemes and toxicity data from human clinical trials, which treated with 500 mg of PT150, or approximately 7 mg/kg. Calculations normalizing to body surface area determined that a dose of approximately 86 mg/kg in mice equates to a Human Equivalent Dose (HED) of 7 mg/kg [24, 33]. Thus, two doses of PT150 were evaluated for the duration of the study, a low dose of 30 mg/kg and high dose of 100 mg/kg.…”

“…In this study, we examined the therapeutic efficacy of the GR modulator, (11b,17b)-11-(1,3-benzodioxol-5-yl)-17-hydroxy-17-(1-propynyl)-estra-4,9-dien-3-one (PT150), in preventing the neuropathology associated with rotenone neurotoxicity [24]. We previously reported on the anti-inflammatory effects of PT150 during viral infection, as well as its capacity to modulate GR-dependent gene expression [25].…”

The Genetic Basis of Future Pharmacological Strategies for the Management of Comorbid Obesity and Depression: A Scoping Review

“…Therefore, direct pharmacological manipulation of this receptor carries definite risks [89]. Nevertheless, a competitive NR3C1 antagonist, named PT150, has been developed for use in humans and appears to be well tolerated in phase I trials [90]. In a mouse model of obesity, another novel NR3C1 antagonist, CORT125281, was associated with weight reduction and an improved lipid profile [91].…”

Effect of the glucocorticoid receptor antagonist PT150 on acquisition and escalation of fentanyl self-administration following early-life stress.

“…PT150 is a selective and competitive GR antagonist, preventing translocation of the GR to the cell nucleus (Peeters et al, 2008). PT150 reduces stress-induced increases in fentanyl seeking in male rats (Hammerslag et al, 2021) and is known to be safe and well-tolerated in humans (Morice et al, 2021).…”