Studies of the pharmacology of 17α-ethynyl-androst-5-ene-3β,7β,17β-triol, a synthetic anti-inflammatory androstene

Abstract

17α-Ethynyl-androst-5ene-3β, 7β, 17β-triol (HE3286) is an orally bioavailable analogue of androst-5-ene-3β,7β,17β-triol, a non-glucocorticoid anti-inflammatory metabolite of the adrenal steroid, dehydroepiandrosterone. The pharmacology of HE3286 was characterized in preparation for clinical trials in type 2 diabetes mellitus and other diseases of inflammation. Interactions with nuclear hormone receptors and P450 enzymes were measured in vitro. Drug metabolism was studied preclinically in mice, rats, dogs, and monkeys. Neurological and cardiopulmonary safety and dose-ranging and chronic toxicity studies were conducted in rats and dogs in accordance with FDA guidelines. Pharmacokinetics and metabolites were measured in Phase I clinical trials. HE3286 was differentially metabolized between species. HE3286 and metabolites did not bind or transactivate steroid binding nuclear hormone receptors or inhibit P450 enzymes. There were no adverse effects in safety pharmacology and canine toxicology studies. Although HE3286 did not elicit systemic toxicity in rats, mild estrogenic effects were observed, but without apparent association to hormonal changes. Safety margins were greater than 20-fold in rats and dogs with respect to the most commonly used clinical dose of 10 mg/day. The terminal half-life in humans was 8 hours in males and 5.5 hours in females. HE3286 is the first derivative of the DHEA metabolome to undergo a comprehensive pharmacological and safety evaluation. The results of these investigations have shown that HE3286 has a low potential for toxicity and possesses pharmacological properties generally suitable for use in human medicine. The favorable profile of HE3286 warrants further exploration of this new class of anti-inflammatory agents.

Keywords: HE3286; Toxicology; androstene; metabolism; pharmacokinetics; pharmacology.

Figure 1

HE3286 metabolites. HE3286 is extensively metabolized in all species (refer to Table 1). Neither HE3640 nor HE3633 are aromatized by CYP19.

Figure 2

HE3286 exposure and half-life in normal subjects. HE3286 is orally bioavailable. Mean drug exposure was dose proportional for QD and BID administration schedules in humans (left panel). In most instances HE3286 was found in plasma for the entire 24-hour period following a single dose of 10 to 100 mg. The terminal half-life of elimination was approximately 8 hours in males and 5.4 hours in females (right panel).

Figure 3

HE3286 mean plasma drug concentration profiles in pre-diabetic and diabetic subjects. HE3286 is detectable throughout the day with BID dose schedules for daily doses of 10 or 20 mg. Pre-diabetic subjects received 10 mg BID for 28 days (left panel). Diabetic subjects received 5 mg BID for 28 days (right panel).