Safety, Pharmacokinetics, and Pharmacodynamics of ASP3662, a Novel 11β‐Hydroxysteroid Dehydrogenase Type 1 Inhibitor, in Healthy Young and Elderly Subjects

Abstract

Inhibition of the enzyme 11 β ‐hydroxysteroid dehydrogenase type 1 (11β‐ HSD 1) represents a potential mechanism for improving pain conditions. ASP 3662 is a potent and selective inhibitor of 11β‐ HSD 1. Two phase I clinical studies were conducted to assess the safety, tolerability, pharmacokinetics ( PK s), and pharmacodynamics (PDs) of single and multiple ascending doses of ASP 3662 in healthy young and elderly non‐Japanese and young Japanese subjects. Nonlinear, more than dose‐proportional PK s were observed for ASP 3662 after single‐dose administration, particularly at lower doses (≤ 6 mg); the PK s at steady state were dose proportional, although the time to ASP 3662 steady state was dose dependent at lower doses (≤ 2 mg). Similar PK s were observed among young Japanese, young non‐Japanese, and elderly non‐Japanese subjects. Specific inhibition of 11β‐ HSD 1 occurred after both single and multiple doses of ASP 3662. A marked dissociation between PKs and PDs was observed after single but not multiple doses of ASP 3662. ASP 3662 was generally safe and well tolerated.

Target‐Mediated Drug Disposition—A Class Effect of Soluble Epoxide Hydrolase Inhibitors

“…ASP3662 exhibited substantial nonlinear PK at low doses and demonstrated essentially linear PK at doses >6 mg. Persistent and almost complete inhibition of hepatic 11β‐HSD1 activity was observed even at a daily dose of 0.7 mg of ASP3662 5 . This result confirms that substantial nonlinear PK occurring at low doses reflects the extent of target occupancy, which means that we can get a good sense of what would be the potential efficacious dose based on the doses at which the nonlinearity occurs and the “turning point” dose at which the nonlinearity tends to disappear.…”

“…A good example is ASP3662, a potent 11β‐HSD1 inhibitor. The PK and pharmacodynamics of ASP3662 were evaluated in the first‐in‐human study in which both single ascending doses (1‐60 mg) and multiple ascending doses (0.2–50 mg) were investigated 5 . ASP3662 exhibited substantial nonlinear PK at low doses and demonstrated essentially linear PK at doses >6 mg.…”

“…Moreover, TMDD in small‐molecule compounds appears to be a class effect. For example, ABT‐384 and ASP3662, 2 11β‐HSD1 inhibitors developed independently by Abbott and Astellas, respectively, demonstrated essentially same nonlinear PK behavior imparted by TMDD 5,6 . Similarly, a series of small‐molecule endothelin receptor antagonists, including bosentan, clazosentan, and tezosentan, have also been reported to have TMDD 7 .…”

A Novel Selective 11β-HSD1 Inhibitor, (E)-4-(2-(6-(2,6-Dichloro-4-(Trifluoromethyl)Phenyl)-4-Methyl-1,1-Dioxido-1,2,6-Thiadiazinan-2-yl)Acetamido)Adamantan-1-Carboxamide (KR-67607), Prevents BAC-Induced Dry Eye Syndrome

“…Glucocorticoids are steroid hormones that mediate immunological and inflammatory responses, energy metabolism, cardiovascular homeostasis, and general responses to stress [4][5][6]. Their intracellular levels are mainly regulated by 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes [7,8]. 11β-HSD1 is an enzyme that converts inactive cortisone into active cortisol [8].…”

“…Their intracellular levels are mainly regulated by 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes [7,8]. 11β-HSD1 is an enzyme that converts inactive cortisone into active cortisol [8]. Overexpression of the glucocorticoid enzyme cortisol has been associated with type 2 diabetes, obesity, osteoporosis, arthritis, myopathy, and inflammatory diseases [9][10][11].…”