Modulation of 11β-Hydroxysteroid Dehydrogenase (11βHSD) Activity Biomarkers and Pharmacokinetics of PF-00915275, a Selective 11βHSD1 Inhibitor

Context: 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) is a promising target for the treatment of type 2 diabetes mellitus. 11βHSD1 catalyzes the intracrine conversion of inactive cortisone to the active glucocorticoid cortisol. Objective: Demonstrating inhibition of 11βHSD1 is challenging because there is no accessible way to directly assess the enzyme activity in vivo. Thus, it was proposed to assess the enzyme activity, in an indirect fashion, using two biomarker methods: the prednisolone generation study (conversion of oral prednisone to prednisolone in plasma) and the ratio of cortisol and cortisone metabolites in urine. Design: This was a phase 1, double-blind, placebo-controlled, randomized, multiple-dose study. Setting: The study was conducted in a clinical research unit. Participants: Sixty healthy adult volunteers participated in the study. Intervention: Oral doses of PF-00915275 (0.3–15 mg) and prednisone (10 mg) were administered during the study. Main Outcome Measures: Safety, tolerabilit...