Modulation of 11beta-hydroxysteroid dehydrogenase (11betaHSD) activity biomarkers and pharmacokinetics of PF-00915275, a selective 11betaHSD1 inhibitor.

Context: 11beta-Hydroxysteroid dehydrogenase type 1 (11betaHSD1) is a promising target for the treatment of type 2 diabetes mellitus. 11betaHSD1 catalyzes the intracrine conversion of inactive cortisone to the active glucocorticoid cortisol.

Objective: Demonstrating inhibition of 11betaHSD1 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, tolerability, pharmacokinetics, and pharmacodynamics of PF-00915275, a selective 11betaHSD1 inhibitor, were measured.

Results: Overall, multiple oral doses of PF-00915275 were safe and well tolerated. After oral administration, PF-00915275 was rapidly absorbed, slowly eliminated, and generally displayed dose-proportional increases in exposure. At the 15-mg dose, mean exposure to prednisolone was reduced by 37%, and there was a dose-dependent fall in the 5alpha-tetrahydrocortisol + 5beta-tetrahydrocortisol to tetrahydrocortisone ratio with maximum inhibition of 26% after 14 d. The urinary free cortisol to urinary free cortisone ratio, an indicator of 11betaHSD2 inhibition, did not change.

Conclusion: PF-00915275 was safe at all doses tested. The results of the prednisolone generation test and the urinary metabolite ratios confirm that PF-00915275 is a selective 11betaHSD1 inhibitor.