Context: 11ß hydroxysteroid dehydrogenase type 1 (11ßHSD1) is a promising target for the treatment of type 2 diabetes mellitus. 11ßHSD1 catalyzes the intracrine conversion of inactive cortisone to the active glucocorticoid cortisol.

Objective: Demonstrating inhibition of 11ßHSD1 is challenging, as 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: Phase 1, double-blind, placebo-controlled, randomized, multiple dose study.

Setting: Clinical research unit

Participants: Sixty healthy adult volunteers.

Intervention: Oral doses of PF-00915275 (0.3 to 15 mg), prednisone 10mg.

Main Outcome Measures: Safety, tolerability, pharmacokinetics and pharmacodynamics of PF-00915275, a selective 11ßHSD1 inhibitor

Results: Overall, multiple oral doses of PF-00915275 were safe and well tolerated. Following 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 5THF + 5ßTHF: THE ratio with maximum inhibition of 26% after 14 days. The urinary free cortisol: urinary free cortisone (UFF:UFE) ratio, an indicator of 11ßHSD2 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 11ßHSD1 inhibitor.