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

Clinical Pharmacology (R.C., M.T.), Pfizer Inc., La Jolla, California 92121; Queen Elizabeth Hospital (P.M.S.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Clinical Research (M.-N.N.), Pfizer Inc., B-1050 Brussels, Belgium; and Cardiovascular and Metabolic Diseases (R.A.C., B.H.), Pfizer Inc., Groton, Connecticut 06340

Address all correspondence and requests for reprints to: Boaz Hirshberg, M.D., AstraZeneca, Room C4C-717 A, 1800 Concord Pike, P.O. Box 15437, Wilmington, Delaware 19850–5437. E-mail: Boaz.Hirshberg{at}AstraZeneca.com; or Rachel Courtney, Ph.D., Pfizer Global Research & Development, 10555 Science Center Drive (CB10; Room 2446), San Diego, California 92121. E-mail: Rachel.Courtney{at}pfizer.com.

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, tolerability, pharmacokinetics, and pharmacodynamics of PF-00915275, a selective 11βHSD1 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 5-tetrahydrocortisol + 5β-tetrahydrocortisol to tetrahydrocortisone ratio with maximum inhibition of 26% after 14 d. The urinary free cortisol to urinary free cortisone ratio, an indicator of 11βHSD2 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 11βHSD1 inhibitor.