Safety, tolerability, pharmacokinetics and pharmacodynamics of single oral doses of BI 187004, an inhibitor of 11beta-hydroxysteroid dehydrogenase-1, in healthy male volunteers with overweight or obesity

Background The study characterizes safety, tolerability, pharmacokinetic and pharmacodynamic profiles of single rising doses of the 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD1) inhibitor BI 187004 in healthy men with overweight or obesity. Methods This was a randomized, double-blind, parallel group, placebo-controlled study with administration of 2.5–360 mg BI 187004 or placebo once daily as single dose in 72 healthy male volunteers with overweight or obesity. Assessments included 11beta-HSD1 inhibition in the liver (assessed indirectly by urinary tetrahydrocortisol/tetrahydrocortisone ratio) and in subcutaneous adipose tissue ex vivo and determination of hypothalamus–pituitary–adrenal axis hormones. Results BI 187004 was well tolerated and safe in all tested dose groups. The incidence of drug-related adverse events was 16.7% (n = 9) for all 9 BI 187004 dose groups and 5.9% (n = 1) for placebo. All treatment groups were similar concerning kind and intensity of adverse events. No clinically relevant deviations in clinical laboratory or ECG parameters were reported. Exposure of BI 187004 increased non-proportionally over the entire dose range tested. The geometric mean apparent terminal half-life decreased from 33.5 h (5 mg) to 14.5 h (160 mg) remaining stable up to 360 mg. Renal excretion of BI 187004 was low (3–5%). Urinary tetrahydrocortisol/tetrahydrocortisone ratio decreased, indicating liver 11beta-HSD1 inhibition. Median inhibition of 11beta-HSD1 in subcutaneous adipose tissue biopsies following single dosing ranged from 86.8% (10 mg) to 99.5% (360 mg) after 10 h and from 59.4% (10 mg) to 98.6% (360 mg) after 24 h. Conclusions BI 187004 as single dose was safe and well tolerated and is suitable for once daily dosing. There was significant, sustained 11beta-HSD1 inhibition in liver and adipose tissue. Trial registration ClinicalTrials.gov, NCT01587417, registered on 26-Apr-2012.

The Metabolism and Excretion of the Dipeptidyl Peptidase 4 Inhibitor [14C] Cetagliptin in Healthy Volunteers

Aims: The metabolism and excretion of teneligliptin were investigated in healthy male volunteers after a single oral dose of 100mg/50μCi [14C] cetagliptin. Methods: Plasma, Urine, and feces were collected at regular intervals from six healthy male volunteers, and were analysed for total radioactivity, unchanged cetagliptin and metabolites profile. Results: The highest concentrations in plasma (Cmax) were achieved at 0.75 h postdose. Approximately 53.13% of plasma AUC of total radioactivity was accounted for by parent drug. By 336 h after administration, 91.68% of the administered radioactivity was excreted, and the cumulative excretion in the urine and faeces was 72.88% and 18.81%, respectively. Each metabolite plasma AUC was not higher than 2.93% of plasma AUC of total radioactivity. Four metabolites were detected at trace levels, and it involved hydroxylation (M436-1 and M436-3), N-sulfation (M500), and N-carbamoyl glucuronidation (M640B). These metabolites were detected also in plasma, urine, and feces at low levels, except that metabolite M640B was not detected in feces. No metabolite was observed with >10% of parent compound systemic exposure after oral administration. There were no apparent treatment-related clinically relevant changes in vital signs and clinical laboratory tests. Conclusion: Unchanged cetagliptin was the most abundant radioactive component in all matrices investigated. The primary route of excretion of radioactivity was via the kidneys. There were no major metabolites in plasma. Cetagliptin is a promising DPP-4 inhibitor for the treatment of patients with type 2 diabetes.