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

Abstract

BackgroundThe 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.MethodsThis 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 volunteers with overweight or obesity.Assessments included 11beta-HSD1 inhibition in the liver (assessed indirectly by urinary tetrahydrocortisol/tetrahydrocotisone ratio) and in subcutaneous adipose tissue ex vivo and determination of hypothalamus-pituitary-adrenal axis hormones.ResultsBI 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 33.5h (5 mg) to 14.5h (160 mg) remaining stable up to 360 mg. Renal excretion of BI 187004 was low (3-5%). Urinary tetrahydrocortisol/tetrahydrocotisone 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 10h and from 59.4% (10 mg) to 98.6% (360 mg) after 24h. ConclusionsBI 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 registry number: ClinicalTrials.gov, NCT01587417, registered on 26-Apr-2012, https://clinicaltrials.gov/ct2/show/study/NCT01587417

Selective Inhibition of 11beta-Hydroxysteroiddehydrogenase-1 with BI 187004 in Patients with Type 2 Diabetes and Overweight or Obesity: Safety, Pharmacokinetics, and Pharmacodynamics After Multiple Dosing Over 14 Days

“…In the investigated dose range of 10-360 mg, there were no hypoglycemic events, and the blood pressure, heart rate, or QTc time in the ECG were not affected. Compared to the SRD study in healthy volunteers [12], where 16.7 % in the BI 187004 group and 5.9 % in the placebo group had a drug-related AEs, the study described here showed 51.8 % drug-related (BI 187004) AEs and 35.7 % in the placebo had AEs. The earlier study treated the healthy subjects with a single dose of BI 187004, while the currently described study treated the healthy subjects over 14 days; therefore, the absolute number of AEs is substantially higher in the current study.…”

“…It has to be taken into account that on day 15, trough tissue concentrations were measured, whereas, on day 2, non-trough tissue concentrations were measured as the AT biopsies were taken 10-45 min after the second dose for logistical reasons (▶ Table 3). In healthy male volunteers, the AT/plasma ratio of BI 187004 was in the range of 8.58-11.4 % 24 h after a single dose BI 187004 [12]. As described previously [15], in response to 11beta-HSD1 inhibition in peripheral tissues, mainly liver and AT, serum cortisol levels tend to decrease, and due to negative feedback of the HPA axis, a compensatory increase of ACTH and adrenal cortisol secretion is seen.…”

“…Hormones of the hypothalamus-pituitary-adrenal (HPA) axis were measured. As previously published [12,14], 11beta-HSD1 inhibition leads to decreased serum cortisol levels leading to increased activity of the HPA axis with the increase in adrenocorticotropic hormone (ACTH) followed by an increased adrenal activity. In all BI 187004 dose groups, the mean ACTH levels increased but within the normal range during treatment and returned to baseline after discontinuation of BI 187004 (▶Fig.…”

“…Furthermore, sufficient (>90%) 11beta-HSD1 enzyme inhibition is expected to enhance the cortisol clearance from the body. In a single rising dose trial 12 with ascending doses of 2.5–360 mg BI 187004, all HPA axis hormones were stable and within the normal range. However, total urinary corticosteroid excretion increased by up to 2-fold.…”

“…It has to be taken into account that on day 15, trough tissue concentrations were measured, whereas, on day 2, non-trough tissue concentrations were measured as the AT biopsies were taken 10–45 min after the second dose for logistical reasons ( Table 3 ). In healthy male volunteers, the AT/plasma ratio of BI 187004 was in the range of 8.58–11.4% 24 h after a single dose of BI 187004 12 .…”