Search

GLPG1205 is a modulator of GPR84, a G‐protein–coupled receptor reported to be associated with several diseases. Safety, tolerability, pharmacokinetics, and pharmacodynamics of GLPG1205 in healthy subjects were evaluated in 2 randomized, double‐blind, placebo‐controlled, single‐site, phase 1 studies. In study 1, 16 (aged 21‐48 years) and 24 (24‐50 years) healthy men received single doses of GLPG1205 10 to 800 mg, and GLPG1205 50, 100, or 200 mg once daily for 14 days, respectively, or placebo. Study 2 evaluated the effect of aging on GLPG1205 pharmacokinetics: 24 healthy men (aged 37–83 years), weight‐matched into 3 age cohorts (65‐74, ≥75, and 18‐50 years), received GLPG1205 50 mg or placebo once daily for 14 days; an open‐label part of this study evaluated a GLPG1205 250‐mg loading dose followed by 50 mg once daily for 13 days in 8 healthy men (aged 68‐74 years). Single (up to 800 mg) and multiple (maximum tolerated dose 100 mg once daily) GLPG1205 doses had favorable safety and tolerability profiles. After single administration of GLPG1205, median time to occurrence of maximum observed plasma concentration and arithmetic mean apparent terminal half‐life ranged from 2.0 to 4.0 and from 30.1 to 140 hours, respectively. Age did not affect GLPG1205 exposure. GPR84 receptor occupancy with GLPG1205 vs placebo confirmed target engagement. These results support further clinical development of GLPG1205. [ABSTRACT FROM AUTHOR]

BI 1356 is a xanthine analogue which exhibits a high potency for DPP-IV inhibition, increases the half-life of circulating incretin hormones, and improves glucose homeostasis in preclinical studies. In a randomised, double-blind, placebo controlled single rising dose study in healthy male volunteers aged 21-65 years, BI 1356 was administered at doses ranging from 2.5 to 600 mg once daily to investigate safety, tolerability, pharmacokinetics, and pharmacodynamics. BI 1356 was well tolerated. There were no serious adverse events and no hypoglycaemic episodes. The Incidence of any adverse event (ALE) (28% for BI 1356, 38% for placebo) or of drug related AEs (19% vs. 31%) was not higher for BI 1356 compared to placebo. The most common AEs reported were headache, influenza-like illness and nausea with an incidence comparable between BI 1356 and placebo. No clinically relevant deviations in laboratory parameters (haematology, coagulation, clinical chemistry, and urinalysis) were reported. ECGs were centrally evaluated by a specialised provider and did not show any clinically relevant deviations or any indication of a QT prolonging effect up to and including the 600 mg dose. The exposure of BI 1356 increased Jess than proportionally from 2.5 to 5 mg, while C[sub max] and AUC increased more than proportionally from 25 to 100 mg and approximately proportionally for doses ranging from 100 to 600 mg. Renal excretion was low and does not constitute the main pathway for elimination of BI 1356. After single doses of 2.5 mg and 5 mg BI 1356, DPP-IV activity was reduced by 73% and 86% within 3 h, respectively. Twenty-four h after administration of 25-600 mg BI 1356, mean plasma DPP-IV inhibition was greater than 90%. In summary, BI 1356 was well tolerated and safe. The results of the pharmacokinetic and pharmacodynamic profile after single doses demonstrate the potency and full 24 h duration of action of BI 1356. Based on an estimated therapeutic dose of 5 mg, the therapeutic window of BI 1356 is expected to be >100 fold. [ABSTRACT FROM AUTHOR]

BI 1356 is a novel, potent, and selective DPP-IV inhibitor currently in development for type 2 diabetes. The safety, pharmacokinetics, and pharmacodynamic properties of BI 1356 were investigated in a randomised, double-blind, placebo-controlled study in patients with type 2 diabetes. Forty-seven male type 2 diabetic patients, aged 21-65 and with a BMI of 18-35 kg/m², were treated once daily with 1, 2.5, 5, or 10 mg BI 1356, or placebo for 12 days. Treatment with BI 1356 was well tolerated. The incidence of adverse events in patients treated with BI 1356 (54%) was not higher when compared to placebo (75%). There were no serious adverse events and no episodes of hypoglycaemia. BI 1356 plasma concentrations and exposure increased less than proportionally with dose. The maximum plasma concentrations of BI 1356 at steady-state ranged from 4.5 nmol/L (1 mg dose group) to 13.6 nmol/L (10 mg), with a median t[sub max] of 1.5 h. Reductions in plasma DPP-IV activity were well correlated with plasma concentrations of BI 1356. Two hours after administration of 2.5 mg BI 1356, DPP-IV activity was reduced by >80% and remained at that level at steady-state. Levels of GLP-1 were increased by more than 2-fold. Following an oGTT on day 13, 24 h after the last dose of BI 1356, area under the plasma glucose excursions were reduced by 53 (1 mg BI 1356), 106 (2.5 mg), 82 (5 mg), 111 (10 mg), and 25 (placebo) mg.h/dL, respectively. Despite the small group sizes, these reductions reached statistical significance for 2.5, 5, and 10 mg BI 1356 compared to baseline and compared to placebo (p<0.05 for both). In summary, 24 h after the last dose, DPP-IV inhibition was >70% after administration of BI 1356 doses of > 1 mg, and significant improvements in glucose parameters were observed in patients with type 2 diabetes. Given this potency and duration of action, BI 1356 has the potential to be a best in class DPP-IV inhibitor. [ABSTRACT FROM AUTHOR]