`and Tolerability with a Wide Therapeutic Window
`
`Poster No. 0586P
`
`ABSTRACT
`BI 1356 is a xanthine analogue, which exhibits a high potency for DPP-4 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 the safety, tolerability, pharmacokinetics, and
`pharmacodynamics. BI 1356 was well tolerated. There were no serious adverse events
`and no hypoglycaemic episodes were observed. The incidence of any adverse event (AE)
`(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 less than proportionally from 2.5 to 5 mg, while Cmax
`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-4 activity was reduced by 73% and 86% within 3 h, respectively.
`Twenty-four hrs after administration of 25-600 mg BI 1356, mean plasma DPP-4 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 hrs
`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.
`
`Silke Huettner, Ulrike Graefe-Mody, Arne Ring, Armin Ritzhaupt, Klaus A Dugi
`Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany
`
`ADA 22-26 June 2007, Chicago
`
`DEMOGRAPHIC AND BASELINE
`CHARACTERISTICS
`•64 Caucasian subjects were randomised to one of 8 treatment groups
`with a ratio of 3:1 active treatment to placebo
`•One subject was randomised but not treated as theQRS interval
`>110 ms at baseline which was a violation of an exclusion criterion
`
`Table 1: Subject characteristics at baseline
`Total subjects treated
`
`N
`
`Age (years±SD)
`
`Weight (kg ±SD)
`
`BMI (kg/m2 ±SD)
`
`63
`
`38.3 (9.4)
`
`80.4 (10.2)
`
`24.8 (2.3)
`
`RESULTS - PHARMACOKINETICS
`
`Figure 1: Arithmetic mean (SD) plasma concentration of BI 1356
`after single oral administration of 2.5 mg to 600 mg
`
`Table 2:
`
`Geometric mean (%gCV) of PK parameters after single oral administration of 2.5 to 600 mg BI 1356
`
`Parameter
`
`2.5 mg
`solution
`
`5 mg
`solution
`
`25 mg
`tablet
`
`50 mg
`tablet
`
`100 mg
`tablet
`
`200 mg
`tablet
`
`400 mg
`tablet
`
`600 mg
`tablet
`
`75.3 (19.1)
`
`100 (23.0)
`
`468 (33.6)
`
`1041 (39.8)
`
`3999 (21.8)
`
`7829 (25.5)
`
`22853 (36.3)
`
`33010 (21.2)
`
`290 (33.8)
`
`427 (33.0)
`
`1111 (15.8)
`
`1932 (25.7)
`
`5692 (21.0)
`
`10707 (16.8)
`
`27720 (35.7)
`
`39569 (19.6)
`
`4.40 (19.1)
`
`5.71 (19.4)
`
`72.4 (40.2)
`
`250 (47.0)
`
`758 (38.8)
`
`1443 (25.9)
`
`3280 (36.7)
`
`4338 (32.1)
`
`1.47
`(1.02 – 5.95)
`69.7 (17.2)
`
`2.97
`(0.70 – 4.02)
`79.9 (24.6)
`
`0.73
`(0.45 – 1.48)
`75.9 (5.60)
`
`1.73
`(0.52 – 3.03)
`143 (19.8)
`
`1.13
`(0.47 – 2.03)
`172 (43.2)
`
`3.00
`(0.68 – 4.00)
`184 (50.9)
`
`2.21
`(0.70 – 3.02)
`128 (41.3)
`
`
`
`120120
`
`
`
`100100
`
`
`
`8080
`
`
`
`6060
`
`
`
`4040
`
`
`
`2020
`
`4
`
`8
`
`16
`
`20
`
`24
`
`6000
`
`5000
`
`4000
`
`3000
`
`2000
`
`1000
`
`0
`
`BI 1356 plasma conc. [nmol/L]
`
`AUC0-24
`[nmol·h/L]
`AUC∞
`[nmol·h/L]
`Cmax
`[nmol/L]
`2.05
`tmax
`1
`(1.48 – 3.05)
`[h]
`79.9 (34.7)
`t½, [h]
`1median tmax and min-max range
`•Exposure of BI 1356 increased less than proportionally from 2.5 to 5 mg. Cmax and AUC increased more than
`proportionally from 25 to 100 mg and approximately proportionally for doses ranging from 100 to 600 mg.
`•The terminal half-life ranged from 70-80 hrs for samples collected up to 120 hrs post-dose, and to 184 hrs for samples
`collected up to 192 hrs. The long terminal half-life can be explained by tight binding of BI 1356 to plasma DPP-4 protein.
`The effective half-life is in the range of 10-30 hrs (see also Poster No. 0588P)
`•Renal excretion of BI 1356 was below 1% for doses up to 5 mg and increased dose-dependently
`RESULTS - PHARMACODYNAMICS
`RESULTS – SAFETY AND TOLERABILITY
`Adverse events
`Figure 2: Arithmetic mean DPP-4 activity measured in
`plasma after administration of 2.5 to 600 mg BI 1356
`• There were no serious adverse events (SAEs) and no hypoglycaemic
`
`Arithmetic mean DPP-IV activityArithmetic mean DPP-IV activity
`episodes
`• The incidence of AEs with BI 1356 (27.7%) was not higher compared with
`placebo (37.5%), and no dose dependency was discerned
`• Headache was reported most commonly with an incidence of 6 subjects
`(37.5%) treated with placebo and 9 subjects (19.1%) treated with BI 1356
`• The number of subjects with AEs considered possibly drug related were
`not higher with BI 1356 (19.1%) compared with placebo (31.3%)
`Clinical laboratory tests
`• No clinically relevant changes were observed in routine blood tests
`(haematology, coagulation parameters, clinical chemistry, and urinalysis)
`12-lead ECG and vital signs
`• No clinically relevant changes in blood pressure or heart rate
`• No evidence for clinically relevant effects of BI 1356 on any ECG parameter
`
`
`
`00
`
`DDP-IV activity in plasma [%]
`DDP-IV activity in plasma [%]
`
`0
`
`2.5 mg (N=5)
`50 mg (N=5)
`400 mg (N=5)
`
`12
`Time [hours]
`
`5 mg (N=6)
`100 mg (N=8)
`600 mg (N=6)
`
`25 mg (N=6)
`200 mg (N=6)
`
`
`
`00
`
`
`
`44
`
`
`
`88
`
`
`
`1212
`
`
`
`1616
`
`
`
`2020
`
`
`
`2424
`
`
`
`Time [hours]Time [hours]
`
`
`2.5 mg (N=5)2.5 mg (N=5)
`
`50 mg (N=5)50 mg (N=5)
`
`400 mg (N=5)400 mg (N=5)
`
`
`5 mg (N=6)5 mg (N=6)
`
`100 mg (N=8)100 mg (N=8)
`
`600 mg (N=6)600 mg (N=6)
`
`Arithmetic mean DPP IV activityArithmetic mean DPP IV activity
`
`
`25 mg (N=6)25 mg (N=6)
`
`200 mg (N=6)200 mg (N=6)
`
`Placebo (N=18)Placebo (N=18)
`
`CONCLUSIONS
`The administration of single rising oral doses of 2.5 mg to 600 mg
`BI 1356 was well tolerated and safe
`
`The overall incidence of adverse events was not different
`between BI 1356 and placebo
`
`The pharmacokinetic and pharmacodynamic profile is consistent
`with a once-daily dosing regimen
`
`DPP-4 activity was reduced by >40% and >60%, 24 hours after
`administration of 2.5 and 5 mg BI 1356, respectively
`
`BI 1356 is a potent DPP-4 inhibitor with a wide therapeutic win-
`dow of >100-fold based on an expected therapeutic dose of 5 mg
`
`ACKNOWLEDGEMENTS
`We would like to thank all those who participated in
`this study and were involved in the preparation,
`conduct, and analysis of the study.
`
`ABCD
`
`
`
`120120
`
`
`
`100100
`
`
`
`8080
`
`
`
`6060
`
`
`
`4040
`
`
`
`2020
`
`
`
`00
`
`DDP-IV activity in plasma [%]
`DDP-IV activity in plasma [%]
`
`Arithmetic mean plasma concentrations of BI 1356
`
`10000
`
`1000
`
`100
`
`10
`
`1
`
`0.1
`
`BI 1356 plasma conc. [nmol/L]
`
`0
`
`12
`
`24
`
`36
`
`2.5 mg (N=5)
`50 mg (N=5)
`400 mg (N=5)
`
`60
`
`48
`Time [hours]
`
`5 mg (N=6)
`100 mg (N=8)
`600 mg (N=6)
`
`72
`
`84
`
`96
`
`25 mg (N=6)
`200 mg (N=6)
`
`
`
`00
`
`
`
`2424
`
`
`
`4848
`
`
`
`7272
`
`
`
`9696
`
`
`
`Time [hours]Time [hours]
`
`
`2.5 mg (N=5)2.5 mg (N=5)
`
`25 mg (N=6)25 mg (N=6)
`
`5 mg (N=6)5 mg (N=6)
`
`50 mg (N=5)50 mg (N=5)
`
`100 mg (N=8)100 mg (N=8)
`
`200 mg (N=6)200 mg (N=6)
`
`400 mg (N=5)400 mg (N=5)
`
`Placebo (N=18)Placebo (N=18)
`
`600 mg (N=6)600 mg (N=6)
`• 2.5 mg and 5 mg BI 1356 reduced DPP-4 activity by 73% and 86%
`within 3 hrs, respectively.
`• Mean plasma DPP-4 activity was below 10% 24 hrs after
`administration of 25-600 mg BI 1356
`
`INTRODUCTION
`Type 2 diabetes is characterised by insulin resistance and progressive
`failure in insulin secretion. Current oral antidiabetic agents cannot prevent
`the progressive failure of pancreatic ß-cells, leading to secondary drug
`failure.
`A novel approach in the treatment of diabetes targets the incretins (e.g.
`GLP-1), hormones secreted in the intestine in response to food intake.
`GLP-1 regulates insulin and glucagon secretion. DPP-4 inhibitors increase
`plasma levels of intact GLP-1. BI 1356 is a potent, novel, orally available,
`selective inhibitor of DPP-4 (see also Poster Nos. 0588P and 0594P).
`The current study was designed to evaluate the safety, tolerability,
`pharmacokinetics (PK), and pharmacodynamics (PD) of single rising doses
`of BI 1356 in healthy men.
`
`OBJECTIVES
`•Safety and tolerability of BI 1356 following administration of single rising
`oral doses of 2.5, 5, 25, 50, 100, 200, 400, and 600 mg BI 1356 in healthy
`men
`•Exploration of the PK and PD parameters of BI 1356 after single doses
`
`METHODS
`
`Subjects
`• Healthy male volunteers from ≥21 to ≤65 years of age and with a BMI
`≥18.5 to ≤29.9 kg/m2
`• Written informed consent
`Study design
`• BI 1356 was administered as solution for doses 2.5 and 5 mg and as
`tablets for doses 25, 50, 100, 200, 400 and 600 mg
`• Study drug was administered in the morning after an overnight fast
`• Pharmacokinetic profiling was performed for up to 192 hours
`• DPP-4 activity was determined as a pharmacodynamic marker by
`incubating diluted EDTA plasma with Ala-Pro-AFC as substrate and
`measuring the increase in absorbance over time
`
`Mylan EX 1004, Page 1