BI 1356, a Novel and Selective Xanthine Based DPP-4 Inhibitor, Demonstrates Good Safety
`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 1019, Page 1
`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 1019, Page 1
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
